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.
Authors: Knop Stefan , Stuebig Thomas , Kull Miriam , Greil Richard , Steiner Normann , Bassermann Florian , Nogai Axel , von Lilienfeld-Toal Marie , Janjetovic Snjezana , Trautmann-Grill Karolin , Bittrich Max , Engelhardt Monika Martha , Hoferer Anette , Theurich Sebastian , Binder Mascha , Zojer Niklas , Duerk Heinz A. , Brueggemann Monika , Held Swantje , Einsele Hermann ,   Deutsche Studiengruppe Multiples Myelom
Published: June 2023

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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 .