IMWG consensus on risk stratification in multiple myeloma
National University of Singapore1, Mayo Clinic2, Queen Mary University of London3, Heidelberg University4, Columbia University5, Harvard University6, University of Turin7, Spanish National Research Council8, Erasmus University Medical Center9, University of Bologna10, University of Arkansas for Medical Sciences11, Cedars-Sinai Medical Center12
TL;DR: The International Myeloma Working Group proposes well-defined and easily applicable risk categories based on current available information and suggests the use of this set of prognostic factors as gold standards in all clinical trials and form the basis of subsequent development of more complex prognostic system or better prognostic Factors.
Abstract: Multiple myeloma is characterized by underlying clinical and biological heterogeneity, which translates to variable response to treatment and outcome. With the recent increase in treatment armamentarium and the projected further increase in approved therapeutic agents in the coming years, the issue of having some mechanism to dissect this heterogeneity and rationally apply treatment is coming to the fore. A number of robustly validated prognostic markers have been identified and the use of these markers in stratifying patients into different risk groups has been proposed. In this consensus statement, the International Myeloma Working Group propose well-defined and easily applicable risk categories based on current available information and suggests the use of this set of prognostic factors as gold standards in all clinical trials and form the basis of subsequent development of more complex prognostic system or better prognostic factors. At the same time, these risk categories serve as a framework to rationalize the use of therapies.
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Mayo Clinic1, University of Navarra2, Harvard University3, Cedars-Sinai Medical Center4, Memorial Sloan Kettering Cancer Center5, Emory University6, National and Kapodistrian University of Athens7, Mount Sinai Hospital8, University of Turin9, University of Texas MD Anderson Cancer Center10, Heidelberg University11, Alfred Hospital12, University Health System13, Carolinas Healthcare System14, University of Bologna15, Aalborg University16, Dalhousie University17, Erasmus University Rotterdam18, Roswell Park Cancer Institute19, Columbia University20, University of Toulouse21
TL;DR: Several aspects of disease response assessment are clarified, along with endpoints for clinical trials, and future directions for disease response assessments are highlighted, to allow uniform reporting within and outside clinical trials.
Abstract: Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.
1,681 citations
TL;DR: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited.
Abstract: BackgroundIxazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. MethodsIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide–dexamethasone (ixazomib group) or placebo plus lenalidomide–dexamethasone (placebo group). The primary end point was progression-free survival. ResultsProgression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of...
821 citations
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...Disease refractory to any prior immunomodulatory drug therapy†† 41/193 (21) 50/204 (25) 91/397 (23)...
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...Standardized MedDRA query 131 (36) 18 (5) 0 82 (23) 6 (2) 0...
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Emory University1, University of Pennsylvania2, Carolinas Healthcare System3, Northwestern University4, Icahn School of Medicine at Mount Sinai5, University of Calgary6, Cross Cancer Institute7, City of Hope National Medical Center8, Cedars-Sinai Medical Center9, University of Salamanca10, New York University11, University of Texas MD Anderson Cancer Center12, University of British Columbia13, Oregon Health & Science University14, Sarah Cannon Research Institute15, Rutgers University16, Hôpital Maisonneuve-Rosemont17, University of Wisconsin-Madison18, University of Chicago19, Dalhousie University20, Harvard University21, Genmab22, Janssen Pharmaceutica23, University of North Carolina at Chapel Hill24
TL;DR: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients.
680 citations
Erasmus University Rotterdam1, Emory University2, Carolinas Healthcare System3, Hackensack University Medical Center4, Harvard University5, Mayo Clinic6, Heidelberg University7, University of Navarra8, University of Barcelona9, University Hospital Heidelberg10, University of Turin11, University of Texas MD Anderson Cancer Center12
TL;DR: Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-based survival and progression- free survival int( 4;14), del( 17/17 p), and t(14;16), and gain(1q).
620 citations
University of Turin1, University of Salamanca2, Mayo Clinic3, Roswell Park Cancer Institute4, Emory University5, VU University Medical Center6, National and Kapodistrian University of Athens7, Cross Cancer Institute8, University of Ostrava9, Harvard University10, Cedars-Sinai Medical Center11, University of Navarra12, Erasmus University Rotterdam13
TL;DR: The frailty score predicts mortality and the risk of toxicity in elderly myeloma patients and is proposed for the measurement of frailty in designing future clinical trials.
533 citations
References
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TL;DR: Initial staging can be quantitatively related to followup using tumor cell mass changes calculated from changes in M‐component production, and should lead to improved study design and analysis in large clinical trials of therapy for multiple myeloma.
Abstract: The presenting clinical features of 71 patients with multiple myeloma were correlated with myeloma cell mass (myeloma cells X 10(12)/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 sould 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.
2,902 citations
TL;DR: The new International Staging System (ISS) is simple, based on easy to use variables (Sbeta2M and serum albumin), and recommended for early adoption and widespread use.
Abstract: 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
2,373 citations
TL;DR: Improved outcome of patients with myeloma in recent years is demonstrated, both in the relapsed setting as well as at diagnosis, both from time of diagnosis and the time of relapse.
2,077 citations
Spanish National Research Council1, National and Kapodistrian University of Athens2, Rabin Medical Center3, University of Münster4, Charles University in Prague5, Sapienza University of Rome6, University of Turin7, Medical University of Lublin8, Peking University9, Harvard University10, Millennium Pharmaceuticals11, Johnson & Johnson12
TL;DR: Bortezomib plus melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy was superior to melphAlan-predisonsone alone.
Abstract: 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%). Conclusions 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.)
1,728 citations
Broad Institute1, Mayo Clinic2, Harvard University3, Multiple Myeloma Research Foundation4, Translational Genomics Research Institute5, Howard Hughes Medical Institute6, Weizmann Institute of Science7, Ohio State University8, Catholic Medical Center9, University of Michigan10, City of Hope National Medical Center11, Emory University12, Rutgers University13, Washington University in St. Louis14, University of Chicago15, Massachusetts Institute of Technology16
TL;DR: The massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs indicates that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.
Abstract: 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.
1,323 citations