Abstract
Introduction: Treatment options are limited for patients who multiple myeloma (MM) relapses after B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy. Although BCMA-directed bispecific antibodies can elicit responses in this setting, their activity is attenuated, and the remissions are typically brief. To address this unmet need, we launched a phase II trial testing a novel quadruplet with reduced intensity belanatmab mafodotin (BCMA antibody-drug conjugate, ‘Bela‘), weekly carfilzomib, pomalidomide, and dexamethasone (KPd) in patients with relapsed/refractory MM previously exposed to BCMA-directed CAR T therapy. Here we present the first efficacy data after the study's primary endpoint has been reached.
Methods: This is a phase II trial including patients with prior BCMA-directed CAR T-cell therapy, regardless of prior drug refractoriness. Patients are assigned treatment with Bela 1.9 mg/kg IV every 8 weeks, carfilzomib 56 mg/m2 IV days 1, 8, and 15 (20 mg/m2 on cycle 1 day 1), pomalidomide 3 mg PO days 1-21, and dexamethasone 40 mg PO weekly for cycles 1-4 and then 20 mg PO weekly thereafter. The primary endpoint is overall response rate (ORR); the null hypothesis is that the true ORR is 10% and the alternative is that the true ORR rate is 35%. If 5 or more responses are seen among 19 patients enrolled, the null hypothesis will be rejected and the primary endpoint will be met, yielding a type I error of 0.05 and power of 0.85. Secondary endpoints include measurable residual disease (MRD) negativity by next generation sequencing (limit of detection 10-6), progression-free survival (PFS), overall survival (OS), and safety.
Results: A total of 11 patients have entered the treatment phase as of June 30, 2025. The median age is 64 years (range 59-82); 5/11 (45%) were Black and 4/11 (36%) were female. High-risk cytogenetic abnormalities by the new IMWG criteria were present in 3/11 (2 with 17p deletion, 1 with two high-risk abnormalities), and another 4 patients had either 1q gain (n=3) or 1q amp (n=1). Extramedullary disease was present in 4/11 (36%) patients. The median prior lines of therapy was 6 (range 3-8); 9/11 (82%) were refractory to both carfilzomib and pomalidomide. Four patients received cilta-cel, five patients received investigational BCMA CAR T-cell therapies, and two patients received both; all patients responded to each CAR T administered.
The ORR was 9/11 (82%) meeting the statistical threshold for efficacy. Four patients achieved a best response of stringent complete response, 3 a very good partial response (VGPR), 2 a partial response, and 2 had stable disease. In the patients with at least a VGPR with MRD evaluation (n=6), 4 (67%) were MRD<10-5 and 2 (33%) were MRD<10-6 (1 pending).
The median follow-up is 8 months (range 1-23 months). There were 5 progression events; 2 patients died following progression of disease. There no treatment-related deaths. The estimated 1-year PFS is 61% (95% CI 27-84%) and 1-year OS is 100%.
Grade 3-4 neutropenia occurred in 4 (36%) patients, grade 3-4 thrombocytopenia in 4 (36%), and grade 3-4 anemia in 1 (9%). Two patients (18%) had serious infections (one grade 2 and one grade 3). One patient (9%) had grade 3 chest pain and one (9%) had grade 3 palpitations. Ocular events were graded with the Keratopathy and Visual Acuity (KVA) scale. Keratopathy developed in 9/11 (82%) patients: grade 1 in 4 patients, grade 2 in patients, and grade 3 in 1 patient. Best corrected visual acuity fell in 8 (73%), but only one patient lost more than a single Snellen line. Blurred vision was reported in 5 patients (45%; grade 1 in 3 patients, grade 2 in 1 patient, and grade 3 in patient). All grade 3 ocular events returned to at least grade 1 or better. No patient discontinued treatment because of ocular toxicity. Bela dose was reduced for ocular events in 6 patients (55%), and the overall Bela dose intensity was 77.5%.
Conclusion: Bela-KPd utilizing less frequent dosing of Bela led to a favorable efficacy and safety profile, even among patients with prior BCMA CAR T-cell therapy and carfilzomib and pomalidomide refractoriness. Bela-KPd is a promising regimen for patients following relapse after BCMA CAR T-cell therapy.
Partial funding and study drug were provided by GSK and Amgen (ClinicalTrials.gov identifier NCT05789303).
