Phase I/II Study of Belantamab Mafodotin, Cyclophosphamide, and Dexamethasone (BelCyd) in Relapsed/Refractory Multiple Myeloma

Background: We hypothesize that combining Belantamab (Bel) direct tumor kill with the immune modulatory properties of cyclophosphamide (Cy) will enhance cytokine profile, cytotoxicity & phagocytosis with improved overall response rate (ORR) & manageable toxicities.

Methods: Phase 1 (dose escalation) evaluated 2 doses: Arm A: Bel 1.9 mg/kg IV Q3W; Arm B: Bel 2.5 mg/kg IV Q6W. On day 1, both arms included oral Cy 300 mg (A-1 & B-1) or 500 mg (A-2 & B-2) plus dexamethasone 40 mg. We report on phase I safety & efficacy; correlative studies: biomarkers [GM-CSF, Granzyme B, TNF, IFN-γ, IL-1, -2, -4, -5, -6, -7, -8, -10, -13,-17a, CXCL10 (IP-10), CCL2 (MCP-1), TGF-β1, MIP-1, & periforin] were measured in tears using BioLegend's LEGENDplex™ platform at baseline, during flare-ups & cycle 2 day 1. T cell subsets using antibodies from BioLegend's & BD Biosciences for the following markers [CD 3, -4, 8, -38, -14, -206, -183, -25, -185, -27, CCR 7 & 6, HLA DR, TCR gamma delta, 5, Treg, T-naive, TEM, Th1, NK cells & activated T cells] were assessed in peripheral blood at baseline & cycle 2 day 1.

Results: 10 patients were treated on phase I; 2/3 patients on Arm A-1 developed DLT (corneal grade 3 with more than 8 weeks to resolution). Arm B-2 was selected for RP2D. Median age was 70 years old (range 56-72), 6 were white, 3 were black & 1 was Asian. Median time since diagnosis was 9 years with a median of 5 prior therapies (range: 4- 7) including Auto-SCT (n=7), Allo-SCT (n=1); all patients had received lenalidomide, pomalidomide, bortezomib, carfilzomib & daratumumab, 2 patients had BCMA CAR T cell therapy. All patients were refractory to last line of therapy. Six patients had high-risk cytogenetics, 5 had extramedullary plasmacytoma; median LDH was 398 units/L (range: 181-2303), median B2M was 3.5 (range: 2.7-5.6). median Marrow plasmacytosis was 40% (range: 20-100%); CD-138/BCMA staining ranged from 70-100%. There were no infusion related reactions, main adverse event was corneal toxicity (keratopathy or superficial epithelial changes) grade 3 (2 on arm A-1 & 1 arm B-2), grade 1-2 (1 arm A-1 & 6 on Arm B). recovery from corneal toxicity was protracted (up to 4 months) but without sequalae in all patients. Median cycles given was 3 (range 2-13); median time to best response was 42 days (range 21-196). All patients had reduction in M-spike; ORR was 50% [VGPR (n=1); PR (n=4)]. Five patients proceeded to CAR-T cell therapy (within 2-4 months of bel), none of them progressed on Bel. All 5 patients responded [sCR (n=3), VGPR (n=1) & PR (n=1)]. The two patients who relapsed (19 & 24 months) after prior BCMA- directed CAR-T therapy progressed within 2 months: 1 patient relapsing with extramedullary disease despite biomarker response to BelCyd. One patient remains on study & 2 discontinued therapy (1 PD & 1 patient preference).

Correlative studies: Therapy evidently had an immune effect in peripheral blood & tears samples. In peripheral blood, percentage of CD3 ⁺ was lower on Cycle 2 day 1 than screening (average: 40%-30%); CD14 ⁺ / CD206 ⁺CD14 ⁺ macrophages were higher (average: 34%-44% & 0.7%-1%, respectively). Interestingly, functionally active HLA-DR ⁺ NK cells doubled on C2 day-1 (average: 0.4%-0.8%); similar increase in HLA-DR ⁺CD38 ⁺ CD8 ⁺ T cells was noted (Average: 7%-18%). In the tears, significantly higher levels of several proinflammatory cytokines (granzyme B, IL-7, IL-13, IP-10, MCP-1, MIP-1 alpha, TNF-beta) were found during symptomatic corneal disease compared with baseline (for e.g. granzyme B, cytotoxic T cell biomarker, increased from 65 pg/ml to 809 pg/ml in a patient with grade 3 corneal toxicity to 40 pg/ml after resolution of symptoms); Additional levels & correlation with corneal toxicity will be presented.

Conclusion: The RP2D of BelCyd is 2.5 mg/kg Q6W plus Cy 500 mg & dexa 40mg; no new safety signal was seen. BelCyd activate NK, cytotoxic T cells & macrophages adding to Bel direct MM cytotoxicity. BelCyd did not negatively impact the efficacy of subsequent BCMA directed CAR-T cell therapy but does not seem effective as salvage after prior CAR-T therapy. Preliminary data suggest that in addition to direct impact of Belantamab on corneal epithelial cells, BelCyd modify the biomarkers of the tears suggestive of immune mediated changes, unclear if these are initiating events or secondary to epithelial damage. Phase 2 expansion is ongoing.

This is an investigator-initiated trial supported by GSK; registered www.clinicaltrials.gov # NCT04896658