EHA Library - The official digital education library of European Hematology Association (EHA)

PHASE 3 DETERMINATION TRIAL IN NEWLY DIAGNOSED MULTIPLE MYELOMA: LENALIDOMIDE, BORTEZOMIB AND DEXAMETHASONE (RVD) ± AUTOLOGOUS STEM CELL TRANSPLANTATION AND LENALIDOMIDE MAINTENANCE TO PROGRESSION
Author(s): ,
Paul G. Richardson
Affiliations:
Department of Medical Oncology,Dana-Farber Cancer Institute, Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School,Boston,United States
,
Susanna J. Jacobus
Affiliations:
Department of Data Science,Dana-Farber Cancer Institute, Harvard Medical School,Boston,United States
,
Edie A. Weller
Affiliations:
Division of Hematology and Oncology,Boston Children’s Hospital,Boston,United States
,
Hani Hassoun
Affiliations:
Myeloma Service, Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,United States
,
Sagar Lonial
Affiliations:
Winship Cancer Institute of Emory University,Atlanta,United States
,
Noopur S. Raje
Affiliations:
Center for Multiple Myeloma,Massachusetts General Hospital, Harvard Medical School,Boston,United States
,
Eva Medvedova
Affiliations:
Knight Cancer Institute,Oregon Health & Science University,Portland,United States
,
Philip L. McCarthy
Affiliations:
Department of Medicine,Roswell Park Comprehensive Cancer Center,Buffalo, New York,United States
,
Edward N. Libby
Affiliations:
Division of Medical Oncology,University of Washington, and Fred Hutchinson Cancer Center,Seattle,United States
,
Peter M. Voorhees
Affiliations:
Department of Hematologic Oncology and Blood Disorders,Levine Cancer Institute, Atrium Health,Charlotte,United States
,
Robert Z. Orlowski
Affiliations:
Department of Lymphoma/Myeloma,The University of Texas MD Anderson Cancer Center,Houston,United States
,
Larry D. Anderson Jr
Affiliations:
Myeloma, Waldenstrom’s and Amyloidosis Program,Simmons Comprehensive Cancer Center, UT Southwestern Medical Center,Dallas,United States
,
David D. Hurd
Affiliations:
Section of Hematology and Oncology,Atrium Health Wake Forest Baptist Medical Center,Winston-Salem,United States
,
Marcelo C. Pasquini
Affiliations:
Center for International Blood and Marrow Transplant Research (CIBMTR), Division of Hematology/Oncology, Department of Medicine,Medical College of Wisconsin,Milwaukee,United States
,
Kelly Masone
Affiliations:
Department of Medical Oncology,Dana-Farber Cancer Institute, Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School,Boston,United States
,
Philippe Moreau
Affiliations:
Department of Hematology,University Hospital Hotel-Dieu,Nantes,France
,
Hervé Avet-Loiseau
Affiliations:
Unit for Genomics in Myeloma,Institut Universitaire du Cancer de Toulouse-Oncopole, University Hospital,Toulouse,France
,
Michel Attal
Affiliations:
Hématologie,Institut Universitaire du Cancer de Toulouse (IUCT) Oncopole,Toulouse,France
,
Nikhil C. Munshi
Affiliations:
Department of Medical Oncology,Dana-Farber Cancer Institute, Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School,Boston,United States;Boston VA Heathcare System,West Roxbury,United States
Kenneth C. Anderson
Affiliations:
Department of Medical Oncology,Dana-Farber Cancer Institute, Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School,Boston,United States
(Abstract release date: 06/12/22) EHA Library. RICHARDSON P. 06/12/22; 366214; LB2366
Dr. PAUL RICHARDSON
Dr. PAUL RICHARDSON
Contributions
Abstract
Presentation during EHA2022: Presentation during EHA2022: The Late-Breaking Oral Session will be held on Sunday, June 12, 2022 (09:45 - 11:15 CEST) and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: LB2366

Type: Late breaking oral

Session title: Late breaking abstract session

Background
The optimal use of induction therapy, autologous stem cell transplantation (ASCT) and maintenance for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) continues to evolve. In IFM 2009, in which patients received lenalidomide (R) maintenance for 1 year, there was a progression-free survival (PFS) benefit with RVd plus ASCT versus RVd alone (median 47.3 vs 35.0 months). However, no overall survival (OS) benefit was seen, with 8-year rates of 62% vs 60% after a median follow-up of 89.8 months, in the context of multiple effective options at relapse, including ASCT at 1st relapse in 77% of patients in the RVd-alone arm (Attal M et al, N Engl J Med 2017; Perrot A et al, ASH 2020).

Aims
We report primary data from our US DETERMINATION trial, in which patients received R maintenance until disease progression.

Methods
Patients aged 18–65 years with NDMM were randomized to receive 3 21-day cycles of RVd (oral R 25 mg, days 1–14, IV/subcutaneous bortezomib 1.3 mg/m2, days 1, 4, 8, and 11, and oral dexamethasone 20/10 mg [cycles 1-3/≥4], days 1, 2, 4, 5, 8, 9, 11, and 12), stem cell mobilization, and then: a further 5 cycles of RVd (RVd-alone arm), or IV melphalan 200 mg/m2 plus ASCT and a further 2 cycles of RVd (RVd+ASCT arm). In both arms, patients then received R 10/15 mg/day (months 1–3/4 onwards if tolerated) until progression or intolerance. The primary endpoint was PFS (90% power to detect a PFS hazard ratio [HR] of 1.43, RVd-alone vs RVd+ASCT, with α=0.05 on stratified two-sided log-rank test; full information was 329 events in 720 patients). The data cut-off was December 10, 2021.

Results
Among 357 and 365 patients randomized to RVd-alone and RVd+ASCT, respectively, median ages were 57 and 55 years, 13.7% and 12.9% had ISS stage III disease, and 19.8% and 19.4% of evaluable patients had high-risk cytogenetics [t(4;14), t(14;16), del17p]; 291 and 289 patients received R maintenance for a median duration of 36.4 and 41.5 months. After median follow-up of 76 months and 328 events, median PFS was 46.2 vs 67.5 months with RVd-alone vs RVd+ASCT (HR 1.53; 95% CI 1.23–1.91; p<0.0001). Overall best response rate (≥partial response) was 95.0% versus 97.5%, with 79.6% vs 82.7% ≥very good partial responses, and 42.0% vs 46.9% ≥complete responses. Preliminary analyses of minimal residual disease (MRD) at the start of maintenance in 108 and 90 patients showed MRD negativity (10-5) rates of 39.8% vs 54.4% (odds ratio 0.55). With 90 vs 88 patients having died, 5-year OS rates were 79.2% and 80.7%, respectively (HR 1.10; 95% CI 0.73–1.65). With RVd-alone and RVd+ASCT, 78.2% and 94.2% of patients had grade ≥3 related adverse events (60.5% vs 89.9% [p<0.0001] grade ≥3 hematologic events); 10.4% vs 10.7% had secondary malignancies (ALL 7 vs 3 patients; AML/MDS 0 vs 10 patients, p=0.002). Mean EORTC QLQ-C30 global health status was similar between arms throughout treatment except at RVd cycle 5 vs post-ASCT (compliance rate 83.1% vs 59.2%; mean change from baseline +3.0 vs –11.1, p<0.0001) and at RVd cycle 8 vs cycle 5 (compliance rate 79.9% vs 77.3%; mean change +1.2 vs +8.3, p=0.021). 79.9% vs 69.6% of patients who had discontinued study treatment have received subsequent non-protocol therapy, with 28.1% receiving ASCT as part of any subsequent therapy after RVd-alone.

Conclusion
RVd ± ASCT and R maintenance to progression resulted in the longest median PFS reported for each approach, and a highly significant 21.4-month gain in median PFS benefit using RVd + ASCT. No OS advantage has been observed to date.

