Continuous Treatment with Lenalidomide and Low-Dose Dexamethasone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma in Asia: Subanalysis of the First Trial
Authors: Lu Jin , Lee Jae Hoon , Huang Shang-Yi , Qiu Lugui , Lee Je-Jung , Liu Ting , Yoon Sung-Soo , Kim Kihyun , Shen Zhi Xiang , Eom HyeonSeok , Chen Wenming , Min Chang-Ki , Kim Hyo Jung , Lee Jeong Ok , Kwak Jae Yong , Yiu Wai , Chen Guang , Ervin Haynes Annette , Hulin Cyrille , Facon Thierry 
Published: October 2019

Abstract
Background: Given the increasing incidence of multiple myeloma (MM) in Asian countries, effective treatment options for these patient (pt) populations are needed (Kim et al, Am J Hematol, 2014). The pivotal phase 3 FIRST trial investigated continuous treatment with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) in pts with newly diagnosed MM (NDMM) who were ineligible for transplant from 18 countries, including China, South Korea, and Taiwan. Treatment with Rd continuous in the FIRST trial improved progression-free survival (PFS; hazard ratio [HR] = 0.72; P < .001) and overall survival (OS; HR = 0.78; P = .02) compared with melphalan-prednisone-thalidomide (MPT; Benboubker et al, N Engl J Med, 2014). This subanalysis of the FIRST trial examined the efficacy and safety of Rd continuous in the Asian population.
Methods: Pts with NDMM aged ≥ 65 years or ineligible for transplant were randomized to 3 treatment arms: Rd continuous, Rd for 18 cycles (Rd18; 72 weeks), or MPT for 12 cycles (72 weeks). The primary endpoint was PFS in pts treated with Rd continuous vs MPT (primary comparators). Secondary endpoints included OS, overall response rate (ORR), duration of response (DOR), and safety. Data cutoff was May 24, 2013; response and progression were assessed by an independent response adjudication committee. OS was assessed with extended follow-up at a data cutoff of March 3, 2014.
Results: Of the 114 pts enrolled in China, South Korea, and Taiwan, the median age (68 yrs [range, 43-86 yrs]) was similar across the Rd continuous (n = 36), Rd18 (n = 38), and MPT (n = 40) arms but was lower than that of the overall study population (73 yrs [range, 40-92 yrs]). Compared with the overall population, pts in Asia also had a higher rate of International Staging System stage III disease (45% in Asia vs 41% overall), a higher rate of Eastern Cooperative Oncology Group performance status ≥ 2 (28% in Asia vs 22% overall), and double the rate of severe renal insufficiency (creatinine clearance < 30 mL/min; 18% in Asia vs 9% overall), the latter of which was more frequent in the MPT (23%) and Rd18 (24%) arms vs the Rd continuous (8%) arm. There were more male than female pts (58% vs 42%) in the Asian population, with the exception of the MPT arm (50% each). The median treatment duration was 18.4 mos (range, 0.5-35.9 mos) for Rd continuous, 11.0 mos (range, 0.6-19.6 mos) for Rd18, and 11.1 mos (range, 0.3-19.1 mos) for MPT. Treatment with Rd continuous vs MPT resulted in a 39% reduction in the risk of progression or death (hazard ratio [HR] = 0.61; 95% CI, 0.33-1.14; Table). Rates of 2-year PFS were nearly doubled with Rd continuous (48%) vs MPT (25%). Rd continuous also resulted in a 48% reduced risk of death vs MPT (HR = 0.52; 95% CI, 0.24-1.13). Rates of 3-year OS were greater with Rd continuous (70%) vs MPT (56%). Similar improvements were observed for PFS and OS with Rd continuous vs Rd18. ORR was greater in the Rd continuous (78%) arm vs the Rd18 (66%) and MPT (58%) arms. Median DOR was not reached for Rd continuous and was 17.2 and 13.8 mos for Rd18 and MPT, respectively. The most frequent grade 3/4 adverse events with Rd continuous, Rd18, and MPT treatment were neutropenia (25%, 34%, 44%), anemia (19%, 5%, 15%), pneumonia (6%, 24%, 15%), and thrombocytopenia (14%, 5%, 5%). Deep vein thrombosis was reported in only 1 pt on the MPT arm, and pulmonary embolism was reported in 1 pt on each treatment arm. There were no reports of second primary malignancies in the Asian population.
Conclusions: Rd continuous treatment was associated with numerically larger PFS and OS benefits and higher response rates compared with MPT in the Asian subgroup of the FIRST trial, although pt numbers were small. Results from the Asian subgroup were consistent with that of the global population, with no unexpected safety signals observed, a low rate of thromboembolic events, and no second primary malignancies as of the data cutoff. These findings support the use of Rd continuous as standard treatment for pts with NDMM who are ineligible for stem cell transplant, including in Asian populations.

Disclosures
Qiu: Celgene Corporation: Speakers Bureau; Johnson & Johnson: Speakers Bureau; Roche: Speakers Bureau. Yiu:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Ervin Haynes:Celgene Corporation: Employment, Equity Ownership. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees.