Outcomes for Older Patients in Stratus (MM-010), a Single-Arm, and Phase 3b Study of Pomalidomide + Low-Dose Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma
Authors: Palumbo Antonio , Dimopoulos Meletios A. , Weisel Katja , Cavo Michele , Ocio Enrique M. , Corradini Paolo , Delforge Michel , Oriol Albert , Goldschmidt Hartmut , Blanchard Maria Jesus , Conticello Concetta , Vacca Angelo , Hansson Markus , Slaughter Ana , Simcock Mathew , Herring Jennifer , Peluso Teresa , Sternas Lars , Zaki Mohamed H. , Moreau Philippe 
Published: October 2019

Abstract

Background: Survival of patients (pts) with multiple myeloma (MM) decreases with increased age (Pulte, Oncologist, 2011). In addition, MM pts with advanced disease who have exhausted treatment (Tx) with novel agents have a poor prognosis (Kumar, Leukemia, 2012). Pomalidomide (POM) is a new oral agent with antimyeloma, stromal cell inhibitory, and immune modulatory effects (Quach, Leukemia, 2010; Mark, Leuk Res, 2014). In the pivotal MM-003 trial, POM in combination with low-dose dexamethasone (LoDEX) demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits vs. high-dose dexamethasone, with a tolerable safety profile in refractory or relapsed and refractory MM (RRMM; Dimopoulos, Blood, 2013). In MM-003, significant PFS and OS benefits with POM + LoDEX Tx were seen in different age groups; tolerability and dose intensity were not affected by age (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 a large pt population. This analysis examines outcomes by age (≤ 65 vs. > 65 yrs, and ≤ 70 vs. > 70 yrs).
Methods: Eligible pts had refractory or relapsed and refractory disease (progressive disease [PD] during or within 60 days of last line of Tx), having previous BORT and LEN failure and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to the last prior Tx line. Pts with Eastern Cooperative Oncology Group performance status > 2 were excluded. Pts received 28-day cycles of POM 4 mg D1-21 + DEX 40 mg (20 mg for pts aged > 75 yrs) once weekly. All pts received thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent based on clinical recommendations. Tx continued until PD or unacceptable toxicity. The primary endpoint was safety; the secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, and OS. Outcomes were analyzed by pt age at baseline (≤ 65 vs. > 65 yrs, and ≤ 70 vs. > 70 yrs).
Results: As of March 17th, 2014, a total of 456 pts have been enrolled, and 452 had received POM + LoDEX; 48% were aged ≤ 65 yrs, 52% were > 65 yrs, 71% were ≤ 70 yrs, and 29% were > 70 yrs. Pts were heavily pretreated (median 4-5 prior Tx depending on age subgroup). Median follow-up was 6.8 mos. Younger pts (≤ 65 yrs) were more likely to have better renal function (creatinine clearance ≥ 60 mL/min; 80%) than those aged > 65 (49%). Median relative dose intensity was similar independent of age (range, 0.95-0.97 mg/day). The most common grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) across age groups were neutropenia, anemia, thrombocytopenia, and pneumonia (Table). Gr 3-4 deep vein thrombosis (DVT) with prophylaxis was 1% in each subgroup. Discontinuations of POM due to TEAEs were low in pts aged ≤ 65 (0.9%), > 65 (3.0%), ≤ 70 (1.3%), and > 70 (3.8%) yrs. Outcomes by age are summarized in the Table. ORR was consistent for pts aged ≤ 65 (38%), > 65 (32%), ≤ 70 (35%), and > 70 (34%) yrs; DORs were 5.1, 6.8, and 5.8 mos and not estimable (NE) in these pt populations, respectively. Median PFS and median OS were similar across all age groups (PFS range, 4.0-4.9 mos, OS range, 10.6-11.5 mos).
Conclusions: The data reported here further demonstrate the tolerability and efficacy of POM + LoDEX in pts with RRMM in the age subgroups analyzed (≤ 65 vs. > 65 yrs and ≤ 70 vs. > 70 yrs). Safety profiles were consistent, while dose intensity was similar across age groups. PFS, OS, and response rates were comparable with those previously reported in trials of POM + LoDEX in pts with RRMM and reinforce 4 mg POM as an appropriate starting dose irrespective of age. These data support POM + LoDEX as a standard Tx option for pts with refractory or RRMM regardless of age.
Table 1. Age ≤ 65 yrs (n = 215) Age > 65 yrs (n = 237) Age ≤ 70 yrs (n = 319) Age > 70 yrs (n = 133) Grade 3-4 TEAEs, % Neutropenia Anemia Thrombocytopenia Pneumonia 38 30 22 13 41 24 16 10 38 29 21 11 44 23 15 11 Grade 3-4 EOI, % DVT/PE PN 1 <1 1 2 1 1 1 2 Efficacy (n = 218) (n = 238) (n = 322) (n = 134) ORR (≥ PR), % (95% CI) Median DOR (95% CI), mos Median PFS (95% CI), mos Median OS (95% CI), mos 38 (31-44) 5.1 (3.8-6.7) 4.1 (3.3-4.9) 10.9 (9.0-NE) 32 (26-38) 6.8 (4.7-11.5) 4.6 (3.6-5.6) 10.6 (9.3-NE) 35 (30-41) 5.8 (20.0-28.1) 4.0 (3.2-4.8) 10.9 (9.2-NE) 34 (26-42) NE (34.4-NE) 4.9 (3.7-6.7) 11.5 (8.5-NE)
EOI: events of interest; NE: Not evaluable.

Disclosures
Palumbo: Array BioPharma: Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy; Celgene Corporation: Honoraria. Cavo:Celgene: Consultancy, Honoraria, Speakers Bureau. Ocio:Celgene Corporation: Honoraria, Research Funding. Corradini:Celgene Corporation: Speakers Bureau. Delforge:Celgene Corp: Honoraria; Janssen: Honoraria. Oriol:Celgene Corporation: Consultancy. Goldschmidt:Celgene: Consultancy, Research Funding, Speakers Bureau. Slaughter:Celgene: Employment. Simcock:Celgene Corporation: Employment. Herring:Celgene Corporation: Employment. Peluso:Celgene: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene Corp: Employment, Equity Ownership. Moreau:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees.