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Medicine › Hematology

Multiple Myeloma Research and Treatments

Works Count: 77596

Description

This cluster of papers focuses on the diagnosis, staging, treatment, and molecular classification of multiple myeloma. It covers topics such as the International Myeloma Working Group criteria, novel therapies including proteasome inhibitors and immunomodulatory drugs, autologous transplantation, genomic abnormalities, and the role of the bone marrow microenvironment in disease progression.

Keywords

International Myeloma Working Group; Diagnosis Criteria; Staging System; Novel Therapies; Autologous Transplantation; Genomic Abnormalities; Proteasome Inhibitors; Immunomodulatory Drugs; Minimal Residual Disease; Bone Marrow Microenvironment

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

2015-08-26
Henk M. Lokhorst , Torben Plesner , Jacob P. Laubach +7 more
Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was … Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy.In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics.No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥ 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months.Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.).
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CRITERIA FOR EVALUATING DISEASE RESPONSE AND PROGRESSION IN PATIENTS WITH MULTIPLE MYELOMA TREATED BY HIGH‐DOSE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION

1998-09-01
Joan Bladé , Diana Samson , Donna Reece +7 more
Multiple myeloma (MM) is a malignant plasma cell disorder accounting for about 10% of haematological malignancies. The disease is characterized by the clonal proliferation of plasma cells which produce a … Multiple myeloma (MM) is a malignant plasma cell disorder accounting for about 10% of haematological malignancies. The disease is characterized by the clonal proliferation of plasma cells which produce a monoclonal immunoglobulin heavy and/or light chain (paraprotein, M-protein or M-component). This patient-specific paraprotein is present in the serum and/or urine of all patients except in the 1–2% of patients with non-secretory myeloma. Typical clinical and laboratory features in patients with MM include bone pain (due to lytic lesions or osteoporosis), anaemia, renal insufficiency, hypercalcaemia, increased susceptibility to infection and constitutional symptoms resulting in poor performance status. Less common complications include cord compression due to extramedullary plasmacytomas or vertebral collapse, peripheral neuropathy, amyloidosis and hyperviscosity syndrome ( Malpas, 1998). Prior to the introduction of alkylating agents, the median survival of patients with MM was less than a year ( Korst et al, 1964 ; Holland et al, 1966 ). Approximately 60% of patients respond to initial treatment with conventional chemotherapy, but although survival is prolonged by treatment the median survival remains approximately 3 years ( Bergsagel, 1998). Complete remissions are rare and all patients ultimately relapse, resulting in c 25% survival at 5 years and <10% survival at 10 years. Criteria by which different treatment regimens can be evaluated include the proportion of patients achieving an objective response, the duration of response, and survival. Over the past 10–15 years high-dose therapy followed by haemopoietic stem-cell rescue, either allogeneic or autologous, has been increasingly employed in the treatment of multiple myeloma. For a number of reasons the existing criteria for the assessment of disease response have not proved entirely satisfactory for the analysis of disease outcome after high-dose therapy. In particular, there has been no generally agreed definition of complete response. Agreed definitions of response and progression are essential to ensure consistency of reporting within the transplant registries and to enable comparison of results from different studies and/or different treatment centres. New criteria for response and progression have therefore been developed as a result of discussions between representatives of the Myeloma Subcommittee of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) and representatives of the Myeloma Working Committee of the Autologous Blood and Marrow Transplant Registry (ABMTR) and the International Bone Marrow Transplant Registry (IBMTR). These criteria will now form the working definitions of response and progression for the purposes of data collection and registry-based studies. Currently none of the registries include specific diagnostic criteria, although all record the relevant investigations performed at diagnosis. However, we wish to emphasize that all patients undergoing high-dose therapy should have proven myeloma which requires treatment. At present high-dose therapy is not recommended for patients with equivocal myeloma or those with stage I disease. We have not at this stage reviewed the criteria for the diagnosis of myeloma, but there may be a requirement for this in the future. For example, because of the increasing use of high-dose therapy for the treatment of primary amyloidosis, it will be important to establish clear guidelines for the differential diagnosis between this condition and multiple myeloma with amyloid. Changes in the level of the serum paraprotein and/or urinary light chain excretion form the basis of assessing the response to therapy and monitoring the progress of the disease. In a minority of patients disease progression will be manifested by increasing marrow or skeletal involvement, or development of other complications, without a rise in paraprotein. In non-secretory myeloma it is difficult to monitor disease accurately. Serial bone marrow examinations are helpful, although the patchy nature of marrow involvement in myeloma makes it difficult to accurately interpret small changes in the percentage of plasma cells present. The currently used response criteria are shown in Tables I. Response criteria were first developed by the Committee of the Chronic Leukemia and Myeloma Task Force (CLMTF) of the U.S. National Cancer Institute in 1968 and were reviewed by the same group in 1973 ( Chronic Leukemia and Myeloma Task Force, 1968, 1973). The main response parameter is a reduction in the paraprotein of at least 50% ( Table I). In 1972 the Southwest Cancer Chemotherapy Study Group, now the Southwest Oncology Group (SWOG), defined ‘objective response’ as a reduction of at least 75% in the calculated serum paraprotein synthetic rate (rather than paraprotein concentration) and/or a decrease of at least 90% in urinary light-chain excretion, sustained for at least 2 months ( Alexanian et al, 1972 ). Patients with a reduction in serum paraprotein synthetic rate of between 50% and 74% were considered to have improved ( Table II). A review of the literature indicates that the CLMTF or SWOG criteria have been used in most subsequent clinical trials, albeit frequently with some modifications of the original proposals. The relative merits of these two sets of criteria in defining outcomes has never been formally assessed, i.e. there is no evidence to indicate whether a 75% reduction in paraprotein synthetic rate has a better prognostic significance than a 50% reduction in serum paraprotein level. Most groups have used paraprotein concentration to define response because of simplicity. The terms partial response or partial remission are also frequently used. Some groups have added additional response categories, such as good or very good partial response and minimal response, again based on the degree of paraprotein reduction. An exception is the United Kingdom Medical Research Council (MRC) Myelomatosis trials, which have evaluated the efficacy of treatment not by the degree of paraprotein reduction but by the proportion of patients achieving plateau ( Table III) ( MacLennan et al, 1992 ). Plateau phase consists of a period of stability after chemotherapy in which tumour progression does not occur despite the persistence of measurable disease. The definition of plateau does not require any specific degree of paraprotein reduction. The minimum period of stable observation required to define plateau was 6 months in the early MRC trials but more recently has been reduced to 3 months ( MacLennan et al, 1992 ). Although the concept of plateau phase was introduced almost 20 years ago ( Durie et al, 1980 ), it has not been extensively used for the evaluation of response in multiple myeloma. Neither the CLMTF nor the SWOG response criteria include a definition of complete response/complete remission (CR), since CR was rarely observed with existing treatments. With the introduction of new regimens such as VAD (vincristine, adriamycin and dexamethasone) and high-dose melphalan (140 mg/m2) without stem cell support, measurable paraprotein disappeared in a significant proportion of patients and criteria for complete remission were formulated ( Selby et al, 1987 ; Gore et al, 1989 ; Samson et al, 1989 ). As the use of high-dose therapy has increased there has been a consequent increase in the number of patients entering CR, and other groups have published their own definitions of CR; as shown in Table IV ( Gahrton et al, 1991 ; Anderson et al, 1993 ; Dimopoulos et al, 1993 ; Bjorkstrand et al 1995b ; Attal et al, 1996 ; Vesole et al, 1996 ; Barlogie et al, 1997 ; Ballester et al, 1997 ; Joshua et al, 1997 ; Schiller et al, 1998 ). All groups agreed that there should be no detectable paraprotein in serum or urine together with a normal number of plasma cells in the marrow (i.e. <4–5%), but differed according to whether the absence of paraprotein is based on routine electrophoresis (EP) alone or whether a more sensitive method such as immunoelectrophoresis (IEP) or immunofixation (IF) was required. In the earliest reports either no method was specified or only EP was required. More recently there has been a trend towards a more stringent definition of CR requiring a negative IF. Some groups have also required the plasma cells in the marrow to be of normal morphology whereas others have not included morphological assessment, and some groups have included factors such as transfusion independence and lack of symptoms. It is perhaps surprising that many groups do not exclude transient responses by specifying a minimum duration of time for which the paraprotein must remain undetectable to fulfil the definition of CR. CR has hitherto been defined by the EBMT Myeloma Transplant Registry as absence of detectable paraprotein in serum and urine and < 5% plasma cells in marrow, without specifying the method to be used for excluding the presence of paraprotein, nor the time period for which results must remain negative. The IBMTR and ABMTR have not hitherto used a standard definition of CR. The current North American National Cancer Institute Intergroup (SWOG, INT, CALGB and ECOG) Myeloma Trial, comparing conventional versus high-dose therapy, defines CR as absence of paraprotein in serum and urine by EP and IF on at least two measurements for a minimum of 6 weeks, and <4% plasma cells in the bone marrow. There are also currently no generally accepted criteria for the definition of disease progression or relapse and papers reporting the results of different treatment regimens do not always specify the criteria used to define progression ( MacLennan et al, 1992 ; Ballester et al, 1997 ; Barlogie et al, 1997 ). Bergsagel et al (1979 ) defined progression as a progressive increase in serum paraprotein of at least 10 g/l or a 100% increase in urinary light chain excretion. Belch et al (1988 ) also used a minimum increase of 10 g/l in serum paraprotein but required an increase of 2.0 g/24 h in urinary light chain excretion. In recent reports most groups have defined progression as an increase in serum paraprotein or urinary light chain excretion by 25% ( Oivanen et al, 1997 ) or 50% ( Samson et al, 1989 ; Bjorkstrand et al 1995a ; Attal et al, 1996 ; Joshua et al, 1997 ). Other indicators of progressive disease such as increasing marrow infiltration or an increase in the number of lytic bone lesions are also included in the definition of disease progression by most groups. For patients in CR a reappearance of paraprotein, by whatever method, is generally accepted to constitute relapse. The EBMT has hitherto defined progression as a 50% increase of measurable paraprotein levels ( Bjorkstrand et al, 1995b ; Gahrton et al, 1995 ). The IBMTR and ABMTR have not previously utilized any defined criteria, but a number of groups recently reporting results of high-dose therapy studies have used a 25% increase for defining progression ( Attal et al, 1996 ; Schiller et al, 1998 ; Barlogie et al, 1997 ) and the current North American Intergroup trial adopts the same definition. In the pioneer study dealing with response to treatment in multiple myeloma, the median survival of patients who responded to melphalan was 41 months compared with 9 months in patients who did not respond ( Bergsagel, 1975) and Alexanian et al (1972 ) reported that the survival of patients treated with combination chemotherapy was directly correlated with the extent of reduction of paraprotein synthesis. This has been a frequently quoted reference supporting the relationship between the degree of response and subsequent survival. However, a similar survival analysis carried out by Palmer et al (1989 ) failed to show such a correlation. Several other studies have also reported a lack of correlation between response and survival ( Baldini et al, 1991 ; Marmont et al, 1991 ; Joshua et al, 1991 ; Blade et al, 1994 ). Even with regimens such as high-dose melphalan 140 mg/m2 and VAD, which produced CR in up to 25% of newly diagnosed patients, duration and survival were not prolonged in patients reaching CR as compared with those achieving PR ( Selby et al, 1987 ; Samson et al, 1989 ). With conventional chemotherapy, stabilization of tumour load is a more powerful prognostic factor than the degree of tumour reduction in predicting survival ( Durie et al, 1980 ; Joshua et al, 1991 ; MacLennan et al, 1992 , 1994; Blade et al, 1994 ; Oivanen, 1996). Since the survival of patients who achieve a partial or minimal response is similar to that of those fulfilling more stringent response criteria, all patients attaining a stable state should be considered in plateau phase regardless of the level of paraprotein. The MRC has been unique among those carrying out clinical trials in multiple myeloma in using stable plateau phase to define treatment efficacy rather than response criteria based on a given degree of paraprotein reduction. In some patients the paraprotein does not fall with treatment but does not increase and may remain stable for months or years. These patients have non-responding but non-progressive disease and may be considered to be in plateau phase at diagnosis. Although these patients are classified as non-responders according to the CLMTF and SWOG criteria, the disease does not progress and such patients in fact usually have a long survival ( Blade et al, 1986 ; Joshua et al, 1991 ). This situation is similar to that observed in patients with smouldering myeloma ( Kyle & Greipp, 1980). In summary, few patients treated with conventional chemotherapy enter CR and the correlation between the degree of tumour response and ultimate survival is questionable. In contrast, up to 50% of patients enter CR after high-dose therapy (with CR being defined on the basis of negative EP). Furthermore, after high-dose therapy a correlation between the degree of tumour response and survival has been demonstrated. Thus, myeloma patients who enter CR post-transplant have a significantly longer progression-free and overall survival than those who enter or remain in PR or who fail to respond ( Gahrton et al, 1991 , 1995; Bjorkstrand et al, 1995a ; Attal et al, 1996 ; Barlogie et al, 1997 ). This cannot be explained entirely by the increasing use of more stringent criteria for CR in more recent studies of high-dose therapy since in some of these reports CR was based on negative EP without negative IF ( Gahrton et al, 1991 , 1995; Bjorkstrand et al, 1995a ). It seems more likely that there is a difference in the quality of CR after conventional chemotherapy and after high-dose therapy; in other words the level of minimal residual disease is presumably lower in patients in CR post-transplant than in those who are in CR after non-myeloablative therapy. The proposed new criteria are shown in Table V. They are based on existing criteria, with modifications. As they will form the basis for data reporting from a large number of centres throughout the world, a pragmatic approach was essential; the investigations required are therefore those which are felt to be the minimum necessary to assess response and to diagnose progression or relapse. Serum paraprotein levels and urinary light chain excretion form the basis for the assessment of response, progression and relapse. Paraprotein levels must remain stable for a minimum of 6 weeks to fulfil the criteria for a given category of response. The response criteria for both serum paraprotein and free urinary light chain must be met in patients in whom both are present. Bone marrow examinations are essential only to confirm complete response or to evaluate response in non-secretory myeloma. It is recognized that there are occasional patients who develop increasing bone marrow plasmacytosis despite a falling paraprotein level (hyposecretory or non-secretory progression), but this is not sufficiently common to justify mandatory marrow examinations in all patients and will become evident on further follow-up. In patients known to have non-secretory myeloma, however, marrow examination is essential to document response. In these patients it was also felt justifiable to require a repeat examination to ensure that the response is not transient and because of the patchy nature of myeloma infiltration. Trephine biopsy of the marrow is not essential, but if biopsy is performed then the marrow plasma cell percentage must independently meet the proposed criteria. Similarly, skeletal X-rays are not required for the definition of response, but if performed there must be no evidence of progression of bone disease. Follow-up X-rays to confirm continuing response are also not mandatory, although periodic radiological examinations are recommended. If radiological examinations are performed as part of routine follow-up, or for other clinical indications, and show evidence of progressive disease, this will constitute relapse or progression even in the absence of any other criteria. It is strongly recommended therefore that a full skeletal survey be performed immediately prior to conditioning in order to ensure that any apparently new lesions subsequently seen were not in fact present at the time of the transplant. It is also emphasized that the development of a new vertebral compression fracture(s) may result from pre-existing bone damage (lytic lesions or osteoporosis) and does not necessarily preclude response nor constitute relapse. Magnetic resonance imaging (MRI) data have not been included in the definitions of response and progression because experience with this technique is still limited and the significance of different MRI patterns is not yet defined. CR is defined on the basis of negative IF on both serum and urine, maintained for a minimum of 6 weeks. Patients who have no detectable paraprotein on EP without a negative IF result (IF either positive or not performed) will no longer be classified as CR. A bone marrow aspirate containing <5% plasma cells is also required for the confirmation of CR. Although it is recognized that in patients with secretory myeloma it would be very unusual to have disappearance of the paraprotein with persisting marrow infiltration, it was felt important to exclude this possibility. Normal morphology of the plasma cells is not specified because morphological assessment was felt to be too subjective. It is not essential to perform a trephine biopsy, but if a biopsy is performed this must also contain <5% plasma cells. In non-secretory myeloma the marrow must be repeated after a 6-week interval to confirm CR. The main requirement in the above definition is the absence of detectable paraprotein by IF as well as by EP. Since CR is a prerequisite for potential cure in myeloma, it is logical that CR should require absence of paraprotein by the most sensitive method in routine use. Studies of minimal residual disease at the molecular or cytogenetic level may prove informative in patients without detectable paraprotein ( Bird et al, 1993 ; Bjorkstrand et al, 1995b ) but the results of such studies are not yet clearly interpretable and are not routinely available; in consequence cytogenetic and molecular data cannot at present be included in the criteria for CR. There are potential problems in the use of IF to determine remission status. The requirement for regular monitoring by IF imposes additional laboratory workload and expense and many laboratories do not routinely perform IF when EP is negative. Therefore it is the treating physician's responsibility specifically to request that IF be performed if EP is negative. A patient is classified as in CR only when a negative IF has been documented on serial samples at a minimum interval of 6 weeks. In patients achieving CR, IF must also be performed at all subsequent evaluations in order to document the time of disease relapse. Most clinicians would repeat IF every 3–4 months post-transplant in these patients. Whether using IF rather than EP to define CR will prove clinically relevant will depend on the evaluation of outcomes utilizing CR as a prognostic variable. To this end the EBMT and ABMTR/IBMTR follow-up forms will record both EP and IF results and will retrospectively compare outcomes in patients in CR and those who are EP-negative but IF-positive or unknown. A 50% decrease in serum paraprotein is required for PR, as in the CLMTF criteria. However, a 50% decrease in urinary light chain excretion was not considered adequate to define PR. Most free light chains are catabolized by the kidney and the urinary excretion therefore represents only the excess that escapes renal catabolism. Therefore a given degree of tumour reduction has a more marked effect on urinary light chain excretion than on serum paraprotein level. McLaughlin & Alexanian (1982) observed that in a series of patients with both serum paraprotein and free urinary light chains a 50% decrease in serum paraprotein level was always accompanied by a decrease of >90% in urinary light chain excretion. We have therefore used the SWOG criterion of 90% decrease in urinary light chain excretion to define PR. However, in contrast to the SWOG criteria, it is not necessary for urinary light chain excretion to fall below 200 mg/24 h if there has been a 90% reduction. Conversely, urinary light chain excretion may decrease by <90% and still qualify for PR if it falls to < 200 mg/24 h, since it is difficult to accurately measure amounts of light chain excretion <200 mg/24 h, which would be necessary to document a reduction of >90% in patients with an initial light chain excretion of 2 g/24 h or less. To avoid recording a transient response as CR or PR a minimum period of negative results or stable paraprotein level needs to be specified, although this is shorter than that required to fulfil the criteria for plateau (see below). It has been agreed that 6 weeks will be the minimum required period; this enables assessment of response to be made at day 100 post-transplant, which corresponds with the Registries' initial data collection forms. Some patients will reach their maximum response after day 100, and in this case the final response will be recorded on the first annual follow-up form. The post-transplant paraprotein level must be compared with a previous reference point in order to accurately assess response. A simple approach is to use the paraprotein level immediately prior to transplant as the reference point. However, this may lead to the paradox of a patient transplanted as consolidation of a chemotherapy-induced remission being termed a non-responder if the paraprotein level does not decrease by a further 50%. Patients in CR pre-transplant who remain in CR post-transplant would similarly be classified as non-responders. Therefore when transplant has been performed as consolidation of a chemotherapy-induced remission the overall response will be assessed by comparing the pre- and post-transplant paraprotein levels with those immediately prior to the previous chemotherapy programme. Thus a patient may move from PR to CR, or from PR to continuing PR, or from non-responsive disease to PR or CR. Patients in CR pre-transplant who remain in CR post-transplant will be designated as being in continuous complete response. Patients who have not responded to initial chemotherapy nor to subsequent transplant will be classified as having no response. For patients who have not received chemotherapy within the 6 months prior to transplant the response to the transplant alone will be assessed solely by comparing post-transplant paraprotein levels with those immediately prior to transplant. Such patients will include some patients transplanted with primary refractory disease or in untreated relapse, as well as those who have remained stable for >6 months after completion of chemotherapy. The attainment of plateau is an important prognostic indicator for the outcome of patients treated with conventional chemotherapy. It may therefore be important to determine if patients in plateau before transplant have a better prognosis in relation to transplant outcome. However, this may be difficult to determine, since transplant is now often performed as the final cycle of a planned treatment programme and insufficient time may have elapsed for stable plateau to be reached before the transplant procedure. It may also be important to know whether reaching plateau post-transplant is also of prognostic significance in those patients who do not achieve CR, and whether the establishment of plateau is more important than the degree of partial response achieved. It has been agreed that plateau phase will be defined on the basis of stable paraprotein levels for a minimum of 3 months, as in the current MRC trials. Plateau will require observations to be within 25% of the value when response is assessed, a rise above 25% being one of the criteria for disease progression. We have used the term progression to describe a definite increase in disease activity in patients in partial remission or plateau phase, whereas the term relapse applies to a recurrence of evident disease in patients previously in CR. Progression is usually defined as an increase of >25% in serum paraprotein or urinary light chain excretion, with reference to the levels documented at the time of response. However, the paraprotein level or urinary light chain excretion post-transplant is often at a very low level, and it would not be appropriate to consider a change in serum paraprotein from a level of 6–8 g/l, for example, as definite evidence of progression. We have therefore defined progression as an increase of >25% in paraprotein or urinary light chain excretion (or marrow plasma cell percentage in the marrow), but in addition we have stipulated minimum absolute increases in these parameters. These criteria have been established to reliably identify a definite increase in disease activity; it is recognized that many patients will be asymptomatic and may not necessarily require treatment at this stage. Progression may also be defined on the basis of increasing marrow infiltration or skeletal disease, but, as noted, it is not essential to repeat these investigations unless there is a clinical indication to do so. Relapse is defined as reappearance of detectable paraprotein or other manifestation of disease in patients previously in CR. Relapse is a more appropriate term than progression in these patients as there was no evidence of disease when they were in CR. Since a negative IF is the criterion for the definition of CR, then recurrence of positivity on IF (confirmed on at least one repeat sample) constitutes relapse, whether or not the paraprotein becomes detectable again by EP. This is a very stringent definition of relapse, especially since recurrence of IF positivity is not always immediately followed by an increase in paraprotein level, and such patients may remain asymptomatic for a prolonged period ( Bjorkstrand et al, 1995b ). Furthermore, the IF result may only be intermittently positive in some patients, a situation analogous to that of patients with CML in whom PCR for bcr-abl mRNA may be intermittently, but not consistently, positive ( Cross et al, 1993 ). In other words, recurrence of IF positivity does not necessarily lead, at least in the short-term, to clinical disease progression. This sensitive definition of relapse in CR patients could, at least theoretically, lead to a paradoxically shorter remission duration in CR patients than those who do not enter CR. It will therefore be important to record the time when treatment was instituted after progression or relapse, in order to evaluate whether the proposed criteria are predictive of subsequent disease evolution. These proposed criteria for response, progression and relapse have been developed with the aim of improving the evaluation of new therapeutic approaches in multiple myeloma, specifically high-dose therapy with haemopoietic stem cell rescue. It is recognized that re-assessment and subsequent modification of these criteria, again using an international forum, may be necessary in the future as they are implemented in clinical practice and as new technologies evolve. For the present, these consensus criteria for complete remission, relapse and progression should provide a useful framework for clinical trials and registry analysis. J. Bladé was supported by a grant from the Fondo de Investigationes Sanitarias de la Seguridad Social FIS 96/0397 and Gosta Gahrton by the Cancer Society of Stockholm.

Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma

2014-12-06
A. Keith Stewart , S. Vincent Rajkumar , Meletios Α. Dimopoulos +7 more
Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and … Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma.
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Lenalidomide plus Dexamethasone for Relapsed or Refractory Multiple Myeloma

2007-11-21
Meletios Α. Dimopoulos , Andrew Spencer , Michael Attal +7 more
Lenalidomide is a structural analogue of thalidomide with similar but more potent biologic activity. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide plus dexamethasone in the treatment of … Lenalidomide is a structural analogue of thalidomide with similar but more potent biologic activity. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide plus dexamethasone in the treatment of relapsed or refractory multiple myeloma.Of 351 patients who had received at least one previous antimyeloma therapy, 176 were randomly assigned to receive 25 mg of oral lenalidomide and 175 to receive placebo on days 1 to 21 of a 28-day cycle. In addition, all patients received 40 mg of oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles and subsequently, after the fourth cycle, only on days 1 to 4. Patients continued in the study until the occurrence of disease progression or unacceptable toxic effects. The primary end point was time to progression.The time to progression was significantly longer in the patients who received lenalidomide plus dexamethasone (lenalidomide group) than in those who received placebo plus dexamethasone (placebo group) (median, 11.3 months vs. 4.7 months; P<0.001). A complete or partial response occurred in 106 patients in the lenalidomide group (60.2%) and in 42 patients in the placebo group (24.0%, P<0.001), with a complete response in 15.9% and 3.4% of patients, respectively (P<0.001). Overall survival was significantly improved in the lenalidomide group (hazard ratio for death, 0.66; P=0.03). Grade 3 or 4 adverse events that occurred in more than 10% of patients in the lenalidomide group were neutropenia (29.5%, vs. 2.3% in the placebo group), thrombocytopenia (11.4% vs. 5.7%), and venous thromboembolism (11.4% vs. 4.6%).Lenalidomide plus dexamethasone is more effective than high-dose dexamethasone alone in relapsed or refractory multiple myeloma. (ClinicalTrials.gov number, NCT00424047 [ClinicalTrials.gov].).
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Identification of a Primary Target of Thalidomide Teratogenicity

2010-03-11
Takumi Ito , Hideki Ando , Takayuki Suzuki +5 more
Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in … Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.

Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1

2011-02-04
S. Vincent Rajkumar , Jean‐Luc Harousseau , Brian G.M. Durie +7 more

A clinical staging system for multiple myeloma correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival

1975-09-01
Brian G.M. Durie , Sydney E. Salmon
The presenting clinical features of 71 patients with multiple myeloma were correlated with myeloma cell mass (myeloma cells × 1012/m2 of body surface area) determined from measurements of monoclonal immunoglobulin … The presenting clinical features of 71 patients with multiple myeloma were correlated with myeloma cell mass (myeloma cells × 1012/m2 of body surface area) determined from measurements of monoclonal immunoglobulin (M-component) synthesis and metabolism. Bivariate correlation and multivariate regression analyses showed that myeloma cell mass could be accurately predicted from A) extent of bone lesions, B) hemoglobin level, C) serum calcium level, and D) M-component levels in serum and urine. Analyses of response to chemotherapy and survival indicated significant correlation with measured myeloma cell burden. The results were synthesized to produce a very reliable and useful clinical staging system with three tumor cell mass levels (Table 7). For clinical research purposes, multivariate regression equations were developed to predict optimally the exact myeloma cell mass. Thus, initial staging can be quantitatively related to followup using tumor cell mass changes calculated from changes in M-component production. Use of the clinical staging system should provide better initial assessment and followup of individual patients, and should lead to improved study design and analysis in large clinical trials of therapy for multiple myeloma.

Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas

1988-03-01
Michio Kawano , Toshio Hirano , Tadashi Matsuda +7 more

Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets

2007-07-24
Teru Hideshima , Constantine S. Mitsiades , Giovanni Tonon +2 more

Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells

2013-11-30
Jan Krönke , Namrata D. Udeshi , Anupama Narla +7 more
Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes … Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.
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Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients

2013-10-25
Shaji Kumar , Angela Dispenzieri , Martha Q. Lacy +7 more
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Lenalidomide plus Dexamethasone for Relapsed Multiple Myeloma in North America

2007-11-21
Donna M. Weber , Christine Chen , Rubén Niesvizky +7 more
Lenalidomide, an oral immunomodulatory drug that is similar to thalidomide but has a different safety profile, has clinical activity in relapsed or refractory multiple myeloma.Patients in the United States and … Lenalidomide, an oral immunomodulatory drug that is similar to thalidomide but has a different safety profile, has clinical activity in relapsed or refractory multiple myeloma.Patients in the United States and Canada who had received at least one previous therapy for multiple myeloma but who required additional treatment were randomly assigned to receive either 25 mg of lenalidomide or placebo on days 1 to 21 of a 28-day cycle. Both groups also received 40 mg of oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for the first four cycles. After the fourth cycle, 40 mg of dexamethasone was administered only on days 1 to 4. Safety, clinical response, time to progression, and overall survival were assessed.We assigned 177 patients to the lenalidomide group and 176 to the placebo group. Complete, near-complete, or partial responses occurred in 108 patients (61.0%) in the lenalidomide group and in 35 patients (19.9%) in the placebo group (P<0.001); complete responses occurred in 14.1% and 0.6%, respectively (P<0.001). The median time to progression was 11.1 months in the lenalidomide group and 4.7 months in the placebo group (P<0.001). Median overall survival times in the two groups were 29.6 months and 20.2 months, respectively (P<0.001). Grade 3 or 4 adverse events were reported in 85.3% of the lenalidomide group and in 73.1% of the placebo group; these events resulted in study discontinuation in 19.8% and 10.2%, respectively. Grade 3 or 4 neutropenia and venous thromboembolism were more common in the lenalidomide group than in the placebo group (41.2% vs. 4.6% and 14.7% vs. 3.4%, respectively; P<0.001 for both comparisons).Lenalidomide plus dexamethasone is superior to placebo plus dexamethasone in patients with relapsed or refractory multiple myeloma. (ClinicalTrials.gov number, NCT00056160 [ClinicalTrials.gov].).
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Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma

2007-08-01
Jonathan J. Keats , Rafaël Fonseca , Marta Chesi +7 more
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Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study

2009-01-30
Ola Landgren , Robert A. Kyle , Ruth M. Pfeiffer +7 more

The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma

2003-12-24
Erming Tian , Fenghuang Zhan , Ronald C. Walker +4 more
Myeloma cells may secrete factors that affect the function of osteoblasts, osteoclasts, or both.We subjected purified plasma cells from the bone marrow of patients with newly diagnosed multiple myeloma and … Myeloma cells may secrete factors that affect the function of osteoblasts, osteoclasts, or both.We subjected purified plasma cells from the bone marrow of patients with newly diagnosed multiple myeloma and control subjects to oligonucleotide microarray profiling and biochemical and immunohistochemical analyses to identify molecular determinants of osteolytic lesions.We studied 45 control subjects, 36 patients with multiple myeloma in whom focal lesions of bone could not be detected by magnetic resonance imaging (MRI), and 137 patients in whom MRI detected such lesions. Different patterns of expression of 57 of approximately 10,000 genes from purified myeloma cells could be used to distinguish the two groups of patients (P<0.001). Permutation analysis, which adjusts the significance level to account for multiple comparisons in the data sets, showed that 4 of these 57 genes were significantly overexpressed by plasma cells from patients with focal lesions. One of these genes, dickkopf 1 (DKK1), and its corresponding protein (DKK1) were studied in detail because DKK1 is a secreted factor that has been linked to the function of osteoblasts. Immunohistochemical analysis of bone marrow-biopsy specimens showed that only myeloma cells contained detectable DKK1. Elevated DKK1 levels in bone marrow plasma and peripheral blood from patients with multiple myeloma correlated with the gene-expression patterns of DKK1 and were associated with the presence of focal bone lesions. Recombinant human DKK1 or bone marrow serum containing an elevated level of DKK1 inhibited the differentiation of osteoblast precursor cells in vitro.The production of DKK1, an inhibitor of osteoblast differentiation, by myeloma cells is associated with the presence of lytic bone lesions in patients with multiple myeloma.
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International uniform response criteria for multiple myeloma

2006-07-20
Brian G.M. Durie , J-L Harousseau , Jesús F. San Miguel +7 more

Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted Therapy

2014-01-01
Jens G. Lohr , Petar Stojanov , Scott L. Carter +7 more
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Improved survival in multiple myeloma and the impact of novel therapies

2007-11-02
Shaji Kumar , S. Vincent Rajkumar , Angela Dispenzieri +7 more
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Prevalence of Monoclonal Gammopathy of Undetermined Significance

2006-03-29
Robert A. Kyle , Terry M. Therneau , S. Vincent Rajkumar +6 more
The prevalence of monoclonal gammopathy of undetermined significance (MGUS), a premalignant plasma-cell disorder, among persons 50 years of age or older has not been accurately determined. We used sensitive laboratory … The prevalence of monoclonal gammopathy of undetermined significance (MGUS), a premalignant plasma-cell disorder, among persons 50 years of age or older has not been accurately determined. We used sensitive laboratory techniques to ascertain the prevalence of MGUS in a large population in a well-defined geographic area.
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Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma

2008-10-30
Robert A. Kyle , S. Vincent Rajkumar

Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma

2008-08-27
Jesús F. San Miguel , Rudolf Schlag , Nuriet K. Khuageva +7 more
The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone … The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy.We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression.The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%).Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)
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Initial genome sequencing and analysis of multiple myeloma

2011-03-01
Michael A. Chapman , Michael S. Lawrence , Jonathan J. Keats +7 more
Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to … Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Chapman et al. have used next-generation sequencing to compare 38 multiple myeloma genomes with those of normal cells from the same patients. The disease involves mutations of genes with roles in protein translation, histone methylation and blood coagulation. In terms of clinically relevant findings, unexpected activating mutations were found in the kinase BRAF, inhibitors of which have recently shown dramatic clinical activity. This suggests that BRAF inhibitors should be evaluated in patients with BRAF-mutated multiple myeloma. Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Using next-generation sequencing of several multiple myeloma genomes reveals that this disease involves mutations of genes involved in protein translation, histone methylation and blood coagulation. The study suggests that BRAF inhibitors should be evaluated in multiple myeloma clinical trials.
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High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma

2003-05-07
J. A. Child , Gareth J. Morgan , Faith E. Davies +6 more
High-dose therapy with supporting autologous stem-cell transplantation remains a controversial treatment for cancer. In multiple myeloma, first-line regimens incorporating high-dose therapy yield higher remission rates than do conventional-dose treatments, but … High-dose therapy with supporting autologous stem-cell transplantation remains a controversial treatment for cancer. In multiple myeloma, first-line regimens incorporating high-dose therapy yield higher remission rates than do conventional-dose treatments, but evidence that this translates into improved survival is limited.
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A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma

2003-06-25
Paul G. Richardson , Bart Barlogie , James R. Berenson +7 more
Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity.In this multicenter, open-label, nonrandomized, phase 2 … Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity.In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation and confirmed by an independent review committee.Of 193 patients who could be evaluated, 92 percent had been treated with three or more of the major classes of agents for myeloma, and in 91 percent, the myeloma was refractory to the therapy received most recently. The rate of response to bortezomib was 35 percent, and those with a response included 7 patients in whom myeloma protein became undetectable and 12 in whom myeloma protein was detectable only by immunofixation. The median overall survival was 16 months, with a median duration of response of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia (in 11 percent). Grade 4 events occurred in 14 percent of patients.Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy.
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International Staging System for Multiple Myeloma

2005-04-05
Philip R. Greipp , Jesús F. San Miguel , Brian G.M. Durie +7 more
Purpose There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. Patients and Methods Clinical and laboratory … Purpose There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. Patients and Methods Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. Results Serum beta 2 -microglobulin (Sβ 2 M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sβ 2 M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sβ 2 M less than 3.5 mg/L plus serum albumin ≥ 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sβ 2 M ≥ 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. Conclusion The new ISS is simple, based on easy to use variables (Sβ 2 M and serum albumin), and recommended for early adoption and widespread use.

Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma

2005-06-15
Paul G. Richardson , Pieter Sonneveld , Michael W. Schuster +7 more
This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies.We randomly assigned 669 patients with relapsed myeloma to receive … This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies.We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3 mg per square meter of body-surface area) on days 1, 4, 8, and 11 for eight three-week cycles, followed by treatment on days 1, 8, 15, and 22 for three five-week cycles, or high-dose dexamethasone (40 mg orally) on days 1 through 4, 9 through 12, and 17 through 20 for four five-week cycles, followed by treatment on days 1 through 4 for five four-week cycles. Patients who were assigned to receive dexamethasone were permitted to cross over to receive bortezomib in a companion study after disease progression.Patients treated with bortezomib had higher response rates, a longer time to progression (the primary end point), and a longer survival than patients treated with dexamethasone. The combined complete and partial response rates were 38 percent for bortezomib and 18 percent for dexamethasone (P<0.001), and the complete response rates were 6 percent and less than 1 percent, respectively (P<0.001). Median times to progression in the bortezomib and dexamethasone groups were 6.22 months (189 days) and 3.49 months (106 days), respectively (hazard ratio, 0.55; P<0.001). The one-year survival rate was 80 percent among patients taking bortezomib and 66 percent among patients taking dexamethasone (P=0.003), and the hazard ratio for overall survival with bortezomib was 0.57 (P=0.001). Grade 3 or 4 adverse events were reported in 75 percent of patients treated with bortezomib and in 60 percent of those treated with dexamethasone.Bortezomib is superior to high-dose dexamethasone for the treatment of patients with multiple myeloma who have had a relapse after one to three previous therapies.
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Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma

2012-05-09
Philip L. McCarthy , Kouros Owzar , Craig C. Hofmeister +7 more
Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma.
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Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma

2012-05-09
Michel Attal , Valérie Lauwers‐Cancès , Gérald Marit +7 more
High-dose chemotherapy with autologous stem-cell transplantation is a standard treatment for young patients with multiple myeloma. Residual disease is almost always present after transplantation and is responsible for relapse. This … High-dose chemotherapy with autologous stem-cell transplantation is a standard treatment for young patients with multiple myeloma. Residual disease is almost always present after transplantation and is responsible for relapse. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide maintenance therapy after transplantation.We randomly assigned 614 patients younger than 65 years of age who had nonprogressive disease after first-line transplantation to maintenance treatment with either lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated) or placebo until relapse. The primary end point was progression-free survival.Lenalidomide maintenance therapy improved median progression-free survival (41 months, vs. 23 months with placebo; hazard ratio, 0.50; P<0.001). This benefit was observed across all patient subgroups, including those based on the β(2)-microglobulin level, cytogenetic profile, and response after transplantation. With a median follow-up period of 45 months, more than 70% of patients in both groups were alive at 4 years. The rates of grade 3 or 4 peripheral neuropathy were similar in the two groups. The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group (P=0.002). Median event-free survival (with events that included second primary cancers) was significantly improved with lenalidomide (40 months, vs. 23 months with placebo; P<0.001).Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma. Four years after randomization, overall survival was similar in the two study groups. (Funded by the Programme Hospitalier de Recherche Clinique and others; ClinicalTrials.gov number, NCT00430365.).
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Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group

2015-08-04
Antonio Palumbo , Hervé Avet‐Loiseau , Stefania Oliva +7 more
The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal … The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM).Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival.ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum β2-microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively.The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival.
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Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors

2010-12-28
Michel de Weers , Yu‐Tzu Tai , Michael S. van der Veer +7 more
Abstract CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic … Abstract CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.
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International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma

2014-10-26
S. Vincent Rajkumar , Meletios Α. Dimopoulos , Antonio Palumbo +7 more
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BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells

2004-01-05
Brian P. O’Connor , Vanitha S. Raman , Loren D. Erickson +7 more
Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and … Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this α-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor–immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA−/− mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.
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The molecular classification of multiple myeloma

2006-05-26
Fenghuang Zhan , Yongsheng Huang , Simona Colla +7 more

Review of 1027 Patients With Newly Diagnosed Multiple Myeloma

2003-01-01
Robert A. Kyle , Morie A. Gertz , Thomas E. Witzig +7 more

Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group

2003-05-28
Summary. The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The … Summary. The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is &lt; 30 g/l and the bone marrow clonal cells &lt; 10% with no evidence of multiple myeloma, other B‐cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M‐protein is ≥ 30 g/l and/or bone marrow clonal cells ≥ 10% but no r elated o rgan or t issue i mpairment (ROTI)(end‐organ damage), which is typically manifested by increased c alcium, r enal insufficiency, a naemia, or b one lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non‐secretory myeloma is characterized by the absence of an M‐protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (± recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.
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Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial

2009-10-23
S. Vincent Rajkumar , Susanna Jacobus , Natalie S. Callander +7 more
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Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma

2015-06-02
Sagar Lonial , Meletios Α. Dimopoulos , Antonio Palumbo +7 more
Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or … Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma.In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival.Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients.Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).
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Antitumor Activity of Thalidomide in Refractory Multiple Myeloma

1999-11-18
Seema Singhal , Jayesh Mehta , Raman Desikan +7 more
Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which … Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease.
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Quantitation of Differential Sensitivity of Human-Tumor Stem Cells to Anticancer Drugs

1978-06-15
Sydney E. Salmon , Anne W. Hamburger , B Soehnlen +3 more
With a direct in vitro tumor-colony assay developed to measure sensitity of human-tumor stem cells to anticancer drugs, we performed 32 retrospective or prospective clinical studies in nine patients with … With a direct in vitro tumor-colony assay developed to measure sensitity of human-tumor stem cells to anticancer drugs, we performed 32 retrospective or prospective clinical studies in nine patients with myeloma and nine with ovarian cancer treated with standard agents that were tested in vitro. The results were clearly correlated (P is less than 0.00001). Unique patterns of sensitivity and resistance to the six drugs tested were observed for individual patients. In eight cases of myeloma and three of obarian carcinoma in vitro sensitivity corresponded with in vivo sensitivity whereas in one case of myeloma it did not. In vitro resistance correlated with clinical resistance in all five comparisons in myeloma and all 15 in ovarian cancer. We conclude that this assay shows sufficient promise to warrant larger-scale testing to determine its efficacy for selection of new agents and individualized cancer chemotherapy regimens.

Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma

1996-02-22
James R. Berenson , Alan Lichtenstein , Lester Porter +7 more
Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity … Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption.Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration > or = 12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly.Among 392 treated patients, the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo. The proportion of patients who had any skeletal events was significantly lower in the pamidronate group (24 percent) than in the placebo group (41 percent, P < 0.001), and the reduction was evident in both stratum 1 (P = 0.04) and stratum 2 (P = 0.004). The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life. Pamidronate was tolerated well.Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma.
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Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

2016-04-27
Philippe Moreau , Tamás Masszi , Norbert Grząśko +7 more
Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma.
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International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma

2016-07-27
Shaji Kumar , Bruno Paiva , Kenneth C. Anderson +7 more

Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma

2016-08-24
Antonio Palumbo , Asher Chanan‐Khan , Katja Weisel +7 more
Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as … Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma.In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival.A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion.Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).
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Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma

2016-10-05
Meletios Α. Dimopoulos , Albert Oriol , Hareth Nahi +7 more
Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1–2 study involving patients with relapsed or refractory multiple myeloma. Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1–2 study involving patients with relapsed or refractory multiple myeloma.
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Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma

2017-04-05
Michel Attal , Valérie Lauwers‐Cancès , Cyrille Hulin +7 more
High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use … High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation.
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Multiple Myeloma

2004-10-28
Robert A. Kyle , S. Vincent Rajkumar
Multiple myeloma, a plasma-cell neoplasm characterized by skeletal destruction, renal failure, anemia, and hypercalcemia, remains incurable. However, recent advances in its treatment, in particular, the use of thalidomide and such … Multiple myeloma, a plasma-cell neoplasm characterized by skeletal destruction, renal failure, anemia, and hypercalcemia, remains incurable. However, recent advances in its treatment, in particular, the use of thalidomide and such new drugs as bortezomib and CC-5013, are promising. This article discusses current therapy for multiple myeloma.

Multiple myeloma

2000-02-01
Noopur Raje , Kenneth C. Anderson

Multiple myeloma

2017-07-20
Shaji Kumar , S. Vincent Rajkumar , Robert A. Kyle +5 more

Multiple Myeloma

2011-03-16
Antonio Palumbo , Kenneth C. Anderson
Autologous stem-cell transplantation and agents such as thalidomide, lenalidomide, and bortezomib have changed the management of myeloma and extended overall survival. This review discusses both the biologic features and the … Autologous stem-cell transplantation and agents such as thalidomide, lenalidomide, and bortezomib have changed the management of myeloma and extended overall survival. This review discusses both the biologic features and the management of multiple myeloma.

Erratum: International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma

2025-06-25
Hervé Avet‐Loiseau , Faith E. Davies , Mehmet Samur +7 more | Journal of Clinical Oncology

Development and Preclinical Validation of a Novel <sup>89</sup>Zr-Labeled BCMA-Targeting Antibody for ImmunoPET Imaging: Application in Multiple Myeloma Models and First-In-Nonhuman-Primates

2025-06-25
Tianyao Wang , Qi Yang , Wenpeng Huang +7 more | Journal of Medicinal Chemistry
B-cell maturation antigen (BCMA) is a clinically validated biomarker and therapeutic target in multiple myeloma (MM). Here, we report the design, synthesis, and preclinical evaluation of an immunoPET probe, [89Zr]Zr-DFO-PFBH0L0, … B-cell maturation antigen (BCMA) is a clinically validated biomarker and therapeutic target in multiple myeloma (MM). Here, we report the design, synthesis, and preclinical evaluation of an immunoPET probe, [89Zr]Zr-DFO-PFBH0L0, derived from a novel humanized anti-BCMA monoclonal antibody. The antibody was conjugated with deferoxamine (DFO) and radiolabeled with zirconium-89 (89Zr), yielding a probe with excellent in vitro stability. The tracer retained high binding affinity and demonstrated specific binding to BCMA-positive MM cell lines. In vivo PET imaging and biodistribution studies demonstrated significantly higher tumor uptake in H929-bearing BCMA xenografts (10.04 ± 1.04% ID/g) and a tumor-to-blood ratio exceeding 88, outperforming all controls. Notably, this study presents the first BCMA-targeted PET/CT imaging in nonhuman primates (rhesus macaques), revealing favorable pharmacokinetics, biodistribution, and metabolic stability - underscoring its translational potential for clinical immunoPET imaging and therapeutic monitoring. These results establish [89Zr]Zr-DFO-PFBH0L0 as a promising immunoPET imaging agent for noninvasive, whole-body evaluation of BCMA-expressing malignancies.

Primary Plasmacytoma Involving Kidney, Ureter &amp; Urinary Bladder

2025-06-25
ATM Mowladad Chowdhury , Md. Sazzad Hossain , Md Mostakim Maoya | Bangladesh Journal of Urology
Primary plasmacytoma of urinary tract is extremely rare clinical entity, presenting diagnostic challenges due to its paucity of evidence. We are presenting a case of primary plasmacytoma of kidney, ureter … Primary plasmacytoma of urinary tract is extremely rare clinical entity, presenting diagnostic challenges due to its paucity of evidence. We are presenting a case of primary plasmacytoma of kidney, ureter &amp; urinary bladder in a 74-year-old female patient. Computed tomography (CT) revealed that the mass was in the pelvis of the right kidney invading the renal vein, ureter &amp; urinary bladder along with enlarged right paracaval lymph nodes. After optimization, radical right nephroureterectomy done with excision of cuff of bladder mucosa and the retroperitoneal lymph nodes was resected. Histopathological examination revealed plasmacytoma involving renal parenchyma, ureter &amp; bladder with lymph nodes, which was confirmed by immunohistochemistry studies. Following this unexpected diagnosis, various examinations were performed, but there was no evidence of systemic plasma cell disease. Although the general prognosis and outcome of extra medullary plasmacytoma (EMP) is good, regular follow-up is recommended due to the possibility of relapse or progression to plasma cell neoplasm (PCN). This case is presented for reference, as it is imperative to keep plasmacytic tumours in mind and to include them in the differential diagnosis of anaplastic tumours, even in unusual location, such as the urinary system. Bangladesh J. Urol. 2025; 28(1): 49-51

Disparidades raciais no acesso ao transplante para mieloma múltiplo:

2025-06-24
C. Pereira , Gabriela Carvalho Barbosa Neves , Isabella Carolina de Oliveira +4 more | Revista Uningá
O mieloma múltiplo (MM) é uma neoplasia cujo tratamento pode incluir o transplante de células-tronco hematopoéticas (TCTH). A literatura aponta desigualdades raciais no acesso ao TCTH, mas há poucas informações … O mieloma múltiplo (MM) é uma neoplasia cujo tratamento pode incluir o transplante de células-tronco hematopoéticas (TCTH). A literatura aponta desigualdades raciais no acesso ao TCTH, mas há poucas informações sobre essa questão no Brasil. O estudo objetivou analisar a composição racial de pacientes submetidos ao TCTH autólogo para mieloma múltiplo em um único centro no Brasil, discutindo o acesso ao tratamento. Foi realizada uma revisão retrospectiva dos TCTH realizados entre 2014 e 2022 em um centro acadêmico no Brasil. Os pacientes foram categorizados conforme o IBGE: brancos, pardos e pretos. Foram avaliadas variáveis como idade no momento do transplante e procedência por macrorregião. Os dados foram apresentados em estatística descritiva. Foram incluídos 130 pacientes: 106 brancos (81,5%), 10 pardos (7,7%) e 14 pretos (10,8%). Quanto ao sexo, 71 eram homens (54,6%) e 59 mulheres (45,4%), sem diferenças significativas entre os grupos raciais. A mediana de idade dos brancos foi de 60 anos e a dos pretos e pardos foi de 53 anos. Entre os subgrupos, os brancos do Sudeste, Centro-Oeste e Nordeste representaram 76,4%, 17% e 2,8%, respectivamente, enquanto pretos e pardos representaram 62,5%, 12,5% e 20,8%. Este estudo identificou maioria branca entre pacientes submetidos a TCTH para o manejo do MM em um único centro. É essencial aprofundar a análise dessas diferenças, pois esses achados podem refletir fenômenos do sistema de saúde brasileiro. Discutir essa questão é crucial para entender melhor o acesso ao transplante, considerando fatores que contribuam para a desigualdade nesse grupo de pacientes vulneráveis.

Associations Between Myeloid-Derived Suppressor Cells, TIM-3+ T Cells, and Clinical Factors During the Post-transplant Neutropenia Period in Patients With Multiple Myeloma

2025-06-24
Е. В. Баторов , Т. В. Тыринова , Tatyana Aristova +6 more | Cureus

Maintenance therapy after ASCT in newly diagnosed multiple myeloma patients: single agent versus combination drugs

2025-06-24
Enrica Antonia Martino , Ernesto Vigna , Caterina Labanca +7 more | Expert Review of Hematology
Maintenance therapy plays a crucial role in prolonging progression-free survival and overall survival in multiple myeloma. Lenalidomide remains the gold standard, as demonstrated in phase 3 trials, consistently showing superior … Maintenance therapy plays a crucial role in prolonging progression-free survival and overall survival in multiple myeloma. Lenalidomide remains the gold standard, as demonstrated in phase 3 trials, consistently showing superior survival compared to observation or placebo. However, both established and novel agents - such as thalidomide and pomalidomide, proteasome inhibitors (PIs), monoclonal antibodies (moAbs), and bispecific antibodies - have been investigated as alternatives to assess their efficacy and safety. This review delivers a comprehensive analysis of the current landscape of maintenance strategies in MM and presents the available evidence supporting the efficacy of novel agents, both as monotherapy and in combination. Maintenance therapy is a critical component of MM management, capable of improving disease control and survival. Lenalidomide has demonstrated its ability to extend patients' survival, but cumulative toxicity remains a significant concern. For high-risk patients, maintenance therapy with PIs and CD38-targeting moAbs has proven to improve outcomes. However, challenges such as quality of life, cost, accessibility, and treatment resistance persist. A minimal residual disease (MRD)-adapted maintenance strategy is desirable, particularly to enable personalized treatment approaches in clinical practice.

Diagnostic Impact of SLiM Criteria in Multiple Myeloma: A Real-World Analysis

2025-06-23
Sooyong Park , Yoon Hwan Chang , Sang Mee Hwang +1 more | Research Square (Research Square)
<title>Abstract</title> <bold>Background: </bold>Multiple myeloma (MM) has traditionally been diagnosed on the basis of the CRAB criteria (hyperCalcemia, Renal insufficiency, Anemia, and osteolytic Bone lesions), which are used only after permanent … <title>Abstract</title> <bold>Background: </bold>Multiple myeloma (MM) has traditionally been diagnosed on the basis of the CRAB criteria (hyperCalcemia, Renal insufficiency, Anemia, and osteolytic Bone lesions), which are used only after permanent end-organ damage has occurred. In 2014, the diagnostic criteria were revised by the International Myeloma Working Group (IMWG) to enable earlier diagnosis, before irreversible organ damage occurs: SLiM criteria (clonal bone marrow plasma cells ≥60%, serum free light chain ratio ≥100, and &gt;1 focal lesion on magnetic resonance imaging) were added to define criteria for myeloma-defining events (MDE; CRAB+SLiM). The aim of this study was to investigate the diagnostic impact of SLiM criteria in real-world clinical practice and explore their relationship with immunoglobulin subgroups. <bold>Methods:</bold> A retrospective review of 257 MM patients diagnosed at Seoul National University Hospital between January 2016 and June 2020 was conducted. The number and percentage of patients meeting MDE criteria were evaluated, and the frequency of each criteria was analyzed by immunoglobulin subgroups. <bold>Results:</bold> Among the 257 patients, 96.9% met CRAB criteria, while 3.1% met only SLiM criteria. 76.7% met SLiM criteria, with subgroups having different proportions of patients meeting each criterion. The light chain (LC) subgroup tended to have the highest number of MDE criteria met. <bold>Conclusion:</bold> The analysis of MDE criteria revealed that the IMWG criteria revised in 2014 led to a slight increase in MM diagnoses (3.2%), from 249 to 257 patients. The addition of SLiM criteria was slightly more helpful in diagnosing MM than traditional CRAB criteria. In subgroup analysis, the LC subgroup tends to meet more CRAB and SLiM criteria than other subgroups, suggesting an association with advanced stage diseases. An increased serum free light chain ratio may indicate underlying plasma cell proliferative disorders.

Clinical Outcome of Extramedullary Multiple Myeloma in the Era of Novel Agents: Insights From a Multicenter Study

2025-06-23
Dong Liang , Yurong Yan , Qiaoli Wang +7 more | Hematological Oncology
This study aimed to discuss the clinical outcomes of extramedullary multiple myeloma in the era of novel agents, based on the largest dataset regarding extramedullary multiple myeloma in China. This … This study aimed to discuss the clinical outcomes of extramedullary multiple myeloma in the era of novel agents, based on the largest dataset regarding extramedullary multiple myeloma in China. This study included 597 patients without extramedullary disease (EMD) (non-EMD), 324 with extramedullary bone-related disease (EMB) and 138 with de novo extramedullary extraosseous disease (EME). There were no significant differences in overall survival (OS, p = 0.638) or progression-free survival (PFS, p = 0.195) between non-EMD and EMB patients. However, de novo EME patients exhibited significantly worse OS (p < 0.01) and PFS (p < 0.01) compared to both EMB and non-EMD groups. Among non-EMD and EMB patients, those with ≥ 2 high-risk cytogenetic abnormalities (HRA) experienced extremely poor prognoses, categorizing them as ultra-high-risk multiple myeloma. Similarly, de novo EME patients with ≥ 1 HRA demonstrated very poor outcomes and should also be considered ultra-high risk. Notably, single transplantation was shown to mitigate the adverse prognosis of de novo EME patients. Furthermore, the daratumumab bortezomib lenalidomide dexamethasone (DVRD) quadruplet regimen showed potential as effective frontline therapies for de novo EME patients, offering hope for improved treatment outcomes in this challenging subgroup. These findings suggest that de novo EME represents an extremely poor prognosis and should be treated as a distinct entity within the multiple myeloma population. Furthermore, the results indicate that EMB may need to be excluded from the current EMD definition to better delineate these subgroups and guide therapeutic strategies.

Leptomeningeal Involvement in Relapsed Multiple Myeloma With Thoracic Spine and Orbital Metastases: A Case Report

2025-06-23
Dania Abuhalima , Maha Akkawi , Razan Odeh | Cureus

Altered dynamics of T cell subsets in peripheral blood impacts disease progression in newly diagnosed multiple myeloma

2025-06-23
Mohini Vig , Lalit Kumar , Shweta Dubey +1 more | Biochemistry and Biophysics Reports

Single-Cell Sequencing Reveals Thalidomide-Induced Teratogenicity in Zebrafish via Endoplasmic Reticulum Stress and Dysregulated Angiogenic Signaling

2025-06-23
Zhao Jingjing , Tao Song | Journal of Craniofacial Surgery
Thalidomide (TD) can lead to zebrafish having various malformations, including pectoral fin bud deformities, ear malformations. It induces the degradation of protein substrates, such as ∆Np63α, TAp63α, and SALL4, thereby … Thalidomide (TD) can lead to zebrafish having various malformations, including pectoral fin bud deformities, ear malformations. It induces the degradation of protein substrates, such as ∆Np63α, TAp63α, and SALL4, thereby exerting teratogenic effects on zebrafish. The degradation of these protein substrates triggers downstream changes, including oxidative stress and anti-angiogenesis. However, the genes involved in oxidative stress and anti-angiogenesis remain unclear. Here, the authors used single-cell RNA sequencing (scRNA-seq) to assess how TD exposure affects the transcriptome diversity of 69,115 cells at 1, 2, and 5 days post-fertilization (dpf). Wide-type group data sets were obtained from the NCBI SRA database (Accession: SRP221273). The authors' analysis identified 43 cell populations, with significant alterations in the gene expression profiles of 16 of these populations. Expression of the heat shock protein family gene hsp was upregulated in several cellular subpopulations (heart, vessel, pectoral fin bud, etc.), and the heat shock protein family genes were associated with stress. A protein-protein interaction (PPI) network was constructed using STRING and Cyto-scape software, and hub genes associated with TD-induced zebrafish teratogenicity were identified through the CytoHubba plugin. These genes play crucial roles in cellular stress responses, particularly the significance of heat shock proteins (HSPs) in regulating cellular stress and protecting cell survival. Functional analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed enrichment in pathways associated with endoplasmic reticulum protein processing and spliceosome. The genes her15.1, her4.3, and her4.4 exert an anti-angiogenic effect by modulating the Notch signaling pathway. The results obtained from RT-qPCR agreed with the sequencing data. This study constructed a single-cell transcriptomic atlas of zebrafish embryos under TD exposure through transcriptomic analysis at the single-cell level, supplementing the investigation of oxidative stress and anti-angiogenesis-related genes in TD-induced zebrafish malformations. Our research on TD, which causes cranio-maxillofacial-related malformations like ear and eye defects across multiple species, holds great significance for cranio-maxillofacial surgery.

Cereblon upregulation overcomes thalidomide resistance in multiple myeloma through mitochondrial functional reprogramming

2025-06-23
Jubert Marquez , Nammi Park , Jae Hyeog Choi +7 more | BMB Reports

Telitacicept

2025-06-21
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Treatment Patterns, Goals, and Decision-Making Criteria for Second- and Third-Line Therapies for Multiple Myeloma in Germany

2025-06-21
T. Steinmetz , Franziska Ertel , Beate Brinkmann +3 more | Advances in Therapy
To document the decision-making criteria physicians use when selecting regimens for second- and third-line therapy for patients with relapsed and/or refractory multiple myeloma (RRMM) in Germany. Experienced multiple myeloma (MM) … To document the decision-making criteria physicians use when selecting regimens for second- and third-line therapy for patients with relapsed and/or refractory multiple myeloma (RRMM) in Germany. Experienced multiple myeloma (MM) physicians extracted data from medical records from 30 June to 8 September 2023 for patients who initiated approved second- and third-line therapy for MM in 2021. Regimens, most important treatment goal, and key reasons for prescribing were reported in addition to patient characteristics. All data were summarised descriptively. MM physicians (33 hospital-based, 16 office-based) with a median of 17 years of treatment experience extracted data from a total of 268 patient records (second-line, n = 170; third-line, n = 98). In second- and third-line, 17 and 16 different regimens were documented, respectively. The most utilized second-line regimens were: daratumumab (D), lenalidomide (R) and dexamethasone (d) (DRd 16.5%); carfilzomib (K), d and D (KdD 12.4%); Kd (11.2%); KRd; (10.0%); D, bortezomib (V) and d (DVd 9.4%); and V with cyclophosphamide (C) and d (VCd 7.1%). The main reasons for selecting the regimen were treatment effectiveness, patient characteristics/status, and relapse. Inducing deepest possible response and prolonging survival or symptom control were the most important treatment goals for triplet regimens. The main third-line regimens were: pomalidomide (P) and d (Pd 15.3%); DRd (13.3%); Rd (13.3%); elotuzumab (E) and Pd (EPd 12.2%); isatuximab (Isa) and Kd or KdD (10.2%); and ixazomib (I) and Rd (IRd 8.2%). The main reasons for selecting the regimens varied for third-line regimens but primarily focused on treatment effectiveness, patient characteristics/status, and prior therapy response or mechanism of action. The most important treatment goal was prolongation of survival. The results suggest that in the absence of a single standard of care for RRMM, prescribers made patient-centred choices of regimens with efficacy as the main goal of therapy.

Pemigatinib

2025-06-21
| Reactions Weekly

Multiple drug

2025-06-21
| Reactions Weekly

Bortezomib/Cyclophosphamide/Dexamethasone

2025-06-21
| Reactions Weekly

Cutaneous Extramedullary Plasmacytoma after Bone Fracture

2025-06-21
Madeline Frizzell , Katie McBee | New England Journal of Medicine

Multiple Myeloma Presenting With Sudden Paraplegia

2025-06-20
Hugo Veiga , M. Almeida , P. Duarte +2 more | Cureus

Spinal intradural lesion as manifestation of multiple myeloma: Illustrative case and systematic review of literature

2025-06-20
Kiana Y. Prather , Beste Gülsuna , Kishore Balasubramanian +3 more | Surgical Neurology International
Background: Multiple myeloma (MM) typically affects the bone marrow. When it spreads to the central nervous system, it usually presents as intracranial metastasis or extradural spinal lesions. Intradural spinal cord … Background: Multiple myeloma (MM) typically affects the bone marrow. When it spreads to the central nervous system, it usually presents as intracranial metastasis or extradural spinal lesions. Intradural spinal cord metastases are exceedingly rare. Case Description: A 53-year-old male with immunoglobulin A kappa MM presented with a contrast-enhancing lesion at the T3-4 level, consisting of an intradural lesion and an extradural lesion extending through the foramen. The lesion’s characteristics suggested a schwannoma, but MM involvement was suspected given the patient’s history. Surgical resection and spinal stabilization were performed, and pathological examination confirmed a plasma cell neoplasm. A systematic review of the literature identified 10 cases of intradural spinal lesions associated with MM or solitary plasmacytoma. Most lesions were intradural extramedullary, located primarily in the thoracic spine. Management often included surgery, chemotherapy, and radiotherapy, but the prognosis remained poor, especially with leptomeningeal spread. Conclusion: This case highlights the diagnostic and therapeutic challenges of intradural spinal MM involvement. While surgery can provide symptomatic relief and confirm the diagnosis, the risk of leptomeningeal dissemination requires close monitoring. A multidisciplinary approach is essential for managing these rare and complex cases, and further studies are needed to refine treatment strategies and improve patient outcomes.

Revolutions at the frontline of multiple myeloma treatment: lessons and challenges to finding a cure

2025-06-20
Jeries Kort , Andrew Rivera , Sindhuja Senigarapu +1 more | Frontiers in Oncology
Multiple myeloma (MM) is a cancer of bone marrow plasma cells. A noteworthy ensemble of therapies has been introduced over the past quarter century that exert antimyeloma activities through diverse … Multiple myeloma (MM) is a cancer of bone marrow plasma cells. A noteworthy ensemble of therapies has been introduced over the past quarter century that exert antimyeloma activities through diverse mechanisms and achieve durable disease control in many patients. The discovery that proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) target specific plasma cell features that reflect disease biology and exert antimyeloma activity led to transformative changes in treatment algorithms. Recently, advances in immunotherapy have emerged and represent a promising option with the potential to capture immunologic memory and yield more durable responses in MM patients. Idecabtagene vicleucel and ciltacabtagene autoleucel are chimeric antigen receptor (CAR) T-cell immunotherapies that attach to the extracellular domain of the B-cell maturation antigen (BCMA) and have demonstrated significant response rates in heavily-treated patients. These agents are FDA-approved for relapsed and/or refractory (RR)MM patients previously treated with PIs, IMiDs, and CD38-directed monoclonal antibodies. Most patients who receive CAR T-cell therapy relapse after prolonged or brief remission, and a more thorough understanding of the resistance mechanisms following CAR T-cell infusion is needed. Bispecific antibodies (BsAbs) are engineered to simultaneously bind to both cancer and immune cells and trigger a direct tumor-specific cytotoxic response. BsAbs and CAR T-cells are major histocompatibility complex (MHC)-independent approaches to treat MM and do not require T-cell receptor (TCR) specificity. Agents that target BCMA and G protein-coupled receptor class C group 5 member D (GPRC5D) demonstrate impressive clinical responses, while early-phase trials targeting FcRH5 are promising. Here, we provide a comprehensive overview of their individual efficacy, adverse effects, and limitations that impact broader application.

Reduced splenic uptake of [68Ga]Ga-Pentixafor following first-line chemotherapy is associated with poor prognosis in patients with newly diagnosed multiple myeloma

2025-06-20
Qingqing Pan , Zhenying Chen , Silu Liu +6 more | EJNMMI Research
We aim to investigate the prognostic value of [68Ga]Ga-Pentixafor PET/CT in multiple myeloma (MM) patients. This is a retrospective analysis of a prospective cohort study. Twenty-five patients with treatment-naïve, newly … We aim to investigate the prognostic value of [68Ga]Ga-Pentixafor PET/CT in multiple myeloma (MM) patients. This is a retrospective analysis of a prospective cohort study. Twenty-five patients with treatment-naïve, newly diagnosed MM were included. All participants underwent [68Ga]Ga-Pentixafor PET/CT scans at baseline and after first-line chemotherapy. The endpoints included the time to progression (TTP) and the time to next treatment (TTNT). The correlation between PET/CT characteristics and survival was then analyzed. Patients with a decline in SUVmax of bone marrow of less than 40% from baseline demonstrated significantly shorter TTP and TTNT (estimated median TTP, 27.5 months [95% CI, 16.7-38.2] vs. not reached, P = 0.047; estimated median TTNT, 31.8 months [95% CI, 20.8-42.8] vs. not reached, P = 0.012). Patients with visually reduced splenic uptake in the follow-up [68Ga]Ga-Pentixafor PET/CT from baseline exhibited significantly shorter TTP and TTNT (estimated median TTP, 24.4 months [95% CI, 7.9-24.4] vs. not reached, P = 0.018; estimated median TTNT, 31.9 months [95% CI, 18.5-31.9] vs. not reached, P = 0.043). A 20% reduction in splenic SUVmax was identified as a predictive indicator for shorter TTP and TTNT (estimated median TTP, 24.4 months [95% CI, 14.5-24.4] vs. not reached, P = 0.025; estimated mean TTNT, 31.9 months [95% CI, 18.5-31.9] vs. not reached, P = 0.048). Patients with splenic SUVmax < 5.0 at follow-up also exhibited significantly shorter TTP and TTNT. However, the splenic SUVmax at baseline PET/CT was not predictive of TTP or TTNT (P > 0.05). Reduced splenic uptake of [68Ga]Ga-Pentixafor following first-line chemotherapy was predictive for poor prognosis in patients with newly diagnosed MM, while baseline splenic uptake is not associated with prognosis. ClinicalTrials. NCT03436342 Registered 25 October 2017, https://register. gov/prs/app/action/SelectProtocol?sid=S0007IL2&selectaction=Edit&uid=U0001JRW&ts=6&cx=-3sdpwu . NCT04504526 Registered 6 August 2020, https://clinicaltrials.gov/study/NCT04504526?cond=NCT04504526&rank=1 .

Case Report: Unveiling the role of genetic abnormalities in myelomatous pleural effusion: a case of IgG lambda-type multiple myeloma

2025-06-20
Shuangyan Chen , Lijuan Yan , Yinjuan Mo +2 more | Frontiers in Oncology
A 73-year-old male with a history of multiple myeloma presented with progressively worsening left shoulder pain that was unresponsive to conservative management. Following comprehensive diagnostic procedures, including imaging and genetic … A 73-year-old male with a history of multiple myeloma presented with progressively worsening left shoulder pain that was unresponsive to conservative management. Following comprehensive diagnostic procedures, including imaging and genetic testing, he was diagnosed with IgG lambda-type multiple myeloma, complicated by the development of myelomatous pleural effusion (MPE). The patient’s treatment regimen consisted of the PDD chemotherapy combination, including Bortezomib, Doxorubicin, and Dexamethasone, alongside adjunctive therapies aimed at controlling the pleural effusion. Post-treatment evaluation revealed resolution of the pleural effusion, with no detectable myeloma cells in the pleural fluid. This case illustrates the clinical utility of combining chemotherapy with supportive treatments for the effective management of MPE in multiple myeloma patients. The patient’s positive response highlights the significance of tailoring therapeutic approaches to the individual, emphasizing the role of personalized care in improving clinical outcomes in similar complex cases of MPE.

A rare aberrant alpha-2 band in an elderly anemic patient

2025-06-20
Vidyavathi Devi GajapathiRaju , Deepika Gujjarlapudi , Wanve Balasaheb Ajinath +1 more | Journal of Hematology and Allied Sciences
Serum protein electrophoresis (SPE) is ordered to diagnose cases of multiple myelomas by detecting monoclonal bands of protein. In this case, an elderly female anemic patient was found to have … Serum protein electrophoresis (SPE) is ordered to diagnose cases of multiple myelomas by detecting monoclonal bands of protein. In this case, an elderly female anemic patient was found to have a monoclonal band in the alpha-2 region. As this is an uncommon presentation and there was no derangement in the kappa-lambda ratio and no accompanying band on Serum immunofixation electrophoresis (IFE) a further look was taken into the history and other investigations that were ordered for this patient to determine the cause. A repeat sample was collected 3 days later which revealed attenuation of this band (Institutional ethics committee approval number – Post BH&amp;R 67/02.2025-07).

