A Phase I/II Study of Twice Weekly Ixazomib Plus Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Introduction: Ixazomib is an oral proteasome inhibitor that is currently approved on a once weekly schedule in combination with lenalidomide and dexamethasone in RRMM. The addition of ixazomib to pomalidomide and dexamethasone has demonstrated encouraging activity in lenalidomide-refractory RRMM versus pomalidomide and dexamethasone (Voorhees EHA 2022). We hypothesized that twice weekly dosing schedule of ixazomib will be more efficacious and as safe as the once weekly dosing. We present our updated results of our phase I/II study of twice weekly ixazomib, pomalidomide and dexamethasone in RRMM.

Methods: This is a phase I/II multicenter, single-arm, open label study evaluating the combination of twice weekly ixazomib with pomalidomide and dexamethasone in RRMM. The primary objective for phase I portion is to determine safety and the maximum tolerated dose of this combination using a standard 3+3 dose escalation design and primary objective of the phase II portion is overall response rate (ORR) with secondary outcomes including progression-free survival (PFS) and clinical benefit rate.

Ixazomib is studied at doses of 3mg or 4mg on days 1, 4, 8, 11, pomalidomide at a dose of 2mg, 3mg and 4mg on days 1-14 and dexamethasone at a dose of 12mg on days 1, 2, 4, 5, 8, 9, 11, 12 (8mg for patients > 75 years old) on a 21 day cycle. RP2D was previously reported at 4mg dose of ixazomib and 4mg dose of pomalidomide. Patients were included if they received 2 prior lines of therapy, but 1 prior line was allowed if first line treatment included a PI and an immunomodulatory agent and disease relapse occurred within 60 days of last therapy. Patients who were ixazomib exposed or pomalidomide-refractory were excluded.

Results: At the time of data cutoff, 30 patients have been enrolled across all cohorts. Median age at the time of enrollment was 70 years old with ISS stage at diagnosis of I (23%), II (23%), and III (20%). High-risk FISH abnormalities were seen in 40% of patients as follows: del 17p (4, 13%), gain 1q (11, 37%), t(4;14) (1, 3%), t(14;16) (2, 7%). Median prior lines of therapy was 2 (range 1-4) with 100% of patients having prior treatment with lenalidomide, 97% with prior bortezomib and 13% prior daratumumab. Forty-three percent of patients had a prior autologous stem cell transplant. Eighteen patients have been enrolled at the RP2D at the time of data cut off.

Most common grade 3 or greater toxicities included neutropenia (20%), thrombocytopenia (10%), and upper respiratory infection (7%). Common grade 1 and 2 toxicities included neutropenia (40%), insomnia (40%), lower extremity edema (37%), fatigue (37%), rash (33%), dyspnea (30%), and weight gain (30%). Peripheral sensory neuropathy was observed in 5 patients (17%) and was mostly low grade (grade 1; 7%, grade 2; 10%). There have been no discontinuations due to toxicity and no treatment-related mortality at the time of data cutoff, including no COVID-related deaths.

The ORR in all cohorts was 50%, with 90% of patients achieving stable disease or better and 20% achieving VGPR or better. At the RP2D (18 patients), the ORR was 56% with 28% of patients achieving VGPR or better including 6% achieving a stringent CR. At the median follow up of 19 months, median PFS was 13 months (95% CI: 11-NR) and median overall survival was not reached. At the RP2D, 12 month PFS is 92%.

Conclusions: Twice weekly ixazomib dosing in combination with pomalidomide and dexamethasone is a well-tolerated regimen with encouraging activity in a lenalidomide-refractory and high-risk RRMM population with a median PFS of 13 months.

Nadeem:GPCR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Barth:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees. Bianchi:Karyopharm: Consultancy, Honoraria; MJH: Honoraria; Jacob D. Fuchsberg Law Firm: Consultancy; Pfizer: Consultancy, Honoraria. Sanchorawala:Proclara, Caelum, Abbvie, Janssen, Regeneron, Protego, Pharmatrace, Telix, Prothena: Consultancy; Celgene, Millennium-Takeda, Janssen, Prothena, Sorrento, Karyopharm, Oncopeptide, Caelum, Alexion, Pfizer, Janssen, Attralus, Proclara, Caelum, Abbvie, Janssen, Regeneron, Protego, Pharmatrace, Telix, Prothena: Consultancy, Research Funding, Speakers Bureau. Richardson:Oncopeptides: Consultancy, Research Funding; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Takeda and GSK: Other: Travel expenses from Takeda and GSK; Takeda, Abbvie, GSK, and Celgene: Consultancy; Takeda, Celgene, and GSK: Honoraria; Takeda: Research Funding.