Part 1 Results of a Dose-Finding Study of Belantamab Mafodotin in Combination with Pomalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)
Bibliographic record
Abstract
Abstract Background: Belantamab mafodotin (belamaf) is a first-in-class antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA) that has shown clinically meaningful activity as a single agent in relapse/refractory multiple myeloma (RRMM). Pre-clinical studies demonstrate that the immune mediated anti-myeloma activities of belamaf are enhanced by immunomodulatory drugs (IMiDs) providing the rationale for combining Belamaf with pomalidomide (POM). The Algonquin study is an ongoing Phase 1/2 trial designed to evaluate the recommended Part 2 dose (RP2D), safety, and preliminary efficacy of belamaf in combination with POM and dexamethasone (DEX) (B-Pd) in patients (pts) with RRMM. The initial data from the dose-escalation phase of the study identified 2.5 mg/kg in combination with standard dosing of POM/DEX as the maximum tolerated dose (MTD) (Trudel et al. ASH 2020). Here we report updated safety and efficacy data and additional dosing cohorts used to identify the RP2D. Methods: Eligibility required > 1 prior lines of treatment (LoT), lenalidomide (LEN) and proteasome inhibitor (PI) exposure and refractoriness to the last LoT. POM was administered at 4 mg days 21/28 days, DEX 40 mg (20 mg age > 75 years) weekly in conjunction with IV belamaf SINGLE (1.92 or 2.5 mg/kg) Q4W, 2.5 mg/kg LOADING dose followed by 1.92 mg/kg Q4W from cycle 2+, 2.5 mg/kg dosed Q8W (BIMONTHLY) or Q12W (TRIMONTHLY), or belamaf SPLIT (2.5 or 3.4 mg/kg), split equally on days 1 and 8 Q4W. Dose escalation was accomplished using a standard 3+3 dose escalation design. Responses were assessed by International Myeloma Working Group (IMWG) criteria and adverse events (AEs) were graded by CTCAE criteria except for corneal findings which were also graded by the pre-specified keratopathy and visual acuity (KVA) scale. Up to 12 pts could be enrolled at dose levels not exceeding the MTD to inform the R2PD. Results: At cut-off (July 15, 2021), 60 pts had been enrolled in the following dose levels and schedules: 1.92 SINGLE (n=12), 2.5 SINGLE (n=7), 2.5 LOADING (n=5), 2.5 BIMONTHLY (n=12), 2.5 TRIMONTHLY (n=11), 2.5 SPLIT (n=8) and 3.4 SPLIT (n=5). The median age was 65 years (range 36-81) and median prior LoT was 3 (1-5). Prior therapies (exposed/refractory) included stem cell transplant (57%), PI (100%/82%), LEN (100%/90%) and daratumumab (DARA) (58%/100%). 76% were refractory to LEN and a PI and 48% to LEN, a PI and DARA. The most frequent AEs regardless of attribution were keratopathy (an ophthalmologic finding) (96.9%), blurred vision (87.5%), fatigue (59.4%), neutropenia (62.5%), thrombocytopenia (50%), fever (46.9%), diarrhea (34.4%), constipation (34.4%), and dry eye (28.1%). Grade 3/4 AEs reported in >20% of pts across all cohorts, were keratopathy (56.7%), neutropenia (38.3%), thrombocytopenia (35%) and blurred vision (30%). Corneal safety profile by dosing cohort as well as dose reductions and dose delays used to manage corneal AEs are listed in Table 1. Two patients discontinued treatment due to AEs (one G4 decreased visual acuity and one G3 elevated ALT) while no grade 5 AEs were observed. At cut-off, 54/60 patients were evaluable for response. Across all cohorts the ORR was 88.9% (11 PR, 24 VGPR, and 13 sCR). Responses by dosing cohort are summarized in Table 1. At a median follow up of 8.6 months (range 0.9-27.9) the median PFS was 24.2 months (95% CI: 14.1, NYR). Conclusions: The safety profile of B-Pd is consistent with that observed for Pd or Belamaf individually. All dosing cohorts demonstrate deep and durable responses however the 2.5 mg/kg dose appears to have better efficacy. The 2.5 BIMONTHLY dosing schedule has been selected for the Part 2 cohort expansion based on optimized safety and efficacy. Figure 1 Figure 1. Disclosures Trudel: Genentech: Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Honoraria; Roche: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. McCurdy: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria. Sutherland: Amgen: Consultancy; Janssen: Consultancy, Research Funding; GSK: Research Funding; Karyopharm: Research Funding; Celgene: Consultancy. Louzada: Celgene: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; BMS: Research Funding; GSK: Research Funding; Sanofi: Research Funding. Mian: Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Kotb: Pfizer: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Celgene: Honoraria; Merck: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Akcea: Honoraria; BMS: Honoraria. Othman: Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria. Camacho: Janssen: Consultancy; AbbVie: Consultancy; Bausch-Health: Consultancy. Reece: Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria; Amgen: Consultancy, Honoraria; Millennium: Research Funding; BMS: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria. White: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; Forus: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm Therapeutics Inc.: Consultancy, Honoraria. OffLabel Disclosure: belantamab and pomalidomide in combination
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".