Optical genome mapping reveals complex cytogenetic abnormalities in multiple myeloma

2025-06-19
Jorge Palacios , Mónica Bernal , José R. Vilchez +7 more | Haematologica
Not available. Not available.

Daratumumab and isatuximab differentially affect <scp>CD38</scp> detection on plasma cells in myeloma: Anti‐<scp>CD38</scp> nanobody (clone <scp>JK36</scp>) and <scp>CD319</scp> combination improve flow cytometric identification of plasma cells after targeted therapies

2025-06-19
Afshin Shameli , Tori Catey , Valerie Woodings +3 more | British Journal of Haematology
Summary Inclusion of daratumumab and isatuximab in therapeutic regimens has improved outcomes in multiple myeloma patients. As these agents block CD38 detection, they may result in difficulties in flow cytometric … Summary Inclusion of daratumumab and isatuximab in therapeutic regimens has improved outcomes in multiple myeloma patients. As these agents block CD38 detection, they may result in difficulties in flow cytometric (FC) identification of plasma cells (PCs). In addition, the heterogeneity of myeloma immunophenotype and the introduction of novel therapeutic agents necessitate FC panels with robust gating markers. To this end, we validated an 11‐colour PC panel that in addition to commonly used gating markers (CD45, CD38, CD138) includes CD319 and anti‐CD38 single variable heavy domain nanobody (clone JK36). A Boolean "or" function was applied to gate PCs using a combination of the above markers. Patterns and intensity of antigen expression were compared in samples from patients receiving daratumumab or isatuximab therapy, or neither. Daratumumab resulted in loss of detectable CD38 expression (clone HB‐7) on abnormal PCs, and JK36 overcame daratumumab blockage in almost all these cases. Interestingly, isatuximab showed an opposite pattern, with complete loss of CD38 detection by JK36, while retaining dim positivity by HB‐7. This combination of markers proved highly effective in identifying abnormal PCs after CD38‐directed therapies, supporting a need for redundancy of gating markers in FC panels.

The Prognostic Significance of Sarcopenia Assessed by the Psoas Muscle Index in Multiple Myeloma Patients

2025-06-19
Ebru Kılıç Güneş , Koray Kaya Kılıç , Meltem Aylı | Indian Journal of Hematology and Blood Transfusion

Relevance of Prescribing Serum Immunofixation Electrophoresis in the Diagnosis of Monoclonal Gammopathies

2025-06-19
Hajar Fadili , Hamza Ouazzani , Ikrame Rhaleb +5 more | Cureus

Precision pre-HSCT conditioning by targeting cMPL

2025-06-19
Markus G. Manz | Blood

A natural head start to MRD negativity in multiple myeloma

2025-06-19
Erin W. Meermeier | Blood

Sequencing Matters: Immunotherapy in Multiple Myeloma

2025-06-19
| Default Digital Object Group

Guidelines for the testing and reporting of cytogenetic results for risk stratification of multiple myeloma: a report of the Cancer Genomics Consortium Plasma Cell Neoplasm Working Group

2025-06-18
Xinyan Lu , Erica Andersen , Rahul Banerjee +7 more | Blood Cancer Journal
Fluorescence in situ hybridization (FISH) remains the gold-standard clinical assay to detect genetic abnormalities in multiple myeloma (MM). However, FISH panel design, use of conventional chromosome banding analysis and reporting … Fluorescence in situ hybridization (FISH) remains the gold-standard clinical assay to detect genetic abnormalities in multiple myeloma (MM). However, FISH panel design, use of conventional chromosome banding analysis and reporting practices have been reported to vary among laboratories. Therefore, standardization in FISH testing and reporting practices is needed to improve report clarity and avoid misinterpretation. The recommendations in this paper represent a consensus of our Cancer Genomics Consortium Plasma Cell Neoplasm Working Group, comprising a joint panel of cytogenetic laboratory directors and clinical investigators with expertise in the diagnosis, risk stratification, and treatment of multiple myeloma. Prior to developing these consensus recommendations, we performed a full literature review and conducted a survey of 102 oncologists to assess current variations and challenges in MM cytogenetic/FISH testing and reporting. Our guidelines establish best practices for the optimization of FISH panel selection, and recommendations for standardized reporting of cytogenetic results to align with the 2025 International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) Updated Risk Stratification.

Efficacy and safety of thalidomide for oncology-related uses approved in Brazil: An overview of systematic reviews

2025-06-18
Paula Lana de Miranda Drummond , Cristine de Araújo Silva , J. Souza +5 more | Journal of Oncology Pharmacy Practice
Objective: The aim of this overview was to summarize evidence of the efficacy and safety of thalidomide in the treatment of oncology-related diseases approved in Brazil, and to assess the … Objective: The aim of this overview was to summarize evidence of the efficacy and safety of thalidomide in the treatment of oncology-related diseases approved in Brazil, and to assess the quality of the available data. Methods: A literature search was performed in the Cochrane Library, PubMed, Embase, Lilacs, and SciELO databases. Studies must contain evidence of efficacy and/or safety of thalidomide use for multiple myeloma – MM, graft-versus-host disease – GVHD, and myelodysplastic syndrome - MDS. The extracted information were: authors, year, literature search, studies design, target population, studies sample, comparisons and thalidomide dose, funding, outcomes, results / pooled effect, heterogeneity, conclusion. Results: This overview showed the available data about efficacy and safety of thalidomide used in the treatment of oncology-related approved indications in Brazil. It also classified the methodological quality of studies according to Amstar 2 tool. Despite of the poor quality of the articles found, they supported the efficacy of thalidomide in MM treatment. The main adverse events reported were peripheral neuropathy, infections, hematological, thromboembolic, and gastrointestinal events. Evidence supported that the more drugs combined, the greater the efficacy, but there is also a greater risk of toxicity. For the indications of GVHD and MDS no systematic reviews and/or meta-analyses that met the inclusion criteria were found. Conclusions: The overview confirmed thalidomide's efficacy on MM. It is important to monitor and manage the occurrence of thalidomide-related adverse events. Strict control over its use must always be reinforced to maintain its safe use.

Primary extramedullary plasmacytoma: a rare case presentation

2025-06-18
Pedro Lucas de Mendonça Barbosa , Clara de Diego , Javier Anaya +1 more | Anais Brasileiros de Dermatologia

Pharmacoeconomic evaluation of carfilzomib <i>versus</i> ixazomib for the treatment of relapsed and refractory multiple myeloma

2025-06-18
Lin Wang , Fen Chen , Yuanyuan Ma +4 more | Future Science OA
This study assesses the cost-effectiveness of carfilzomib plus lenalidomide and dexamethasone (KRd) versus ixazomib plus lenalidomide and dexamethasone for relapsed and refractory multiple myeloma (RRMM) in China. A survival model … This study assesses the cost-effectiveness of carfilzomib plus lenalidomide and dexamethasone (KRd) versus ixazomib plus lenalidomide and dexamethasone for relapsed and refractory multiple myeloma (RRMM) in China. A survival model was used to analyze health states and costs over a lifetime, with a 4-week cycle. Treatment effects on progression-free survival (PFS) and overall survival (OS) were modeled using hazard ratios (HRs) derived from the network meta-analysis (NMA). Health state utility values and disutility values for adverse events were obtained from published literature. Direct medical costs included drug costs, disease management costs, and costs associated with adverse event management. Costs and utilities were discounted by 5% annually. Both one-way and probabilistic sensitivity analyses were conducted. The carfilzomib combination was found to be cost-effective, saving $127,513.22 per additional quality-adjusted life year (QALY) gained compared to the ixazomib combination. Sensitivity analysis showed that ixazomib's price, progression state utility, and carfilzomib's price significantly affected the results. At a $40,023.27 willingness-to-pay (WTP) threshold, the carfilzomib combination has a 100% probability of being cost-effective. The study shows that, based on evidence from indirect comparisons, KRd is a cost-effective treatment option for RRMM patients in China.

Subcutaneous administration of isatuximab in patients with multiple myeloma by an on-body delivery system: results of a nurse survey

2025-06-18
Nuria Sánchez Avello , Paula Calvo Pajares , Pául Cordero +2 more | Frontiers in Oncology
Introduction Subcutaneous (SC) administration of the anti-CD38 antibody isatuximab (Isa) by an on-body delivery system (OBDS), plus pomalidomide-dexamethasone, has demonstrated safety and efficacy comparable to intravenous (IV) administration, with no … Introduction Subcutaneous (SC) administration of the anti-CD38 antibody isatuximab (Isa) by an on-body delivery system (OBDS), plus pomalidomide-dexamethasone, has demonstrated safety and efficacy comparable to intravenous (IV) administration, with no infusion reactions and excellent local tolerability in multiple myeloma (MM) patients. We report here results of a nurse survey designed to evaluate convenience of treatment with SC Isa, via OBDS, for healthcare providers and MM patients. Methods A newly developed, expert-vetted questionnaire was used to survey nurses with experience in SC administration to MM patients enrolled in clinical trials. Results on extent of agreement with pre-vetted statements were expressed as percentages of respondents. Free-text answers were analyzed for each respondent and grouped by topic. Results All surveyed nurses (N=12) agreed that OBDS administration improved efficiency and was easy to learn and administer with a low level of physical burden, leading to a preference for OBDS over IV Isa administration and facilitating a positive treatment experience for the patients. Compared with IV dosing, the OBDS improved patient comfort and could reduce time spent in the clinic. As agreed by most nurses, main advantages for patients included no needle visibility, short treatment duration, and a generally well-tolerated and painless SC injection. Conclusions Our findings show a high level of confidence among nurses in SC Isa administration via OBDS, due to the ease of use, tolerability, and time savings achieved with hands-free OBDS injections. Our findings suggest applicability of the OBDS for convenient SC Isa administration to MM patients in routine clinical practice.

A phase 2 study of Daratumumab with Thalidomide and dexamethasone in relapsed and/or Refractory Myeloma (RRMM)

2025-06-17
Chandramouli Nagarajan , Wei‐Ying Jen , Melissa Ooi +7 more | Blood Cancer Journal
NCT03153036. NCT03153036.

Can we identify individuals at risk to develop multiple myeloma? A machine learning‐based predictive model

2025-06-16
Moshe Mittelman , Ariel Israel , Howard S. Oster +6 more | British Journal of Haematology
Multiple myeloma evolves unnoticed over years, and when diagnosed, organ damage is common. Electronic health records (EHR) can help in developing predictive models identifying 'healthy' people at risk. MM patients … Multiple myeloma evolves unnoticed over years, and when diagnosed, organ damage is common. Electronic health records (EHR) can help in developing predictive models identifying 'healthy' people at risk. MM patients from Clalit Health Services (2002-2019) were matched with healthy controls. Stage I: EHR from 5 years prior to MM diagnosis were reviewed and >200 parameters were compared (patients vs. controls). Stage II: Establishing xgboost model predicting 5 year risk for MM, with validation. Stage III: A simplified logistic regression model for community, requiring 20 variables (Age; Hb; RBC; MCV; RDW; WBC; neutrophils; lymphocytes; monocytes; basophils; glucose; creatinine; total protein; albumin; calcium; uric acid; bilirubin; HDL-C; LDL-C; triglycerides). EHR from the pre-MM period of 4256 patients were compared to controls. Future MM patients had higher ESR, lower Hb, ANC, neutrophil/lymphocyte ratio, higher globulins and ferritin, more immune deficiencies, MDS and FMF. They took fewer tranquilizers, anti-diabetics and statins. Using labs from future MM (n = 19 129) and controls (n = 382 580, 20:1), a predictive model was developed (ROC AUC = 0.836). The simple LR model provided individual risk prediction for MM within 5 years (AUC = 0.72). Two models with machine learning predict the risk of myeloma in 'healthy' individuals within 5 years. The models can be used in practice.

