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Clinical Trial
. 2022 Sep 1;8(9):1278-1286.
doi: 10.1001/jamaoncol.2022.2424.

Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study

Benjamin A Derman  1 , Ankit Kansagra  2 , Jeffrey Zonder  3 , Andrew T Stefka  1 , David L Grinblatt  4 , Larry D Anderson Jr  2 , Sandeep Gurbuxani  1 , Sunil Narula  1 , Shayan Rayani  1 , Ajay Major  1 , Andrew Kin  3 , Ken Jiang  1 , Theodore Karrison  1 , Jagoda Jasielec  1 , Andrzej J Jakubowiak  1
Affiliations
Clinical Trial

Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study

Benjamin A Derman et al. JAMA Oncol. .

Abstract

Importance: Treatment of newly diagnosed multiple myeloma (NDMM) with a quadruplet regimen consisting of a monoclonal antibody, proteasome inhibitor, immunomodulatory imide, and corticosteroid has been associated with improved progression-free survival (PFS) compared with triplet regimens. The optimal quadruplet combination, and whether this obviates the need for frontline autologous stem cell transplant (ASCT), remains unknown. We evaluated elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without ASCT in NDMM.

Objective: To investigate the efficacy of Elo-KRd using a measurable residual disease (MRD)-adapted design in NDMM regardless of ASCT eligibility.

Design, setting, and participants: This multicenter, single-arm, phase 2 study enrolled patients between July 2017 and February 2021. Median follow-up was 29 months.

Interventions: Twelve to 24 cycles of Elo-KRd; consecutive MRD-negative results at 10-6 by next-generation sequencing (NGS) after cycles 8 (C8) and 12 determined the duration of Elo-KRd. This was followed by Elo-Rd (no carfilzomib) maintenance therapy until disease progression.

Main outcomes and measures: The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10-5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS). As an exploratory analysis, MRD was assessed using liquid chromatography mass spectrometry (MS) on peripheral blood samples.

Results: Forty-six patients were enrolled (median age 62 years, 11 [24%] aged >70 years). Overall, 32 (70%) were White, 6 (13%) were Black, 3 (6%) were more than 1 race, and 5 (11%) were of unknown race. Thirty-three (72%) were men and 13 (28%) were women. High-risk cytogenetic abnormalities were present in 22 (48%) patients. The rate of sCR and/or MRD-negativity after C8 was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy. Responses deepened over time, with the MRD-negativity (10-5) rate increasing to 70% and MS-negativity rate increasing to 65%; concordance between MRD by NGS and MS increased over time. The most common (>10%) grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively). There was 1 grade 5 myocardial infarction. The estimated 3-year PFS was 72% overall and 92% for patients with MRD-negativity (10-5) at C8.

Conclusions and relevance: An MRD-adapted design using elotuzumab and weekly KRd without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses.

Trial registration: ClinicalTrials.gov Identifier: NCT02969837.

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Conflict of interest statement

Conflict of Interest Disclosures: Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr Kansagra reported grants from University of Chicago/BMS funding to conduct the study and, During the conduct of the study; advisory board membership at AbbVie, BMS/Celgene, Cota Health, GSK, Alynlyam, and has been on the advisory board and is an employee at Janssen. He also is on the advisory board at Oncopeptide and Takeda outside the submitted work. Dr Zonder reported grants from BMS, personal fees from Takeda, grants from Janssen, and personal fees from Amgen during the conduct of the study; personal fees from Prothena, personal fees from Intellia, and personal fees from Caelum outside the submitted work; and Dr Zonder's spouse is a recently hired employee of BMS. Throughout the time that this study was actually being conducted, however, she was an employee of the Karmanos Cancer Institute. Dr Grinblatt reported grants from University of Chicago during the conduct of the study; personal fees from Celgene Scientific Advisory Committee, personal fees from Astellas Advisory Committe, personal fees from MorphoSys, and personal fees from AbbVie outside the submitted work. Dr Anderson reported grants from Multiple Myeloma Research Foundation during the conduct of the study; personal fees from BMS Consulting and Advisory Board activity, personal fees from Celgene Consulting and Advisory Board activity, personal fees from AbbVie Consulting and Advisory Board activity, personal fees from Oncopeptides Consulting and Advisory Board activity, personal fees from Beigene Consulting and Advisory Board activity, personal fees from Prothena Consulting and Advisory Board activity, personal fees from Karyopharm Consulting and Advisory Board activity, personal fees from GSK Consulting and Advisory Board activity, and personal fees from Amgen Consulting and Advisory Board activity outside the submitted work. Dr Gurbuxani reported personal fees from AbbVie Consulting outside the submitted work. Dr Karrison reported grants from National Cancer Institute during the conduct of the study. Dr Jasielec reported employment at Janssen outside the submitted work. Dr Jakubowiak reported personal fees from Amgen and personal fees from BMS during the conduct of the study; personal fees from AbbVie, GSK, Janssen, Karyopharm, and Sanofi-Aventis outside the submitted work; and also serving as a consultant and on advisory boards with honoraria for AbbVie, Amgen, BMS, GSK, Janssen, Karyopharm, and Sanofi-Aventis. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram for Enrolled Patients
ASCT indicates autologous stem cell transplant; MRD, measurable residual disease by next-generation sequencing.
Figure 2.
Figure 2.. Duration and Depth of Response to Therapy
Swimmer lane plot showing duration and depth of response to therapy, by number of cycles and follow-up. ASCT indicates autologous stem cell transplant; CR, complete response; MRD, measurable residual disease; MS, mass spectrometry; PD, progressive disease; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
Figure 3.
Figure 3.. Progression-Free Survival (PFS) and Overall Survival (OS), by Cytogenetic Risk, and by Measurable Residual Disease (MRD) Status
A, Overall PFS and OS by intent to treat (ITT) analysis; B, PFS stratified by cytogenetic risk. One patient had unknown cytogenetics. C, PFS; and D, OS stratified by MRD by next-generation sequencing (NGS) status at a sensitivity threshold of 10−5 after cycle 8. Patients who did not have a clone identification at baseline or who discontinued protocol therapy for any reason before cycle 8 were not included.
See this image and copyright information in PMC

Comment in

References

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