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4747 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)

Program: Oral and Poster Abstracts
Session: 653. Multiple Myeloma: Prospective Therapeutic Trials: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research, Plasma Cell Disorders, Diseases, Lymphoid Malignancies, Minimal Residual Disease
Monday, December 11, 2023, 6:00 PM-8:00 PM

Benjamin A Derman, MD1, Jennifer H Cooperrider2, Jacalyn Rosenblatt, MD3, David Avigan, MD3, Murtuza M. Rampurwala, MD, MPH4*, Ajay Major, MD, MBA5, Theodore Karrison2*, Ken Jiang2*, Tadeusz Kubicki2* and Andrzej J Jakubowiak, MD, PhD6

1Section of Hematology/Oncology, University of Chicago, CHICAGO, IL
2University of Chicago, Chicago, IL
3Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
4University of Wisconsin System, Orland Park, IL
5University of Colorado Cancer Center, Aurora, CO
6Section of Hematology/Oncology, University of Chicago, Chicago, IL

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/m2 on days 1, 2, 8, 9, 15, 16 for C1-8, then 36 mg/m2 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 > 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 <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(-) <10-5 at the end of C8; the hypothesis was that >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 8.91x106 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 (<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(-) >12 months was achieved in 11 (26%) pts; 6 pts were <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.

Disclosures: Derman: Janssen: Consultancy; BMS: Other: independent reviewer for a clinical trial; COTA Healthcare: Consultancy. Rosenblatt: Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Karyopharm; Advare: Consultancy; Bristol Myers Squibb: Research Funding; Parexel: Consultancy; Bioclinica: Consultancy. Avigan: Juno Therapeutics: Consultancy, Other: Advisory role; Karyopharm Therapeutics: Consultancy, Other: Advisory role; Chugai Pharma: Consultancy, Other: Advisory role; Sanofi: Consultancy, Other: Advisory board; Janssen: Consultancy, Other: Advisory board; Partner Therapeutics: Consultancy, Other: Advisory board; Aviv Med Tech: Consultancy, Other: Advisory board; Bristol-Myers Squibb: Consultancy, Other: Advisory board; Takeda: Consultancy, Other: Advisory role; Legend Biotech: Consultancy, Other: Advisory role; Kite/Gilead: Consultancy, Other: Advisory role, Research Funding; Celgene: Consultancy, Other: Advisory role, Research Funding; Paraxel: Current Employment; Kowa Pharmaceutical: Consultancy, Other: Advisory board; Pharmacyclics: Research Funding; Kite, a Gilead Company: Research Funding. Jakubowiak: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Sanofi-Aventi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH