Pomalidomide + Low-Dose Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma and Renal Impairment: Analysis of Patients from the Phase 3b Stratus Trial (MM-010)

Abstract Background: Treatment (Tx) with novel agents, including lenalidomide (LEN) and bortezomib (BORT), has extended survival of patients (pts) with multiple myeloma (MM); however, pts who have relapsed on or become refractory to Tx have significantly shortened overall survival (OS) and poorer outcomes (Kumar, Leukemia, 2012). Renal impairment (RI) occurs frequently, in approximately 20% to 40% of MM pts (Kastritis, Haematologica, 2007), and is a leading cause of death in this pt population (Korbet, J Am Soc Nephrol, 2006). In the phase 3 MM-003 trial, pomalidomide plus low-dose dexamethasone (POM + LoDEX) significantly extended progression-free survival (PFS) and OS vs. high-dose dexamethasone in pts in whom BORT and LEN Tx failed, including those with moderate RI (creatinine clearance [CrCl] < 60 mL/min; Weisel, Blood, 2013). STRATUS is a multicenter, single-arm, open-label, European, phase 3b trial to further evaluate safety and efficacy of POM + LoDEX in pts with refractory or relapsed and refractory MM (N = 456), including those with moderate RI. Methods: Pts must have had refractory or relapsed and refractory disease (progressive disease [PD] during or within 60 days of last line of Tx), at least 2 prior therapies, BORT and LEN failure after ≥ 2 cycles of each (alone or in combination), and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to their last line of Tx; pts with CrCl < 45 mL/min were excluded. POM was administered 4 mg D1-21/28-day cycle and LoDEX 40 mg/day (20 mg for pts aged > 75 yrs) on D1, 8, 15, and 22 until PD or unacceptable toxicity. All pts received thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent based on clinical recommendations. The primary endpoint was safety, and secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, and OS. For this analysis, pts were retrospectively grouped by baseline CrCl (< 60 mL/min vs. ≥ 60 mL/min). Results: A total of 456 pts have been enrolled, of whom 452 received POM + LoDEX and 165 (36%) had moderate RI (CrCl < 60 mL/min). After a median follow-up of 6.8 mos, the most frequently reported grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) in pts with moderate RI vs. without moderate RI (CrCl ≥ 60 mL/min) were neutropenia (39% vs. 40%), anemia (33% vs. 24%), and thrombocytopenia (19% vs. 19%); the most common Gr 3-4 nonhematologic TEAEs were pneumonia (12% vs. 11%), fatigue (6% vs. 4%), and hypercalcemia (4% vs. 4%), respectively. Only 2% of pts in each respective renal subgroup discontinued POM due to Tx-related TEAEs. Gr 3-4 renal toxicities were similar in both subgroups: acute renal failure occurred in 3% of pts with moderate RI and 2% of pts without moderate RI; blood creatinine increased in 2% and 1% of pts, respectively. Overall, Gr 3-4 deep vein thrombosis (DVT), pulmonary embolism (PE), and peripheral neuropathy (PN) were infrequent independent of renal status (Table). Median relative POM dose intensity was similar between subgroups (0.95 in pts with moderate RI vs. 0.96 in pts without moderate RI). In pts with moderate RI vs. without moderate RI, ORR was 35% vs. 34%, median DOR was 5.8 mos vs. 6.5 mos, median PFS was 3.7 vs. 4.6 mos, and median OS was 9.3 vs. not reached, respectively (Table). The 1-yr OS was 33% for pts with moderate RI vs. 53% for pts without moderate RI. Conclusions: POM + LoDEX has acceptable safety and efficacy profiles comparable to those observed in the pivotal MM-003 trial. Tolerability was consistent across renal function subgroups, with few discontinuations due to adverse events. In addition, responses to POM + LoDEX were similar between pts, irrespective of renal function. POM is currently being prospectively evaluated in pts with severe RI in the MM-008 (US) and MM-013 (EU) trials. Table.With Moderate RICrCl < 60 mL/min (n = 162)Without Moderate RICrCl ≥ 60 mL/min(n = 290)Grade 3-4 TEAEs, %Neutropenia Anemia Thrombocytopenia Pneumonia39 33 19 1240 24 19 11Grade 3-4 EOI, %DVT/PE PN2 20 1Efficacy(n = 165)(n = 291)ORR (≥ PR), % (95% CI) Median DOR (95% CI), mos Median PFS (95% CI), mos Median OS (95% CI), mos35 (27.9-43.0) 5.8 (3.7-NE) 3.7 (2.9-5.2) 9.3 (6.3-11.5)34 (28.9-40.1) 6.5 (4.7-7.9) 4.6 (3.7-5.6) NR (10.9-NR) EOI, events of interest; NE, not estimable, NR, not reached. Disclosures Weisel: Celgene Corporation: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Dimopoulos:Celgene: Consultancy, Honoraria. Cavo:Celgene: Consultancy, Honoraria, Speakers Bureau. Ocio:Celgene Corporation: Honoraria, Research Funding. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Delforge:Celgene Corp: Honoraria; Janssen: Honoraria. Oriol:Celgene Corporation: Consultancy. Goldschmidt:Celgene Corp: Consultancy, Honoraria, Speakers Bureau. Miller:Celgene Corporation: Employment, Equity Ownership. Peluso:Celgene: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene : Employment, Equity Ownership. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.