P-227: Alternate day dosing of pomalidomide in patients with refractory/relapsed multiple myeloma (RRMM): Results of a multicenter, single arm phase 2 trial (SAKK 39/16 OptiPOM Study)

Abstract

<h3>Background</h3> Pomalidomide (POM) with dexamethasone (DEX) is approved in patients (pts) with relapsed and refractory (RRMM) myeloma and achieved a progression free survival (PFS) between 4.0 and 4.6 months in two pivotal phase III trials (MM-003 and MM-010). In addition, POM-DEX is a current standard backbone for triplet combinations in RRMM. However, POM-DEX with registered POM dosing (4mg daily, 21/28 day cycle) has significant toxicity with G3/4 neutropenia (48%), anemia (33%), infections (34%) and thrombocytopenia (22%) in MM-003, and up to 85% G3/4 neutropenia in triplets containing CD38 antibodies. The relationship between dose, efficacy and toxicity of POM is poorly established and POM delivered on a 2mg daily continuous schedule was similarly active compared to the standard schedule, but less toxic. Half life time of POM (7.5h) is significantly longer compared to lenalidomide (3h) with a slow decline of the POM plasma concentration at the terminal phase. Alternate day dosing of POM 4mg may therefore maintain efficacy while mitigating toxicity. This multicenter, open label, non-randomized phase II study investigated the activity and toxicity of POM 4mg given continuously every second day in RRMM pts. <h3>Methods</h3> Inclusion criteria matched MM-003. Pts with RRMM must have had ≥ 2 prior lines including bortezomib (BORT), lenalidomide (LEN), adequate alkylator treatment, and progressive myeloma on or within 60 days of the last MM treatment. Continuous oral POM 4mg on alternate days 1 to 28 was combined with weekly oral DEX 40mg (pts > 75 years 20mg) until intolerance or progression (PD). Pts received prophylaxis with acyclovir/valacyclovir, cotrimoxazole and ASS. Prophylactic G-CSF was not allowed. Primary endpoint was overall response rate (ORR, minimal response (MR) or better by IMWG criteria). Secondary objectives were overall survival (OS), 12 months OS, PFS and adverse events (AE). <h3>Results</h3> 34 patients were enrolled (median age 75 yrs, range 52-87) with time from diagnosis of 5.1 yrs (range 1.9-16.8). Prior treatments included LEN (100%), BORT (100%), alkylator (100%), carfilzomib (29%) and daratumumab (27%); 14 (41%) pts had high-risk cytogenetic features. Median treatment duration was 3.6 months. G3/4 AE occurred in less than one quarter of patients: (neutropenia 24%; anemia 18%; infections 18%; thrombocytopenia 12%). Neutropenic fever was not observed. ORR was 29 % (95% confidence interval [CI], 16%-50%; 3 (9%) VGPRs, 6 (8%) PRs and 1 (3%) MR; 15 pts (44%) achieved SD. 9 pts (26%) progressed. Median PFS was 4.2 months (95% CI, 1.9-5.5 months). OS at 12 months was 66.5% (95% CI, 47.6-79.9). <h3>Conclusion</h3> POM 4mg on an alternate day continuous dosing schedule is an active and well-tolerated option to deliver POM-DEX to RRMM pts and is especially reasonable for patients at increased risk of toxicity. This dosing schedule may have comparable efficacy, improved safety and should be explored in triplet combination.