Keyword(s): Myeloma, Autologous hematopoietic stem cell transplantation, Maintenance, Survival



© 2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2022 ASCO Annual Meeting. All rights reserved.
Presentation during EHA2022: Presentation during EHA2022: The Late-Breaking Oral Session will be held on Sunday, June 12, 2022 (09:45 - 11:15 CEST) and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: LB2366

Type: Late breaking oral

Session title: Late breaking abstract session

Background
The optimal use of induction therapy, autologous stem cell transplantation (ASCT) and maintenance for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) continues to evolve. In IFM 2009, in which patients received lenalidomide (R) maintenance for 1 year, there was a progression-free survival (PFS) benefit with RVd plus ASCT versus RVd alone (median 47.3 vs 35.0 months). However, no overall survival (OS) benefit was seen, with 8-year rates of 62% vs 60% after a median follow-up of 89.8 months, in the context of multiple effective options at relapse, including ASCT at 1st relapse in 77% of patients in the RVd-alone arm (Attal M et al, N Engl J Med 2017; Perrot A et al, ASH 2020).

Aims
We report primary data from our US DETERMINATION trial, in which patients received R maintenance until disease progression.

Methods
Patients aged 18–65 years with NDMM were randomized to receive 3 21-day cycles of RVd (oral R 25 mg, days 1–14, IV/subcutaneous bortezomib 1.3 mg/m2, days 1, 4, 8, and 11, and oral dexamethasone 20/10 mg [cycles 1-3/≥4], days 1, 2, 4, 5, 8, 9, 11, and 12), stem cell mobilization, and then: a further 5 cycles of RVd (RVd-alone arm), or IV melphalan 200 mg/m2 plus ASCT and a further 2 cycles of RVd (RVd+ASCT arm). In both arms, patients then received R 10/15 mg/day (months 1–3/4 onwards if tolerated) until progression or intolerance. The primary endpoint was PFS (90% power to detect a PFS hazard ratio [HR] of 1.43, RVd-alone vs RVd+ASCT, with α=0.05 on stratified two-sided log-rank test; full information was 329 events in 720 patients). The data cut-off was December 10, 2021.

Results
Among 357 and 365 patients randomized to RVd-alone and RVd+ASCT, respectively, median ages were 57 and 55 years, 13.7% and 12.9% had ISS stage III disease, and 19.8% and 19.4% of evaluable patients had high-risk cytogenetics [t(4;14), t(14;16), del17p]; 291 and 289 patients received R maintenance for a median duration of 36.4 and 41.5 months. After median follow-up of 76 months and 328 events, median PFS was 46.2 vs 67.5 months with RVd-alone vs RVd+ASCT (HR 1.53; 95% CI 1.23–1.91; p<0.0001). Overall best response rate (≥partial response) was 95.0% versus 97.5%, with 79.6% vs 82.7% ≥very good partial responses, and 42.0% vs 46.9% ≥complete responses. Preliminary analyses of minimal residual disease (MRD) at the start of maintenance in 108 and 90 patients showed MRD negativity (10-5) rates of 39.8% vs 54.4% (odds ratio 0.55). With 90 vs 88 patients having died, 5-year OS rates were 79.2% and 80.7%, respectively (HR 1.10; 95% CI 0.73–1.65). With RVd-alone and RVd+ASCT, 78.2% and 94.2% of patients had grade ≥3 related adverse events (60.5% vs 89.9% [p<0.0001] grade ≥3 hematologic events); 10.4% vs 10.7% had secondary malignancies (ALL 7 vs 3 patients; AML/MDS 0 vs 10 patients, p=0.002). Mean EORTC QLQ-C30 global health status was similar between arms throughout treatment except at RVd cycle 5 vs post-ASCT (compliance rate 83.1% vs 59.2%; mean change from baseline +3.0 vs –11.1, p<0.0001) and at RVd cycle 8 vs cycle 5 (compliance rate 79.9% vs 77.3%; mean change +1.2 vs +8.3, p=0.021). 79.9% vs 69.6% of patients who had discontinued study treatment have received subsequent non-protocol therapy, with 28.1% receiving ASCT as part of any subsequent therapy after RVd-alone.

Conclusion
RVd ± ASCT and R maintenance to progression resulted in the longest median PFS reported for each approach, and a highly significant 21.4-month gain in median PFS benefit using RVd + ASCT. No OS advantage has been observed to date.

Keyword(s): Myeloma, Autologous hematopoietic stem cell transplantation, Maintenance, Survival



© 2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2022 ASCO Annual Meeting. All rights reserved.

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies