A Phase 1/2, Dose and Schedule Evaluation Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin Administered in Combination with Lenalidomide and Dexamethasone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Introduction Lenalidomide and dexamethasone (Rd) treatment is common for transplant ineligible (TI) patients (pts) with newly diagnosed multiple myeloma (NDMM). Addition of a third antimyeloma agent with a different mode of action than lenalidomide (e.g., proteasome inhibitors or anti-CD38 monoclonal antibodies) leads to higher response rates and deeper responses. Single-agent belantamab mafodotin (belamaf), an antibody-drug conjugate directed against B-cell maturation antigen, has shown a clinically meaningful antimyeloma activity with a manageable safety profile in double/triple class exposed pts with relapsed or refractory multiple myeloma. Preclinical data demonstrate synergy between belamaf and lenalidomide, suggesting added benefit in the combination of belamaf plus Rd. We report on the safety and efficacy of upfront belamaf plus Rd in TI pts with NDMM.

Methods The ongoing, prospective, open-label, 2-part, phase 1/2 BelaRd study (NCT04808037) aims to enroll 66 pts with TI NDMM from a Greek center. Eligible are adult pts with an Eastern Cooperative Oncology Group status 0-2 and adequate organ function. In Part 1, 18 pts are randomized (1:1:1) in 3 cohorts to receive belamaf 2.5, 1.9, or 1.4 mg/kg doses by intravenous infusion once every 8 weeks (Q8W) plus Rd and the safety/tolerability of the combination is evaluated for pts with ≥4 weeks of follow up. As safety review found no unexpected findings, an additional 6 pts were enrolled in each dose cohort to select the belamaf recommended phase 2 dose (RP2D). Part 2 (dose expansion; not initiated as yet) will further evaluate the safety and preliminary clinical activity of belamaf RP2D Q8W plus Rd in 30 additional pts. This descriptive analysis presents the safety and efficacy data for all Part 1 pts (data cut-off: 24 June 2022).

Results Thirty-six pts (median age: 72.5 years [range 64.0-86.0]; male: 19 (52.8%) were included in this analysis. By data cut-off, 31 (86.1%) were still on treatment and 5 (13.9%) pts had discontinued (death due to a belamaf-unrelated adverse event [AE]: 4 [11.1%]; consent withdrawal: 1 [2.8%]). At baseline, most (27, 75.0%) pts were at Revised International Staging System stage II, and 3 (8.3%) pts had high-risk cytogenetics (i.e., del(17p13), t(4;14), t[14;16]). At a median follow up of 9.5 months (range 3.2-15.4), a median of 4.0 (range 2.0-8.0) belamaf infusions were administered and the median number of cycles reached was 10.0 (range 3.0-16.0).

Thirty-one (86.1%) pts experienced ≥1 grade (Gr) ≥3 treatment-emergent AEs (TEAEs). Most common (≥ 10.0% of pts) Gr ≥3 TEAEs were fatigue (16 pts, 44.4%), visual acuity reduced (12 pts, 33.3%), rash (6 pts, 16.7%), and COVID-19 infection (4 pts, 11.1%); Gr 3-4 thrombocytopenias were not reported, nor were any Gr infusion-related reactions. Pts with Gr 1-2 ocular symptoms, visual acuity reduced, and keratopathy were 34 (94.4%), 22 (61.1%), and 28 (77.8%), respectively; pts with Gr 3 ocular symptoms, visual acuity reduced, and keratopathy were 1 (2.8%), 12 (33.3%), and 0 (0.0%), respectively; no Gr 4 events occurred (Table). The overall response rate (partial response [PR] or better) was 97.2% (35 pts; stringent complete response: 8.3% [3 pts]; complete response: 11.1% [4 pts]; very good partial response: 52.8% [19 pts]; partial response: 25.0% [9 pts]); no disease progression was reported. Median time to first response was 1.0 months (range 0.9-6.0). RP2D was 1.9 mg/kg, as in this dose Gr ≥ 3 ocular TEAE and difficulties in activities of daily living 'most of the time' were observed in only 1 (8.3%) pt each at the time of the RP2D analysis, concurrently with a high ORR (91.7%).

Conclusions Part 1 of the BelaRd study showed that, in TI pts with NDMM, the safety profile of belamaf Q8W plus Rd was manageable. The belamaf Rd combination induced rapid and deep hematological responses, with almost all (97.2%) pts achieving at least PR and first response observed at a median of 1.0 months. The selected belamaf RP2D dose was 1.9 mg/kg.

Terpos:Janssen: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Sanofi: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel expenses, Research Funding; BMS: Honoraria; EUSA Pharma: Honoraria, Other: Travel expenses; Genesis: Honoraria, Research Funding. Gavriatopoulou:Genesis Pharma: Honoraria; Karyopharm: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen Cilag: Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Gkolfinopoulos:Health Data Specialists: Current Employment. Manousou:Health Data Specialists: Current Employment. Kastritis:Genesis: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos:Beigene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; BMS: Honoraria.