Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)
Andrew J. Yee, MD
Assistant Professor of Medicine
Massachusetts General Hospital Cancer Center
Boston, Massachusetts
The treatment of newly diagnosed multiple myeloma (NDMM) has rapidly evolved, and induction combining an anti-CD38 monoclonal antibody, lenalidomide, a proteasome inhibitor, and dexamethasone has become a standard of care. In this prospective randomized phase 2 trial, we evaluated the efficacy and safety of induction with a 4-drug combination of daratumumab (Dara), lenalidomide (R), ixazomib (I), and dexamethasone (d) (Dara-RId) in transplant ineligible or deferred patients (pts), followed by maintenance with Dara RI versus R for up to 2 years. We hypothesized that this quadruplet would improve tolerability with less peripheral neuropathy in this older population. Here, we present the results of the induction phase.
Methods:
Transplant-ineligible or deferred pts with NDMM were eligible. This was a multicenter trial sponsored by the Alliance Foundation Trials, LLC, AFT-41 (NCT04009109). Each cycle was 28 days. All pts received 12 cycles with daratumumab 1800 mg s.c. on the conventional schedule, lenalidomide 15 mg p.o. on days 1-21, ixazomib 4 mg p.o. on days 1, 8, 15, and dexamethasone weekly. After 12 cycles, pts received maintenance based on prior randomization to Dara-RI or R for up to 2 years. In maintenance, R was reduced to 10 mg and I was reduced to 3 mg. Randomization occurred before starting induction. Stratification was based on presence of high-risk features: ISS stage III or high-risk FISH cytogenetics (del 17, t (14;16), t (14;20), t (4;14), del (1p), or gain (1q)). The primary endpoint was progression-free survival (PFS).
Results: We enrolled 79 pts across 7 sites from October 2020 until December 2023. Accrual was affected by the COVID19 pandemic, leading to early closure to accrual in December 2023. Median age was 74 years (range 63-86); ≥75 years of age (45.6%); female (59.5%); white (83.5%), African American (7.6%), Asian (1.3%), and Hispanic ethnicity (6.3%). Additional baseline characteristics included ISS staging I (41.8%), II (35.4%), and III (22.8%) with high-risk features in 37% by ISS stage III and/or high-risk FISH. The 12-month PFS was 92% (95% CI 86.1-98.4%). The ORR during induction was 92.4% (PR 22.8%; VGPR 46.8%; CR 15.2%; sCR 7.6%). Grade ≥3 adverse events included neutropenia (16.5%), infections (11.4%), anemia (10.1%), thrombocytopenia (8.9%), and syncope (7.6%). There was no grade ≥3 neuropathy (grade 1, 15%; grade 2, 14%). There was no treatment-related mortality reported; 61 pts went on to maintenance therapy and 7 pts discontinued treatment for adverse events during induction.
Conclusions:
Dara-RId offers a regimen that has the efficacy of a 4 drug combination with the convenience of oral ixazomib and minimizes the risk of peripheral neuropathy for older, transplant ineligible NDMM. There is ongoing follow up to determine the benefit of maintenance with dara RI v. R alone. Support: AFT, Celgene, Janssen, Takeda