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

Introduction Increasing evidence supports that depth of response is associated with improved survival in patients (pts) with newly diagnosed multiple myeloma (NDMM). Previously, addition of the anti-CD38 antibody daratumumab (D) to standard treatment lenalidomide and dexamethasone (Rd) showed survival advantage compared to Rd in transplant ineligible (TI) pts with NDMM (Facon T, 2019). Single-agent belantamab mafodotin (belamaf), an antibody-drug conjugate directed against B-cell maturation antigen (BCMA), has shown antimyeloma activity with manageable safety in pts with relapsed/refractory multiple myeloma (Lonial S, 2020). Combining antimyeloma agents with unique modes of action (i.e., anti-BCMA and anti-CD38 antibodies) with standard therapies (i.e., Rd) may be advantageous in terms of efficacy in the upfront treatment of TI pts with NDMM without compromising tolerability. We report a preliminary analysis of 2 belamaf dosing schemes given in combination with DRd in TI pts with NDMM participating in the EAE120 study.

Methods The ongoing EAE120 phase 1/2, open-label, single-center study (NCT05280275) aims to enroll 36 adult TI pts with NDMM. In Part 1 of the study (dose-finding), 24 pts are randomized (1:1) in 2 cohorts to receive belamaf 1.9 or 1.4 mg/kg doses by intravenous infusion once every 8 weeks (wks) plus DRd; depending on toxicity, belamaf dosing may be rescheduled to once every 4 wks (1.4 mg/kg cohort) or once every 12 wks (both cohorts). A safety review is planned after 6 pts in each cohort receive ≥1 belamaf dose with a 4 wk follow-up. If no new safety signals are detected, pt enrolment will continue to the planned 12 pts per cohort to further assess the safety of study treatment and determine the belamaf recommended phase 2 dose (RP2D). Part 2 of the study (dose expansion) will further evaluate the safety and clinical activity of belamaf RP2D plus DRd in a single cohort of 12 pts. This descriptive analysis included pts who received ≥1 belamaf dose by data cut-off (24 June 2022).

Results Eleven pts (cohort 1.9 mg/kg: 6 pts; cohort 1.4 mg/kg: 5 pts) were included in this analysis; all pts were still on treatment at data cut-off. At baseline, pts had a median age of 73.0 years [range 66.0-84.0] and most (6, 54.5%) were male. Most (8, 72.7%) pts had Eastern Cooperative Oncology Group performance status (ECOG PS) 1 followed by those at ECOG PS 0 (2, 18.2%) and 2 (1, 9.1%). Of pts with available Revised International Staging System staging (n=7), most (5, 71.4%) were at stage II, followed by those at stages I and III (1, 14.3% each stage). Lytic bone lesions and extramedullary disease were detected in 7 (63.6%) and 1 (9.1%) pts, respectively. Of pts with available high-risk cytogenetic data (i.e., del(17p13), t(4;14), t[14;16]); n=7), 1 (14.3%) had high-risk cytogenetics (t[4;14]).

At a median follow-up of 1.3 months (range 0.1-2.4), pts had reached a median of 2.0 treatment cycles (range 1.0-3.0). No belamaf dose reductions/delays were reported. No serious TEAEs were reported. Non-ocular TEAEs included constipation (2 pts, 18.2%), fatigue (2 pts, 18.2%), and osteolysis and insomnia (1 pt, 9.1% each). Grade (gr) ≥3 non-ocular TEAEs were fatigue, constipation and insomnia, observed in 1 (14.3%) pts each of the belamaf 1.4 mg/kg cohort. Overall, Gr 1-2 ocular adverse events (OAEs, i.e., ocular symptoms, change in BCVA, and keratopathy) were observed in 6 (54.5%) pts; no gr 3-4 OAEs were recorded. All pts that had at least one response assessment, manifested partial response; in pts with at least two post-baseline efficacy assessments, the overall response rate was 100% (Table).

Conclusions This preliminary analysis of the EAE120 study, showed that the frequency of ocular events was within the anticipated range with no new safety signals being observed in TI pts with NDMM treated upfront with belamaf plus DRd. Study enrollment is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis.

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