MM-003 Phase 3 Study Of Pomalidomide In Combination With Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM): POM + Lodex Is Beneficial For Elderly Patients (> 65 Years of Age) (2013)

Abstract Background RRMM patients (pts) who have exhausted bortezomib (BORT) and lenalidomide (LEN) or thalidomide treatment (Tx) have short overall survival (OS; Kumar, 2012). MM pt survival decreases with increased age (Pulte, 2011). POM is a distinct oral IMiD® immunomodulatory agent with direct anti-myeloma, stromal cell–support inhibition, and immune-modulation activities (Quach, 2010). The US FDA approved POM for the Tx of pts who have received ≥ 2 prior Tx, including LEN and BORT, and have demonstrated disease progression (PD) on or within 60 days of completion of the last line of Tx. POM + LoDEX has demonstrated clinical benefit in pts aged ≤ 65 y and > 65 y (Jagannath, EHA 2013; Leleu, 2013). The randomized phase 3 study MM-003 demonstrated significant progression-free survival (PFS) and OS benefits for POM + LoDEX vs HiDEX, despite half of HiDEX pts subsequently receiving POM (San Miguel, EHA 2013). This analysis examined outcomes based on age (≤ 65 y vs > 65 y). Methods Pts had to be refractory to last prior Tx (PD during Tx or within 60 days) and exhausted BORT and LEN after ≥ 2 consecutive cycles of each (alone or in combination). Pts were randomized 2:1 to receive 28-day cycles of POM 4 mg D1-21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly or DEX 40 mg (20 mg for pts aged > 75 y) D1-4, 9-12, and 17-20. HiDEX was chosen as the comparator to isolate the effects of POM as at the time of trial design, it was the standard salvage Tx for heavily pretreated pts. Tx continued until PD or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included OS, overall response rate (ORR; ≥ partial response), and safety. Results 455 pts were randomized to POM + LoDEX (n = 302) or HiDEX (n = 153). 45% (135/302) of POM + LoDEX pts and 47% (72/153) of HiDEX pts were aged > 65 y. Since only 8% of POM + LoDEX and HiDEX pts were aged > 75 y, this analysis focused on pts aged ≤ 65 y vs > 65 y. Pts aged ≤ 65 y were more likely to have prior stem cell transplant (91% vs 45%), better renal function (creatinine clearance [CrCl] ≥ 60 mL/min: 78% vs 51%), and less advanced disease (ISS stage III: 28% vs 38%) vs pts aged > 65 y. For pts aged > 65 y, HiDEX pts were less likely to have CrCl ≥ 60 mL/min vs POM + LoDEX (43% vs 55%). All groups had a median of 5 prior Tx. Median follow-up was 10 mos. POM + LoDEX significantly extended PFS vs HiDEX in all pts, with similar benefits observed for pts aged ≤ 65 y or > 65 y (Table). For all pts, OS was significantly longer for POM + LoDEX vs HiDEX, with favorable results for POM + LoDEX in both age subgroups despite a large proportion of HiDEX pts subsequently receiving POM (Table). ORR was significantly higher for POM + LoDEX vs HiDEX in all pts and both age groups (Table). Median duration of POM Tx was similar in pts aged ≤ 65 y (4.4 mos) and > 65 y (4.0 mos). The most common grade 3/4 adverse events (AEs) for pts aged ≤ 65 y (POM + LoDEX vs HiDEX) were neutropenia (50% vs 20%), anemia (35% vs 39%), and infections (31% vs 19%). Neutropenia (45% vs 11%), anemia (30% vs 34%), and infections (30% in both arms) were also the most frequent grade 3/4 AEs for pts aged > 65 y. Grade 3/4 DVT/PE was infrequent (POM + LoDEX vs HiDEX): 1% vs 0% (≤ 65 y) and 1% vs 0% (> 65 y). Grade 3/4 peripheral neuropathy was also infrequent: 1% vs 2% (≤ 65 y) and 1% vs 0% (> 65 y). Discontinuation due to AE was low in pts aged ≤ 65 y (POM + LoDEX: 6%; HiDEX 10%) and > 65 y (POM + LoDEX: 12%; HiDEX: 11%). Importantly, the median relative POM dose intensity was consistent at 90% for both age groups. Conclusion POM + LoDEX significantly extended PFS, with comparable benefits across age groups (approximately 50% reduction in rate of progression). OS results were similar to that of the overall pt population, and favored POM + LoDEX in both age groups. Tolerability profiles were consistent for pts ≤ 65 y or > 65 y. POM at 4 mg appears to be a feasible starting dose for pts aged > 65 y. These data support considering POM + LoDEX as a standard Tx option in RRMM pts regardless of age. Disclosures: Weisel: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Off Label Use: POM is approved in the US but not in Europe. San Miguel:Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Song:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Delforge:Celgene: Honoraria. Karlin:Celgene: Export board committee Other, Honoraria; Janssen: Honoraria. Goldschmidt:Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Moreau:Celgene: Honoraria, Speakers Bureau. Oriol:Celgene: Consultancy. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Alegre:Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Martinez-Lopez:Celgene: Honoraria, Research Funding. Chen:Celgene: Consultancy, Honoraria, Research Funding. Knop:Celgene: Honoraria. Yu:Celgene: Employment, Equity Ownership. Watkins:Celgene: Employment, Equity Ownership. Sternas:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Dimopoulos:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees.