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    Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

    Category: Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

    A randomized study comparing carfilzomib, lenalidomide, and dexamethasone (KRd) with elotuzumab-KRd in transplant-eligible patients with newly diagnosed myeloma: initial results for 3-year PFS and OS

    (PA-404) A Randomized Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (KRd) with Elotuzumab-KRd in Transplant-eligible Patients with Newly Diagnosed Myeloma: Initial Results for 3-year PFS and OS

    Wednesday, September 17, 2025
    Introduction: The treatment approach in newly diagnosed multiple myeloma (NDMM) has evolved dramatically. Adding monoclonal antibodies (mAbs) directed against CD38 to a triplet consisting of bortezomib (V), lenalidomide (R) and dexamethasone (d; VRd) was a major achievement improving outcomes. In a recent phase 3 study of a German group in transplant-eligible (TE) NDMM subjects, VRd and the mAb elotuzumab (targeting SLAMF7) however, did not prove superior over VRd alone. As the irreversible proteasome inhibitor carfilzomib (K) is thought to be more effective than V, we decided to compare KRd plus elotuzumab (E; associated with less severe respiratory infections than anti-CD38 mAbs) with KRd.

    Methods: For this phase 3 study (registered as NCT03948035), TE NDMM pts up to 70 years (yrs) were randomized 1:1 to receive six cycles of KRd or E-KRd, single (tandem, if < CR/high risk NDMM) HDT/ASCT, followed by four consolidation cycles (KRd/E-KRd) and R or ER maintenance (maint). For induction (28-day cycles), pts received 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). For maint, pts. received continuous R 10 mg (R maint) or E 20 mg/kg IV on D1 plus R 10mg, (ER maint) until PD/toxicity. Minimal residual disease (MRD) was analyzed by next-generation flow. The 1st co-primary endpoint, the rate of pts who were in > VGPR and were MRD-negative post induction, was met showing superiority of E-KRd over KRd. Here, we present initial results for the 2nd co-primary endpoint: 3-year PFS rate since randomization. We estimated 3-year rate for KRd to be 58%. The data extract was 01/28/2025.

    Results:

    579 pts (of whom 574 received treatment) were randomized between 08/2018 and 10/2021 at 52 sites. Median age was 60 (range, 31-71) yrs and 15.4% had ISS stage III disease. After a median follow-up of 46.4 (0.03-74.0) months (mos) for KRd and 47.4 (range, 1.1-73.1) mos for E-KRd, median PFS/OS could not be estimated. The 3-year PFS rate was comparable between groups: 72.2% (97.47% CI, 66.0-77.7) for KRd versus 78.7% (97.47% CI, 72.9-83.6) for E-KRd (OR, 1.421 [97.47% CI, 0.920-2.195]; Chi-square p=0.0703). For OS, HR was 1.563 (97.47% CI 0.976 , 2.504); Log-rank p=0.0608. During maint, the rate of treatment-related AEs was 78.1% with R versus 80.9% with ER (p=0.4583). The rate of grade 3-5 related AEs was 39.9% (R) versus 46.1% (ER; p=0.1820). With 249/574 (43%) of pts still on treatment, median duration of maint was comparable between the arms: 27.8 (range, 0.4-55.0) mos for R versus 28.5 (range, 0.1-55.8) mos for ER.

    Conclusions: In our study, the addition of elotuzumab to KRd (ind/cons) and to R (maint) showed a clear trend in favor of the elotuzumab arm regarding 3-year PFS and OS rates without reaching statistical significance yet. This was mainly due to a better-than-estimated PFS in the KRd arm. ER maint was not associated with more toxicity than R.