Initial Clinical Results and Immune Correlates of a Phase 2 Study of Daratumumab, Bortezomib, Dexamethasone Followed By a Proteasome Inhibitor in-Class Transition ( iCT) to Daratumumab, Ixazomib, Dexamethasone in Relapsed Refractory Multiple Myeloma

Background: The regimen of daratumumab, bortezomib, and dexamethasone (DVd) was approved in relapsed refractory multiple myeloma (RRMM) patients (pts) with >1 line of therapy based on the pivotal phase 3 CASTOR study. Notably in CASTOR, bortezomib was administered for a fixed duration of 8 cycles, and both the parenteral administration route and treatment-related peripheral neuropathy (PN) may limit continuous bortezomib exposure in clinical practice. As an alternative, we conducted a phase 2 study of DVd, followed by daratumumab, ixazomib, dexamethasone (DId) utilizing a proteasome inhibitor (PI) in-class transition ( iCT) with the hypothesis that oral ixazomib may provide a more tolerable and convenient way to deliver continuous PI- and anti-CD38-based therapy to improve efficacy (NCT03763162).

Methods: This phase 2 single-center study enrolled RRMM pts with 1-3 lines of prior therapy with disease progression on or following the last line of therapy. Key exclusion criteria included prior ixazomib exposure, refractoriness to anti-CD38 therapy, and refractoriness to bortezomib or carfilzomib therapy at last exposure.

Enrolled pts received DVd for 3 cycles on a 21-day (D) cycle with daratumumab on D1, D8, and D15 and subcutaneous (SC) bortezomib 1.3 mg/m ² on D1, D4, D8, and D11. Starting cycle (C) 4, pts transitioned to DId on a 28-day cycle, with daratumumab on D1 and D15 for C3-C7 and on D1 starting C8 and oral ixazomib 4 mg on D1, D8 and D15. Daratumumab was initially administered intravenously (16 mg/kg) but later changed to SC injection (1800 mg) with a protocol amendment.

Bone marrow (BM) aspirates were performed pre-treatment, post-C3, post-C6 (optional), and at progression to evaluate immune correlates of therapeutic response and resistance using 4 16-color multiparameter flow cytometry panels (2 T-cell, 1 NK/myeloid, and 1 B-cell). The primary endpoint of the study was progression free survival (PFS) with planned enrollment of 40 pts.

Results: As of 15 May 2023, 36 pts have enrolled with a median of 1 prior line of therapy. Median age was 66, 67% were male, 28% were Black, 97% were lenalidomide-refractory, and 42% had high-risk cytogenetics (Cg; del 17p, t(4;14), t(14;16), and/or +1q21 gain/amplification). Overall response rate was 83%, ≥very good partial response (VGPR) rate was 53%, and ≥complete response rate was 19%. At a median follow-up of 24.8 months, median PFS was 21.1 months and median response duration was 26.2 months. Median PFS among pts with high-risk Cg, 1 line of prior therapy, and 2-3 lines of prior therapy was 21.1 months, 22.8 months, and 14.3 months, respectively.

The most common treatment emergent adverse events (TEAEs) of any grade were diarrhea (69%), thrombocytopenia (69%), fatigue (67%), and lymphopenia (67%). The most common ≥grade 3 TEAEs were lymphopenia (42%), thrombocytopenia (42%), and hypertension (31%). Treatment emergent PN occurred in 61% pts (11% ≥ grade 3). The most common reason for treatment discontinuation was disease progression (42%), and 16 (44%) pts remain on study with ongoing responses. Efficacy and safety stopping rules for the study have not been met.

Multiparameter flow cytometry immune correlates from BM aspirates demonstrated significantly lower Ki67 ⁺ cell frequency and significantly higher PD-1 ⁺ cell frequency within the CD8 ⁺ T-cell population at baseline in pts with no response versus those with optimal responses (≥VGPR). Among pts with short PFS (<12 months), CD4 ⁺/CD8 ⁺ ratio and CD4 ⁺ non-T-reg naïve T-cells were significantly higher post-C3 and post-C6 compared to pts with longer PFS (>12 months). Among initial responders who later progressed on therapy, T-regulatory cells were significant increased at progression compared to pre-C4, and NK cell CD16 expression was significantly reduced at progression compared to baseline. Finally, distinct patterns of CD4 ⁺ T effector memory (EM) cell subsets were observed with significantly decreased EM1 and increased EM3 subsets at progression compared to baseline.

Conclusion: Treatment with DVd followed by DId with a PI iCT from bortezomib to ixazomib is a feasible approach for continuous PI and anti-CD38 therapy, leading to durable responses in RRMM pts, among whom nearly all (97%) were lenalidomide refractory. Immune correlates revealed distinct patterns of T-cell and NK-cell phenotypes when profiled serially in responding and non-responding pts. Additional correlative analyses are ongoing.