Elotuzumab in Combination with Lenalidomide, Bortezomib, Dexamethasone and Autologous Transplantation for Newly-Diagnosed Multiple Myeloma: Results from the Randomized Phase III GMMG-HD6 Trial
Authors: Goldschmidt Hartmut , Mai Elias K , Bertsch Uta , Besemer Britta , Haenel Mathias , Miah Kaya , Fenk Roland , Schlenzka Jana , Munder Markus , Dürig Jan , Blau Igor Wolfgang , Huhn Stefanie , Hose Dirk , Jauch Anna , Kunz Christina , Neubauer Andreas , Scheid Christof , Schroers Roland , Metzler Ivana v. , Schieferdecker Aneta , Thomalla Joerg , Reimer Peter , Mahlberg Rolf , Graeven Ullrich , Kremers Stephan , Martens Uwe M. , Kunz Christian , Hensel Manfred , Seidel-Glaetzer Andrea , Weisel Katja , Raab Marc-Steffen , Salwender Hans 
Published: November 2021

Abstract
Background: Treatment regimens including a proteasome inhibitor, immunomodulating agent and a monoclonal antibody (moAb) play an emerging role in the treatment of newly-diagnosed multiple myeloma (NDMM). This multicenter phase III trial of the German-speaking Myeloma Multicenter Group (GMMG HD6) investigated the addition of the anti-SLAMF7 moAb elotuzumab to lenalidomide / bortezomib / dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible NDMM.
Patients and Methods: Patients were equally randomized into four treatment arms, stratified by International Staging System (ISS). Treatment consisted of four 21-day cycles of RVd (arms A1/A2) or elotuzumab-RVd (arms B1/B2) induction therapy, respectively. High-dose melphalan (HDM) and autologous blood stem cell transplantation (ASCT) were followed by two 21-day cycles of RVd or elotuzumab-RVd consolidation and lenalidomide or elotuzumab-lenalidomide maintenance for two years (arms A1/B1 vs. A2/B2). Primary objective of the trial was determination of the best of four treatment strategies regarding progression-free survival (PFS) from randomization. Secondary endpoints included overall survival (OS), response rates and safety.
Results: Between 06/2015 and 09/2017, 564 patients were included in the trial. The evaluable intention-to-treat (ITT) and safety population comprised 559 and 555 patients (A1: n=139/137; A2: n=141/138; B1: n=137/138; B2: n=142/142). Median age at randomization was 59 (range 27-70) years. Baseline characteristics were well balanced between the four treatment arms. Four cycles of induction therapy were completed by 517 patients (92.5% of ITT). At least one HDM/ASCT was applied in 495 (88.6%), of which 116 patients (20.8%) received tandem HDM/ASCT. Consolidation and maintenance therapy were initiated in 469 (83.9%) and 454 (81.2%) patients, respectively. Rates of very good partial response or better (≥VGPR) prior to start of consolidation therapy were 78.9%, 78.2%, 81.5% and 80.7% in arms A1, A2, B1 and B2, respectively (p=0.95). With a median follow-up time of 49.8 months, PFS was not significantly different between the four treatment arms (adjusted log-rank p value stratified by ISS, p=0.86; primary endpoint). OS was similar in all treatment arms (stratified log-rank p=0.43). 3-year PFS/OS rates are 68.8%/89.4%, 68.5%/89.1%, 66.2%/92.5% and 67.2%/89.7% in arm A1, A2, B1 and B2, respectively.
Multivariate analyses including age, sex, ISS stage, performance status, serum lactate dehydrogenase level, renal impairment at diagnosis, adverse cytogenetics (del17p, t[4;14] and t[14;16]) and treatment arms identified ISS stages II and III (hazard ratio [HR]=1.42/2.04, 95% confidence interval [95% CI]= 1.00-2.02/1.36-3.07, p=0.048/&lt;0.001) and adverse cytogenetics (HR=1.63, 95% CI: 1.19-2.25, p=0.003) as significant predictors for shortened PFS.
On induction, consolidation and maintenance treatment, at least one (serious) adverse event (grade ≥3 for all AE or ≥2 for infections and infestations, neuropathy, cardiac disorders and thromboembolic events, and any grade for serious AE) occurred in 95.6%, 91.3%, 92.8% and 89.4% of patients in arm A1, A2, B1 and B2, respectively (p=0.25). Most common system organ classes (SOCs) were "infections and infestations", "neurological disorders", "blood and lymphatic system disorders", and "investigations" with no significant differences between the four treatment arms (p=0.39/0.64/0.13/0.42). Overall AE/SAE during lenalidomide vs. elotuzumab-lenalidomide maintenance were comparable (A1/B1: 65.5% vs. A2/B2: 66.4%,p=0.86), though SOC "infections and infestations" was increased in the elotuzumab-lenalidomide arms (A1/B1: 42.9% vs. A2/B2: 51.4%, p=0.05).
Conclusions: This is the first phase III trial evaluating elotuzumab in patients with transplant-eligible NDMM. The addition of elotuzumab to RVd induction/consolidation therapy and lenalidomide maintenance did not result in improved PFS or OS. This is in line with previous reports from the ELOQUENT-1 and SWOG-1211 trials, investigating elotuzumab in non-transplant-eligible and high-risk NDMM, while elotuzumab-based combination therapies are effective in relapsed MM (ELOQUENT-2/-3 trials). Further analyses to identify potential subgroups that benefit from elotuzumab-based treatment in our trial are ongoing.

Disclosures
Goldschmidt: Incyte: Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; GSK: Honoraria; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Mai: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Glaxo Smith Kline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Celgene / BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding. Besemer: GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Fenk: Janssen: Honoraria; Amgen: Honoraria; GSK: Honoraria; Takeda: Honoraria; BMS/Celgene: Honoraria. Munder: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Consultancy; GSK: Consultancy; Incyte: Research Funding. Dürig: Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Hose: LamKap Bio: Consultancy, Current Employment; BMS: Research Funding. Scheid: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Metzler: GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; BMS: Consultancy; Takeda: Consultancy. Schieferdecker: Sebia: Consultancy. Mahlberg: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; BMS: Honoraria; GSK: Honoraria. Graeven: Amgen: Honoraria; Sanofi Aventis: Honoraria; Celgene: Honoraria, Research Funding; Johnson & Johnson: Honoraria; Astra Zeneca: Honoraria; MSD: Consultancy; Boehringer Ingelheim: Honoraria; BMS: Honoraria; Fujifilm: Honoraria; Roche: Research Funding; Gilead: Research Funding; Ipsen Bioscience: Research Funding; MacroGenics: Research Funding. Martens: Celgene: Consultancy; Sanofi-Aventis: Consultancy. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raab: Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salwender: Takeda: Honoraria; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Oncopeptides: Honoraria; Chugai: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Honoraria.

OffLabel Disclosure:
Lenalidomide and ELotuzumab in first line therapy prior to autologous stem cell transplantation, Elotuzumab in maintenance after autologous transplantation.