Early-Onset High-Risk Multiple Myeloma: A Case Report from Bogotá (Colombia)

2025-06-16
Santiago Gómez Jordan , Santiago Escalante Pérez , Olga Paola Omaña | Salud Uninorte
El mieloma múltiple (MM) se caracteriza por el crecimiento excesivo de células plasmáticas, y afecta típicamente a individuos de mayor edad. Sin embargo, es excepcionalmente raro en adultos jóvenes, representando … El mieloma múltiple (MM) se caracteriza por el crecimiento excesivo de células plasmáticas, y afecta típicamente a individuos de mayor edad. Sin embargo, es excepcionalmente raro en adultos jóvenes, representando solo el 2,2 % de los casos en aquellos menores de 40 años. Una paciente mujer de 35 años con anemia de reciente diagnóstico que requirió transfusión se presentó con sangrado gingival y equimosis. Presentó anemia severa sin trombocitopenia, creatinina elevada y fracturas vertebrales (T10 y T11). La electroforesis reveló un pico monoclonal, el aspirado de médula ósea mostró una infiltración del 80 % por células plasmáticas lambda, y los estudios citogenéticos identificaron una t(4;14). El tratamiento incluyó terapia de inducción con 4 ciclos de bortezomib, lenalidomida, dexametasona (protocolo VRd) y consolidación con daratumumab-VRd, con plan de trasplante autólogo. Este caso destaca los desafíos y la importancia de diagnosticar el MM en adultos jóvenes. Las anormalidades citogenéticas, como la t(4;14), desempeñan un papel crucial, influyendo en el pronóstico y orientando las decisiones terapéuticas. Por lo tanto, comprender la interacción entre la edad temprana y la citogenética es vital en esta enfermedad.

Risk factors associated with mortality in patients with multiple myeloma

2025-06-16
Sergey G. Bolotin , A. V. Solovieva , Alexander Pristupa +1 more | Meditsinskiy sovet = Medical Council
Introduction. According to foreign authors some laboratory markers and comorbidity are independent predictors of death in multiple myeloma (MM). Aim. To identify risk factors associated with mortality in patients with … Introduction. According to foreign authors some laboratory markers and comorbidity are independent predictors of death in multiple myeloma (MM). Aim. To identify risk factors associated with mortality in patients with MM. Materials and methods. A retrospective analysis of 149 medical records of patients of the hematology department of the Regional Clinical Hospital with a diagnosis of multiple myeloma was carried out. The patients are divided into two groups depending on the clinical outcome: the 1 st group includes 90 living patients; the 2 nd group includes 59 patients whose death occurred in the hospital during the period from 2010–2019. Of the 149 patients: 87 women (58%), 62 men (42%). The mean age of the patients was 65.7 ± 8.7 years. The clinical, demographic and laboratory indicators of the groups were analyzed, and comorbidity was assessed using the Charlson index. Results. In the 1 st group of patients, there were 35 men (39%) and 55 women (61%). The ratio of men to women is 1:1.6. The mean age in this group is 67 ± 9.1 years. The 2 nd group is represented by 27 (46%) men, 32 (54%) women. The mean age was 63.7 ± 7.6 years. In the 1 st group of patients, all patients were diagnosed with stage III disease, with most patients in the subgroup associated with renal dysfunction (p = 0.002). Anaemia and markers of renal damage were more frequent in the group of deceased patients (p &lt; 0.001, p = 0.002, respectively). Comparative analysis of laboratory indicators showed that in the haemogram of the group of living patients, the level of erythrocytes, haemoglobin, platelets was significantly higher than in group 2 (p &lt; 0.05); the level of creatinine, urea was 1.8 times higher in the group of deceased patients than in the group of living patients (p &lt; 0.05). Chronic heart failure was statistically significantly more common in the deceased group than in the living group (22% vs. 7.8%, p = 0.025). The incidence of pneumonia was higher in the deceased group than in the 1 st group (p &lt; 0.001). Conclusion. Risk factors associated with mortality include manifestations of MM such as anaemia, thrombocytopenia, renal dysfunction and late diagnosis at stage III of the disease. Chronic heart failure, as a complication of cardiovascular disease, is a risk factor for adverse outcome. Comorbidity, infectious diseases (pneumonia) are associated with a worse prognosis, probably due to poorer tolerability of standard therapy.

Multiple myeloma

2025-06-14
Ashesh Ranchod | Radiopaedia.org

Advances in multiple myeloma blood-based monitoring and its clinical applications

2025-06-14
Anastasia Tzasta , Charissa Wijnands , Kim Baalman +3 more | Critical Reviews in Clinical Laboratory Sciences
Multiple myeloma (MM) is currently still considered incurable. The recent introduction of novel therapeutic options has significantly improved patient outcomes, with more patients achieving positive responses. While this is positive, … Multiple myeloma (MM) is currently still considered incurable. The recent introduction of novel therapeutic options has significantly improved patient outcomes, with more patients achieving positive responses. While this is positive, these deep remissions pose a challenge in disease monitoring and early detection of relapse, causing uncertainty of disease status among patients and healthcare providers. Current blood-based M-protein diagnostics are not sensitive enough to detect minimal residual disease (MRD) and the gold standard method for MRD-evaluation relies on invasive bone marrow biopsies. Several blood-based methods are currently being investigated as potential minimally invasive alternatives. Of these, mass spectrometry-based methods targeting clonotypic peptides (MS-MRD) offers up to 1,000 times higher sensitivity than traditional electrophoresis and immuno-based techniques for M-protein quantification in blood. In addition, methods initially developed for detecting clonal plasma cells in bone marrow are now being explored in peripheral blood, where circulating myeloma cells and cell-free DNA provide independent prognostic value. Next to its value as biomarker of disease activity, the unique M-protein can also play a direct role in causing tissue damage through a variety of different mechanisms. Currently, no diagnostic tests are available that assess M-proteins pathogenicity. Mass spectrometry-based techniques are suited to characterize the structural properties, stability, and post-translational modifications of M-proteins. This may improve our understanding regarding the pathogenic potential of M-proteins and pave the way for novel diagnostics and early identification of those patients who are at risk. This review highlights the emerging landscape of blood-based diagnostics in MM and their potential for clinically relevant applications.

Simultaneous separation and quantification of pomalidomide chiral impurity using reversed phase–ultra-high-performance liquid chromatography method

2025-06-13
Gyan Vardhan , Vikas Kumar , Anuj Prakash +5 more | Indian Journal of Physiology and Pharmacology
Objectives: This study develops and validates an RP-UHPLC method for simultaneously separating and quantifying the R(+) and S(-) enantiomers of Pomalidomide, a 2 nd generation immunomodulatory drug, in API using … Objectives: This study develops and validates an RP-UHPLC method for simultaneously separating and quantifying the R(+) and S(-) enantiomers of Pomalidomide, a 2 nd generation immunomodulatory drug, in API using an orthogonal experimental design approach. Materials &amp; Methods: Chromatographic conditions involve an Ultisil Cellu-JR column, a flow rate of 0.8 mL/min, an injection volume of 10 µL, and a 15-minute run time at ambient temperature. Peak purity analysis, facilitated by OpenLab LC software, ensures the reliability of separation by evaluating UV spectra similarity within the 170–700 nm range. Results: The method successfully achieves Pomalidomide enantiomeric separation in the isocratic mode, with retention times of 7.507 minutes for the enantiomer-I and 8.943 minutes for the enantiomer-II. Conclusion: The study underscores the need for diverse chromatographic methods to overcome the challenges posed by Pomalidomide’s chiral nature. The results provide valuable insights into optimizing chromatographic techniques for the analysis of chiral impurities, contributing to the advancement of pharmaceutical quality control and research.

De-escalated Teclistamab Dosing in Relapsed/Refractory Multiple Myeloma: Czech Myeloma Group Real- World Evidence Analysis

2025-06-13
Martin Stork , Jakub Radocha , Jana Mihályová +7 more | Research Square (Research Square)
<title>Abstract</title> Teclistamab, a BCMA×CD3 bispecific antibody, demonstrates high efficacy in relapsed/refractory multiple myeloma (RRMM). However, optimal dosing strategies outside clinical trials remain undefined. Thus, we performed a retrospective, multicentre analysis … <title>Abstract</title> Teclistamab, a BCMA×CD3 bispecific antibody, demonstrates high efficacy in relapsed/refractory multiple myeloma (RRMM). However, optimal dosing strategies outside clinical trials remain undefined. Thus, we performed a retrospective, multicentre analysis of 73 RRMM patients treated with teclistamab monotherapy at Czech Myeloma Group centres between 2023 and 2025. The study compared efficacy and safety between patients receiving standard weekly dosing and those with reduced-frequency dosing. The whole cohort had a median age of 67 years; 68.5% were penta-refractory. Dosing was de-escalated in 24.7% of patients, typically within one month of treatment initiation. Median progression-free survival (PFS) was 9.41 months and was comparable between weekly and non-weekly groups (9.1 vs. 11.3 months; p = 0.141), despite a significantly lower relative dose intensity in the latter (60.5% vs. 87.0%; p &lt; 0.001). Infection rates and severe adverse events were similar between groups. A lower incidence of neutropenia was observed with less frequent dosing, but this did not translate into reduced infection burden. In conclusion, in real-world practice, early de-escalation of teclistamab dosing appears to maintain clinical efficacy. These findings support ongoing efforts to individualize treatment schedules with the aim of balancing effectiveness, tolerability, and patient-specific factors in BCMA-targeted therapy.

Multiple myeloma in Nigeria: are we diagnosing it enough?

2025-06-13
Ogochukwu Izuegbuna | Academia oncology.
Multiple myeloma (MM) is a malignant plasma cell dyscrasia characterized by the expansion of monoclonal plasma cells. It is diagnosed based on certain criteria with the acronym CRAB (hyperCalcemia, Renal … Multiple myeloma (MM) is a malignant plasma cell dyscrasia characterized by the expansion of monoclonal plasma cells. It is diagnosed based on certain criteria with the acronym CRAB (hyperCalcemia, Renal insufficiency, Anaemia, and lytic Bone lesion), along with increased bone marrow plasma cells. MM is one of the most common haematological malignancies in the Western world. It is also more common in African Americans than in Caucasians. However, in most of Africa, especially West Africa, and particularly Nigeria—the most populous Black nation on Earth—a very low incidence rate and prevalence have been reported. It is believed that this may not actually be representative of the factual situation and may instead be a result of a low index of suspicion and the prohibitive cost of diagnostic tests. However, more profoundly, the reason for the low index of suspicion may be the anomalous presentation of some cases of MM, which may be befuddling even to the experts; hence, diagnosis can be missed. This review intends to look at some of the recondite points, as well as other germane issues, pertaining to MM diagnosis in Nigeria. It recommends running a new and comprehensive screening research project to obtain better data on the incidence of monoclonal gammopathy in Nigeria.

DNA damage repair (DDR) related prognostic risk model in multiple myeloma based on single-cell and bulk sequencing

2025-06-13
Hongxiu Liu , Zhihua Li , Yihua Wang +3 more | DNA repair

Abstract P2-06-01: CBP/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in TNBC

2025-06-13
Xueying Yuan , Xiaoxin Hao , Hilda Chan +7 more | Clinical Cancer Research
Abstract Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding … Abstract Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated cytotoxic T cells. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC. Citation Format: Xueying Yuan, Xiaoxin Hao, Hilda Chan, Na Zhao, Diego Pedroza, Fengshuo Liu, Le Kang, Alex Smith, Sebastian Calderon, Nadia Lieu, Michael Soth, Philip Jones, Xiang Zhang, Jeffrey Rosen. CBP/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in TNBC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-06-01.

Pyrites

2025-06-13
Bun Sereyleak , Has Sothearak , Sam Lyvannak +7 more | Journal of Pediatric Hematology/Oncology