Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone in Early Relapsed/Refractory Multiple Myeloma

Background: The combination of daratumumab (D), pomalidomide (P), and dexamethasone (d) has previously demonstrated high overall response rates in patients with relapsed/refractory (R/R) MM. Results of the phase 3 APOLLO study of DPd vs Pd in patients with R/R MM with at least 1 prior line of therapy showed 69% ORR with a median PFS of 12.4 months in those patients who received the triplet combination (Dimopoulos, et al. Lancet 2021). Quadruplet regimens may further improve results by providing deeper and more durable responses with more intensive regimens. We report interim findings from a phase 2 multicenter trial of the addition of ixazomib to DPd (DIPd) in patients with early R/R MM. Methods: This is a prospective, multi-center, open-label, single arm phase 2 study (NCT03590652) with a primary endpoint of overall response rate (ORR), safety, and efficacy of DIPd. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and MRD-negativity rate. A Simon's optimal 2-stage design was used, with 14 subjects in stage 1 and 32 patients for stage 2. Eligible patients may not have had prior exposure to daratumumab or ixazomib, may not have progressed on prior pomalidomide, and must have received ≥1 or ≤3 prior lines of therapy including lenalidomide and a proteasome inhibitor. The first six patients in a safety run-in received daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg orally on days 1-21, ixazomib 4mg orally on days 1, 8, 15, and dexamethasone 20-40mg weekly on a 28-day cycle. Grade 3-4 neutropenia was observed in 100% of patients in the safety run-in, prompting starting dose reductions to ixazomib 3 mg and pomalidomide 3 mg by the DSMB. An amendment allowed for subcutaneous daratumumab administration. MRD assessments are being performed by EuroFlow for patients in suspected CR. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: To date, 14 subjects were treated in stage 1, and 23 of 32 planned subjects in stage 2. Of the 30 evaluable patients to date, the median age was 62.5y (range 41-87), and were 50% female and 70% white. Patients had a median of 1 prior line of therapy (range 1-3), and 52% (12/23) had at least one high-risk FISH feature including -17p, +1q, t(14;16), t(14;20), or t(4;14) . Grade 3-4 treatment emergent adverse events include neutropenia (63%), lymphopenia (9%), non-specific leukopenia (3%), thrombocytopenia (9%), febrile neutropenia (13%), infection (22%), electrolyte disturbance (6%), respiratory condition (6%), infusion reaction (3%), thrombosis (3%), and psychiatric condition (3%). Median time on treatment (n=25) is 4.8 months (range: 0.4-30.8), with 15 patients currently remaining on DIPd therapy and 7 deaths (4 PD, 1 sepsis, 1 COVID, 1 surgical complication). ORR to date is 83% (25/30) in evaluable patients, and best responses include 8 (27%) sCR, 3 (10%) CR, 6 (20%) VGPR, 8 (27%) PR. After a median follow up of 15.1 months, the median PFS is 11.6 (95% lower bound: ≥ 7.4) months and median OS is 38.9 (95% lower bound: ≥ 18.8) months. Conclusion: The quadruplet regimen DIPd builds upon the successes of daratumumab-based triplet regimens showing that the addition of a 4th agent can result in improved overall response rates with manageable toxicity and the convenience of a nearly all-oral drug regimen in patients with early R/R MM. These data are particularly compelling for high risk disease as more than half of the patients treated to date had at least one high risk feature, offering a promising option for the management of early relapse in high risk patients.