Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma
05 Apr 2017-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 376, Iss: 14, pp 1311-1320
TL;DR: Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression‐free survival than RVD Therapy alone, but overall survival did not differ significantly between the two approaches.
Abstract: BackgroundHigh-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. MethodsWe randomly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD (350 patients) or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD (350 patients). Patients in both groups received maintenance therapy with lenalidomide for 1 year. The primary end point was progression-free survival. ResultsMedian progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazar...
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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
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
TL;DR: Multiple myeloma accounts for approximately 10% of hematologic malignancies in the United States and is the second most common cancer in women.
Abstract: Disease overview Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE) namely CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) features felt related to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L), or >1 focal lesion on magnetic resonance imaging (MRI). Risk stratification The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma. Risk-adapted initial therapy In transplant eligible patients, induction therapy consists of bortezomib, lenalidomide, dexamethasone (VRd) given for approximately 3-4 cycles followed by autologous stem cell transplantation (ASCT). In high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd. Selected standard risk patients can get additional cycles of induction, and delay transplant until first relapse. Patients not candidates for transplant are typically treated with VRd for approximately 8-12 cycles followed by lenalidomide; alternatively these patients can be treated with daratumumab, lenalidomide, dexamethasone (DRd). Maintenance therapy After ASCT, standard risk patients need lenalidomide maintenance, while bortezomib-based maintenance is needed for patients with high-risk myeloma. Management of refractory disease Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse.
444 citations
Cites methods from "Lenalidomide, Bortezomib, and Dexam..."
...The data to support their use from recent randomized trials using new active agents for multiple myeloma are provided in Table 7.(38,39,88,89) In order to initiate therapy, patients must meet criteria for multiple myeloma as outlined in Table 1....
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...A trial by the Intergroupe Francophone du Myelome (IFM) compared early vs delayed ASCT in patients treated with VRd followed by lenalidomide maintenance.(39) Patients were randomized to receive either VRd (three cycles) followed by ASCT and then VRd consolidation (two cycles) vs VRd × eight cycles with ASCT reserved for...
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TL;DR: A meta-analysis demonstrates a significant OS benefit and confirms the PFS benefit with lenalidomide maintenance after ASCT in patients with NDMM when compared with placebo or observation.
Abstract: PurposeLenalidomide maintenance therapy after autologous stem-cell transplantation (ASCT) demonstrated prolonged progression-free survival (PFS) versus placebo or observation in several randomized controlled trials (RCTs) of patients with newly diagnosed multiple myeloma (NDMM). All studies had PFS as the primary end point, and none were powered for overall survival (OS) as a primary end point. Thus, a meta-analysis was conducted to better understand the impact of lenalidomide maintenance in this setting.Patients and MethodsThe meta-analysis was conducted using primary-source patient-level data and documentation from three RCTs (Cancer and Leukemia Group B 100104, Gruppo Italiano Malattie Ematologiche dell'Adulto RV-MM-PI-209, and Intergroupe Francophone du Myelome 2005-02) that met the following prespecified inclusion criteria: an RCT in patients with NDMM receiving ASCT followed by lenalidomide maintenance versus placebo or observation with patient-level data available and achieved database lock for pri...
419 citations
Additional excerpts
...Mean, months (range)§ 30 (0-108) 13 (0-51) 25 (0-61) 25 (0-55) 39 (27-55) 20 (0-49) 35 (2-71) 29 (0-75) 28 (0-108) 22 (0-86)...
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...0) Adverse-risk cytogenetics, t(4;14) or del17pk¶ Yes — — 41 (13....
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Emory University1, Harvard University2, Huntsman Cancer Institute3, University of North Carolina at Chapel Hill4, Wake Forest University5, Icahn School of Medicine at Mount Sinai6, Oregon Health & Science University7, University of Alabama at Birmingham8, University of Texas Southwestern Medical Center9, City of Hope National Medical Center10, University of California, San Francisco11, Ohio State University12, University of Nebraska Medical Center13, University of California, San Diego14, University of Chicago15, Washington University in St. Louis16, University of Texas MD Anderson Cancer Center17, University of South Florida18, University of Washington19, Janssen Pharmaceutica20
TL;DR: Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns.
359 citations
References
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TL;DR: The response rate among the patients who received high-dose therapy was 81 percent, whereas it was 57 percent in the group treated with conventional chemotherapy (P<0.001).
Abstract: Background The median survival of patients with myeloma after conventional chemotherapy is three years or less. Promising results have been reported with high-dose therapy supported by autologous bone marrow transplantation. We conducted a randomized study comparing conventional chemotherapy and high-dose therapy. Methods Two hundred previously untreated patients under the age of 65 years who had myeloma were randomly assigned at the time of diagnosis to receive either conventional chemotherapy or high-dose therapy and autologous bone marrow transplantation. Results The response rate among the patients who received high-dose therapy was 81 percent (including complete responses in 22 percent and very good partial responses in 16 percent), whereas it was 57 percent (complete responses in 5 percent and very good partial responses in 9 percent) in the group treated with conventional chemotherapy (P<0.001). The probability of event-free survival for five years was 28 percent in the high-dose group and 10 perce...
2,650 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: It is shown that values of median follow-up may differ substantially depending on the method used, and standard analytical methods for survival data, such as the log-rank test 121, the generalized Wilcoxon test, or the proportional hazards model 141, estimate average effects for the observed response times and test those effects for significance.
2,030 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
Mayo Clinic1, University of Navarra2, Harvard University3, Cedars-Sinai Medical Center4, Memorial Sloan Kettering Cancer Center5, Emory University6, National and Kapodistrian University of Athens7, University of Turin8, Mount Sinai Hospital9, 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