Carfilzomib, lenalidomide, and dexamethasone (KRd) versus elotuzumab and KRd in transplant-eligible patients with newly diagnosed multiple myeloma: Post-induction response and MRD results from an open-label randomized phase 3 study.

person Stefan Knop Wuerzburg University Medical Center, Wuerzburg, Germany info_outline Stefan Knop, Thomas Stuebig, Miriam Kull, Richard Greil, Normann Steiner, Florian Bassermann, Axel Nogai, Marie von Lilienfeld-Toal, Snjezana Janjetovic, Karolin Trautmann-Grill, Max Bittrich, Monika Martha Engelhardt, Anette Hoferer, Sebastian Theurich, Mascha Binder, Niklas Zojer, Heinz A. Duerk, Monika Brueggemann, Swantje Held, Hermann Einsele

Authors person Stefan Knop Wuerzburg University Medical Center, Wuerzburg, Germany info_outline Stefan Knop, Thomas Stuebig, Miriam Kull, Richard Greil, Normann Steiner, Florian Bassermann, Axel Nogai, Marie von Lilienfeld-Toal, Snjezana Janjetovic, Karolin Trautmann-Grill, Max Bittrich, Monika Martha Engelhardt, Anette Hoferer, Sebastian Theurich, Mascha Binder, Niklas Zojer, Heinz A. Duerk, Monika Brueggemann, Swantje Held, Hermann Einsele Organizations Wuerzburg University Medical Center, Wuerzburg, Germany, Schleswig-Holstein University Hospital, Kiel Campus, Kiel, Germany, Ulm University Hospital, Dept. of Internal Medicine 3, Ulm, Germany, Hospital Salzburg Paracelus University, Salzburg, Austria, Medical University Innsbruck, Dept. of Internal Medicine V, Innsbruck, Austria, University Hospital rechts der Isar, Munich, Germany, Charité– Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Medizinische Klinik m.S. Hämatologie, Onkologie Und Tumorimmunologie, Berlin, Germany, Jena University Hospital, Dept. of Hematology and Oncology, Jena, Germany, Helios Klinikum Berlin-Buch, Dept. of Hematology and Oncology, Berlin, Germany, Department of Hematology and Oncology, Dresden University Hospital Carl Gustav Carus, Dresden, Germany, University Hospital Medical Centre, Freiburg, Germany, Robert Bosch Hospital, Dept. of Hematology and Oncology, Stuttgart, Germany, Department of internal Medicine III, Hematology and Oncology, Gene Center, Cancer- and Immunometabolism Research Group, Ludwig-Maximilians University Munich, Mu, Munich, Germany, Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Germany, Wilhelminen Cancer Research Institute, First Department of Medicine, Center for Oncology, Hematology, and Palliative Care, Clinic Ottakring, Vienna, Austria, St Barbara Hospital Hamm, Dept. of Hematology and Oncology, Hamm, Germany, Medical Department II, University Schleswig Holstein in the City Hospital Kiel, Kiel, Germany, Clinassess Inc., Leverkusen, Germany, Würzburg University Medical Center, Würzburg, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company AMGEN, Celgene, BMS Background: In medically fit patients with newly diagnosed (ND) multiple myeloma (MM), triplet or quadruplet induction regimens, high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) remain a standard of care. Carfilzomib (K), lenalidomide (R) and dexamethasone (d, KRd) induction/consolidation has proven exceptionally effective. Elotuzumab (E), an anti-SLAMF-7 monoclonal antibody bears favorable tolerability in relapsed/refractory MM while its role in NDMM remains unclear. Methods: Transplant-eligible (TE) NDMM patients (pts) up to 70 years (yrs) were randomized 1:1 to receive six cycles (C) of KRd or E-KRd, (chemomobilisation for ASCT after C3), single (tandem, if <CR/high risk NDMM) HDT/ASCT, followed by four consolidation C (KRd/E-KRd) and R or ER maintenance. Induction (IND, 28-day C) consisted of K on D1/2, 8/9 and 15/16 (20 mg/m² IV on D 1/2 in C1 and 36 mg/m² thereafter), R (25 mg PO, D1-21) and d (36/40 mg D 1, 8, 15, 22). E was given on D 1, 8, 15, and 22 (C1/C2) and on D 1 and 15 (C3-6; 10 mg/kg IV). After IND, pts underwent restaging when bone marrow was analyzed for minimal residual disease (MRD) by next-generation flow cytometry. The first co-primary endpoint of the study was the rate of pts who were in ≥ VGPR and were MRD negative. The study is registered as NCT03948035. Results: 579 pts (574 of whom received treatment) were randomized between 08/2018 and 10/2021 at 52 sites and included in the intent-to-treat analysis. Median age was 60 (range, 31-71) yrs.15.4% had ISS stage III disease. 108/459 evaluable pts (23.5%) had high-risk cytogenetics (del[17p]; t[4;14]; t[14;16]; ≥ 3 1q21 copies). 525/574 pts (91.5%) completed 6 IND cycles. MRD negativity and ≥ VGPR was achieved in 145 of E-KRd (49.8%) and 102 (35.4%) of KRd patients, respectively (p=.0005). 212 (72.9%) of E-KRd versus 177 (62.5%) of KRd patients experienced treatment-emergent AEs (TEAEs) of ≥ grade 3. Febrile neutropenia occurred in 26 (6.4%) E-KRd versus 14 (4.9%) KRd pts. Grade 3/4 thrombocytopenia was seen in 36 (12.4%) E-KRd and 30 (10.6%) KRd pts. Pneumonia occurred in 24 E-KRd (8.2%) and 18 KRd (6.4%) pts. Grade 3/4 cardiac events occurred in 16 E-KRd (5.5%) and of grades 3 to 5 in 16 (5.7%) of KRd pts. 12 E-KRd (4%) and 9 KRd (3.2%) pts had COVID-19 infections with one grade 5 event each (0.3% and 0.4%, respectively). Three pts on E-KRd (1.0%) versus 7 on KRd (2.5%) died on induction due to infections (N=3), MM progression (2), AML (1), a cardiac event (N=1), other (N=3). Conclusions: In this study, the addition of elotuzumab to KRd significantly improved the rate of early, deep (≥ VGPR) MRD-negative remission in TE NDMM. E-KRd pts had slightly more TEAEs. Events were mainly hematotoxicity. To the best of our knowledge, this is the first study to show a benefit for the addition of elotuzumab to a front-line regimen. Clinical trial information: NCT03948035.