Final Analysis of a Phase 2 Trial of Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma (NDMM) without Autologous Stem Cell Transplantation (ASCT)
Authors: Derman Benjamin A , Cooperrider Jennifer H , Rosenblatt Jacalyn , Avigan David , Rampurwala Murtuza M. , Major Ajay , Karrison Theodore , Jiang Ken , Kubicki Tadeusz , Jakubowiak Andrzej J 
Published: December 2023

Introduction: A previous trial showed that Dara-KRd for 8 cycles without ASCT led to a minimal residual disease (MRD) negativity rate of 71% at 10 -5 in NDMM (Landgren et al. JAMA Oncology 2021). MRD-adapted Dara-KRd with ASCT led to an MRD(-) rate of 71% at 10 -6 with a 3-year progression-free survival (PFS) of 88%, 79%, and 50% in pts with 0, 1 or 2+ high-risk cytogenetic abnormalities (HRCA), respectively (Costa et al. EHA 2022). In this phase 2 study, we evaluated the safety and efficacy of 24 cycles of Dara-KRd without ASCT in pts with NDMM.

Methods: Pts with NDMM with up to 1 cycle of prior therapy were enrolled regardless of ASCT eligibility. Pts received Dara-KRd for planned 24 cycles: daratumumab 16 mg/kg IV weekly for cycles (C) 1 & 2, q2weeks for C3-8, then q4weeks for C9-24; carfilzomib 20/36 mg/m 2 on days 1, 2, 8, 9, 15, 16 for C1-8, then 36 mg/m 2 on days 1, 2, 15, 16 for C9-24; lenalidomide 25 mg PO days 1-21 of a 28 day cycle for 24 cycles; dexamethasone 40 mg PO weekly (20 mg if age &gt; 75) for C1-9, and 20 mg PO weekly for C9-24. Pts had the option to harvest stem cells (SC) to permit ASCT in the future.

MRD testing was performed by NGS (clonoSEQ, Adaptive Biotechnologies) with sensitivity &lt;10 -6 at the end of cycles 8 (C8), C12, and C24. Mass spectrometry (MS) of peripheral blood samples were also performed using MALDI and liquid-chromatography (LCMS) (The Binding Site Group). The primary endpoint was the rate of stringent CR and/or MRD(-) &lt;10 -5 at the end of C8; the hypothesis was that &gt;50% would meet the primary endpoint with Dara-KRd compared to historical 30% with KRd (85% power, one-sided alpha=0.10).

Results: 42 pts enrolled from March 2019-January 2022. Median age was 58 years (range 39-79). 13 (31%) were Black and 5 (12%) were Hispanic. HRCA (t(4;14), t(14;16), t(14;20), +1q, del17p) were present in 24/42 (57%); 10 (24%) had 2+ HRCA. 34 pts (81%) underwent SC collection, all with plerixafor (median yield 8.91x10 6 CD34+/kg).

40 pts (95%) were evaluable for the primary endpoint at C8. Two pts withdrew before C8 for reasons unrelated to treatment. There were 32 (80%) MRD-evaluable pts at C8. The sCR and/or MRD(-) rate (&lt;10 -5) was 30/40 (75%, 95% CI 61%-89%). The C8 10 -5 MRD(-) rate was 20/32 (63%) and at 10 -6 it was 12/32 (38%). Responses deepened over time; 1/12 (8%) and 6/20 (30%) pts converted from MRD(+) at C8 to MRD(-) at later timepoints at 10 -5 and 10 -6 thresholds, respectively, for a best MRD(-) rate of 21/32 (66%) at 10 -5 and 18/32 (56%) at 10 -6 . Sustained 10 -5 MRD(-) &gt;12 months was achieved in 11 (26%) pts; 6 pts were &lt;1 year from first MRD(-) result. Overall response rate at C8 was 38/40 (95%) with 27 (68%) sCR, 38 (95%) VGPR+, and 2 PD.

Of the 39 pts with trackable mass spectra in the peripheral blood, the MALDI(-) rate was 22/39 (56%) after C8 and 24/39 (62%) as best response. The LCMS(-) rate was 7/39 (18%) after C8 and 12/39 (31%) as best response.

Median follow-up was 27 months. 21 pts (50%) completed all 24 cycles, and 11 (26%) remain on protocol. 7 pts (17%) had disease progression (6 on protocol), including 4 pts who reached the primary endpoint at C8. 4 pts (10%) discontinued protocol therapy early (additional 2 pts due to nonadherence). 1 pt received ASCT after discontinuing while in response. 2 deaths occurred, both early in treatment and due to primary refractory disease. The 3-year PFS was 85%: 100% for standard-risk disease, 92% for 1 HRCA, and 60% for 2+ HRCA. Of the 7 pts with progression, 6 had at least one of: extramedullary disease (4), 2+ HRCA (4), or circulating plasma cells (1). Neither NGS nor mass spectrometry status at C8 were associated with PFS differences using the landmark method. The 3-year OS was 95%.

All-grade/grade 3+ (G3) neutropenia occurred in 26%/21%, anemia in 59%/2%, and thrombocytopenia in 64%/26%. Notable nonhematologic adverse events were hyperglycemia (all 76%/ G3+ 7%), diarrhea (71%/5%), hypertension (57%/17%), and neuropathy (40%/0%). COVID infections occurred in 38% (2% G3) and upper respiratory infections in 45% (0% G3+). There was one case of thrombotic microangiopathy leading to discontinuation of carfilzomib. G3 atrial fibrillation and heart failure each occurred in 1 pt.

Conclusions: Extended frontline Dara-KRd for NDMM without ASCT induced high rates of sCR and/or MRD(-) within 8 cycles, meeting the primary endpoint. The rate and depth of MRD(-) improved beyond C8. This ASCT-free approach led to lower PFS for pts with 2+ HRCA, as also seen with ASCT, but excellent PFS in those with standard-risk disease and 1 HRCA.