Background: High dose melphalan and ASCT, followed by lenalidomide (len) maintenance, improves progression-free survival (PFS) in MM but is generally not curative. Achieving a minimal residual disease (MRD)-negative state 12 months post-ASCT predicts for prolonged PFS and overall survival (OS). Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate with activity in relapsed/refractory MM. We hypothesized that reduced-frequency belamaf with ASCT and len maintenance would be feasible and improve MRD-negative rates and clinical outcomes.

Study Design and Methods: This is an ongoing investigator-initiated, single institution, phase 2 study (NCT04680468). Subjects have newly-diagnosed MM with at least partial response (PR), but not complete response (CR), after ≥4 cycles of induction therapy, and meet institutional criteria for ASCT. They receive 1 dose of belamaf on day (D) -42 (relative to ASCT), followed by stem cell collection starting D -14, and ASCT on D0. They restart belamaf on D+60, continuing every 3 months until 2 years post-ASCT, in conjunction with standard len maintenance starting D+100, given until progression. Subjects undergo serial ophthalmologic exams, with belamaf dose reductions and/or holds for corneal toxicity. Bone marrow MRD is assessed at 3, 12 and 24 months post-ASCT by next generation sequencing (NGS, Adaptive Clonoseq). The primary endpoint is the rate of MRD-negativity (at 10-6 sensitivity) 12 months post-ASCT.

Results: As of 7/1/24, 24 subjects (15 M and 9 F; median age 61 (range 37-72); 20 White, 4 Black) had received ≥1 dose of belamaf. R-ISS at diagnosis was stage 1 in 29%, 2 in 38%, 3 in 13%, and unknown in 21%. Fifteen (63%) had high risk cytogenetics, with 7 (29%) having ≥2 high risk features. One (4%) and 8 (33%) had extramedullary and paramedullary disease, respectively. Induction regimens were VRd in 29%, DaraVRd in 58% and other in 13%, with 67% receiving an anti-CD38 antibody. Responses at enrollment: 9 (38%) in PR and 15 (63%) in VGPR. The 1st 13 subjects started belamaf at 2.5 mg/kg; 8 had either their 2nd (D+60) or 3rd (D+150) dose skipped due to corneal toxicity, with 3 choosing to discontinue belamaf after 1 dose. After an amendment, subsequent subjects started at 1.9 mg/kg, with only 1 missed dose so far, and no discontinuations.

Of 17 subjects who have received at least 2 belamaf doses, 13 have required ≥1 dose reduction, with 7 having 2 dose reductions. Ocular toxicities were the most common treatment-emergent adverse events (TEAEs, n=22 with at least 1 follow-up visit post-belamaf), including keratopathy (100%, Gr 3 9%), blurred vision (91%, Gr 3 0%), decreased visual acuity (91%, Gr 3 41%), dry eye (68%, Gr 3 0%), photophobia and eye pain (32% each, Gr 3 0%). No grade 4 ocular toxicities were noted. Other common TEAEs included thrombocytopenia (45%, Gr 3/4 9%), upper respiratory infection (45%, Gr 3/4 0%), fatigue and leukopenia (36% each, Gr 3/4 0%), neutropenia, flu-like symptoms, and diarrhea (27% each, Gr 3/4 0%), myalgias (23%, Gr 3/4 0%), and increased ALT (23%, Gr 3/4 5%). Ten serious AE's were seen in 7 subjects, including 1 grade 5 cardiac arrest D+132 post-ASCT in a patient with multiple cardiovascular co-morbidities, unrelated to study treatment. Belamaf had no apparent impact on stem cell collection (median 9.3x106 CD34+/kg in median 2 days) or post-ASCT engraftment (median time to ANC>1000 and platelets>50 of 11 and 15 days, respectively).

Seventeen subjects have reached the D+90 response assessment; all were able to start len maintenance, with 3 requiring dose reductions and none requiring len discontinuation. Best responses to date in these subjects are VGPR in 24% and sCR in 76%. At D+90, 14 were MRD-evaluable (2 had no baseline clone identified, 1 refused BM biopsy), with 9 (64%) MRD-neg at 10-5 and 8 (57%) at 10-6. At 12 months post-ASCT, 12 are MRD-evaluable (2 not yet at M12, 1 no baseline clone, 1 expired, 1 progressed), with 10 (83%) MRD-neg at 10-5 and 8 (67%) at 10-6. With median follow-up of 15.5 months (range 0.5 - 36), 1 patient has progressed at D+187, with 1-year PFS and OS estimates of 87% and 93%, respectively.

Conclusions: In newly-diagnosed MM patients with <CR after induction, belamaf every 3 months in conjunction with ASCT and len maintenance appears feasible (at 1.9 mg/kg starting dose), with expected reversible ocular toxicities, and so far has promising rates of sCR, MRD-negativity, and PFS. Accrual and follow-up are ongoing.

Disclosures

Cohen:Novartis: Patents & Royalties; Ichnos: Membership on an entity's Board of Directors or advisory committees; University of Pennsylvania: Current Employment; Roche/Genentech, Janssen, GSK, AstraZeneca, BMS, Pfizer, AbbVie, iTeos, Arcellx, Legend, Sanofi: Consultancy; GSK, Novartis, Roche/Genentech, Janssen: Research Funding. Garfall:Tmunity Therapeutics: Research Funding; Crispr: Research Funding; GSK: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Janssen: Consultancy, Research Funding. Vogl:Abbvie: Consultancy; GlaxoSmithKline: Consultancy; BMS: Consultancy; Active Biotech: Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy. Stadtmauer:Celgene, Takeda, Novartis, Teva, Janssen, Amgen, Sanofi: Consultancy; Astra zeneca: Research Funding.

Off Label Disclosure:

This abstract describes the use of belantamab mafodotin, an anti-BCMA antibody-drug conjugate, for multiple myeloma patients with less than a complete response after induction therapy.

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2024
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