Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma
University of Turin1, Mayo Clinic2, University of Tübingen3, Emory University4, Semmelweis University5, Ankara University6, Charles University in Prague7, University of Mainz8, Cornell University9, Johnson & Johnson Pharmaceutical Research and Development10, Janssen Pharmaceutica11, Monash University12, Erasmus University Rotterdam13
24 Aug 2016-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 375, Iss: 8, pp 754-766
TL;DR: 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 borteonib and DexamethAsone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia.
Abstract: BackgroundDaratumumab, 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. MethodsIn 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. ResultsA 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 ...
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National and Kapodistrian University of Athens1, Karolinska University Hospital2, University of Navarra3, University of Calgary4, University College London5, University of Texas at Austin6, Poznan University of Medical Sciences7, New Generation University College8, Hadassah Medical Center9, Harvard University10, University Hospital Heidelberg11, German Cancer Research Center12, Princess Margaret Cancer Centre13, Genmab14, Janssen Pharmaceutica15
TL;DR: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma.
Abstract: BackgroundDaratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1–2 study involving patients with relapsed or refractory multiple myeloma. MethodsIn this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. ResultsAt a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan–Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in t...
1,100 citations
TL;DR: Investigation of the mechanisms of resistance is essential to further maximize the utility of this class of drugs in the era of personalized medicine.
Abstract: The ubiquitin proteasome pathway was discovered in the 1980s to be a central component of the cellular protein-degradation machinery with essential functions in homeostasis, which include preventing the accumulation of misfolded or deleterious proteins. Cancer cells produce proteins that promote both cell survival and proliferation, and/or inhibit mechanisms of cell death. This notion set the stage for preclinical testing of proteasome inhibitors as a means to shift this fine equilibrium towards cell death. Since the late 1990s, clinical trials have been conducted for a variety of malignancies, leading to regulatory approvals of proteasome inhibitors to treat multiple myeloma and mantle-cell lymphoma. First-generation and second-generation proteasome inhibitors can elicit deep initial responses in patients with myeloma, for whom these drugs have dramatically improved outcomes, but relapses are frequent and acquired resistance to treatment eventually emerges. In addition, promising preclinical data obtained with proteasome inhibitors in models of solid tumours have not been confirmed in the clinic, indicating the importance of primary resistance. Investigation of the mechanisms of resistance is, therefore, essential to further maximize the utility of this class of drugs in the era of personalized medicine. Herein, we discuss the advances and challenges resulting from the introduction of proteasome inhibitors into the clinic.
725 citations
National and Kapodistrian University of Athens1, University of Bologna2, University of Chicago3, University of Würzburg4, Université catholique de Louvain5, Champalimaud Foundation6, Semmelweis University7, Masaryk University8, University Hospitals Birmingham NHS Foundation Trust9, University Hospitals of Leicester NHS Trust10, University of Silesia in Katowice11, Johnson & Johnson12, University of Navarra13
TL;DR: Among patients with newly diagnosed multiple myeloma who were ineligible for stem‐cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without darumumab.
Abstract: Background The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. Methods In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival. Results At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death,...
675 citations
TL;DR: These Clinical Practice Guidelines are endorsed by the Japanese Society of Medical Oncology (JSMO) incidence and epidemiology Multiple myeloma accounts for 1% ofall cancers and ∼10% of all haematological malignancies.
658 citations
Cites background from "Daratumumab, Bortezomib, and Dexame..."
...weekly cycle 1 and 2, every other week cycles 3þ; repeated every 28 days Lenalidomide/dexamethasone/ixazomib (IRd) [35] Lenalidomide 25 mg orally days 1–21; dexamethasone orally 40 mg days 1, 8, 15, 22; ixazomib 4 mg orally days 1, 8, 15; repeated every 28 days Bortezomib/dexamethasone/daratumumab (DVd) [38] Bortezomib 1....
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...Daratumumab has also shown significant efficacy at earlier stages of the disease, first relapse and beyond in combination with bortezomib-dexamethasone [II, A] [38] or lenalidomide-dexamethasone [II, A] [39] in two randomised phase III clinical trials....
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Erasmus University Medical Center1, Universitaire Ziekenhuizen Leuven2, University of Paris3, Curie Institute4, Institut Français5, VU University Amsterdam6, La Roche College7, Université libre de Bruxelles8, Cliniques Universitaires Saint-Luc9, Albert Schweitzer Hospital10, French Institute of Health and Medical Research11, Princeton University12, Janssen Pharmaceutica13
TL;DR: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety and CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma.
569 citations
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Harvard University1, University of Arkansas at Little Rock2, Cedars-Sinai Medical Center3, Northwestern University4, Catholic Medical Center5, Mayo Clinic6, Cleveland Clinic7, University of South Florida8, University of Texas MD Anderson Cancer Center9, University of North Carolina at Chapel Hill10, Takeda Pharmaceutical Company11
TL;DR: Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy.
Abstract: Background Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. Methods 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. Results 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 wa...
2,586 citations
Cedars-Sinai Medical Center1, University of Salamanca2, University of Arkansas for Medical Sciences3, Mayo Clinic4, Alexandra Hospital5, Lund University6, Karolinska Institutet7, Ankara University8, Washington University in St. Louis9, Cross Cancer Institute10, University of Turin11, Royal Prince Alfred Hospital12, University of Texas MD Anderson Cancer Center13, University of Pavia14, Harvard University15, University of Bologna16, The Royal Marsden NHS Foundation Trust17
TL;DR: The European Group for Blood and Bone Marrow Transplant/International Bone Marrows Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system to adequately assess clinical outcomes in myeloma.
Abstract: New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.
2,411 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: In this article, the authors proposed a more flexible method to construct discrete sequential boundaries based on the choice of a function, a*(t), which characterizes the rate at which the error level ac is spent.
Abstract: SUMMARY Pocock (1977), O'Brien & Fleming (1979) and Slud & Wei (1982) have proposed different methods to construct discrete sequential boundaries for clinical trials. These methods require that the total number of decision times be specified in advance. In the present paper, we propose a more flexible way to construct discrete sequential boundaries. The method is based on the choice of a function, a*(t), which characterizes the rate at which the error level ac is spent. The boundary at a decision time is determined by a*(t), and by past and current decision times, but does not depend on the future decision times or the total number of decision times.
1,913 citations
TL;DR: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma, and no maximum tolerated dose was identified in part 1.
Abstract: BACKGROUND 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. METHODS 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. RESULTS 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 thrombocytope nia. 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. CONCLUSIONS 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.)
882 citations