Phase 2 Study of Lenalidomide in Combination with Low-Dose Dexamethasone in Japanese Transplantation-Ineligible Newly-Diagnosed Multiple Myeloma Patients
Authors: Chou Takaaki , Shinagawa Atsushi , Uchida Toshiki , Taniwaki Masafumi , Hirata Hirokazu , Ishizawa Kenichi , Matsue Kosei , Ogawa Yoshiaki , Shimizu Takayuki , Otsuka Maki , Matsumoto Morio , Iida Shinsuke , Terui Yasuhito , Matsumura Itaru , Ikeda Takashi , Takezako Naoki , Ogaki Yumi , Midorikawa Shuichi , Houck Vanessa , Ervin-Haynes Annette , Suzuki Kenshi 
Published: October 2019

Abstract
Introduction: Lenalidomide (LEN) plus low-dose dexamethasone (Rd) has been shown to be effective and to have a manageable safety profile in non-Japanese patients (pts) with newly diagnosed multiple myeloma (NDMM) (Rajkumar, Lancet Oncol 2010). Recently, the FIRST trial showed prolonged progression-free survival (PFS) and favorable overall survival (OS) benefits for pts who were administered continuous Rd until progressive disease (PD) vs. the standard of care melphalan-prednisolone-thalidomide (Facon, Blood 2013). In Japan, the combination of melphalan- prednisolone -Velcade®(MPV) is the current standard of care for transplant-ineligible NDMM pts. However, prolonged treatment (Tx) with MPV is associated with increased toxicity including peripheral neuropathy (PN) and bone marrow suppression. Consequently, continuous Tx with MPV may have limited benefits due to toxicity and related Tx discontinuation. MM-025 is a phase 2, multicenter, open-label, registration, single-arm trial. It aimed to evaluate the efficacy and safety of the continuous Rd regimen in Japanese NDMM pts who are transplant-ineligible.
Methods: The study enrolled Japanese NDMM pts who were aged ≥ 65 years (yrs), or were not candidates for hematopoietic stem cell transplantation. Pts with an ECOG performance status (PS) score &gt; 2 or with grade ≥ 2 PN were excluded from the study. Tx consisted of LEN (25 mg once daily on days 1–21 of each 28-day cycle) and dexamethasone (40 mg for pts aged ≤ 75 yrs or 20 mg for pts aged &gt; 75 yrs, once daily on days 1, 8, 15, and 22 of each 28-day cycle) until PD or discontinuation. The dose of LEN was adjusted according to baseline renal function: 25 mg/day for pts with normal or mild renal impairment (RI) (creatinine clearance [CrCl] ≥ 60 mL/min); 10 mg/day for moderate RI (CrCl ≥ 30 to &lt; 60 mL/min); and 15 mg every other day for those with severe RI (CrCl &lt; 30 mL/min, not requiring dialysis). Pts who discontinued Tx were followed up every 2 months (mos) for ≥ 5 yrs from the start of Tx. The primary endpoint was overall response rate (ORR; defined as complete response [CR] + very good partial response [VGPR] + partial response [PR]) based on the IMWG criteria. The secondary endpoints included time to response (TTR), duration of response (DOR), PFS, OS, and safety. Statistical analyses included the one-sample binomial test for ORR and Kaplan-Meier analysis for DOR, PFS, and OS. The data cutoff date for this analysis was November 2013.
Results: A total of 26 pts were enrolled. Of these, 46.2% of pts (n = 12) were aged &gt; 75 yrs, 50.0% (n = 13) were male, 19.2% (n = 5) had ISS stage III disease, 23.1% (n = 6) had an ECOG PS score of 2, and 7.7% (n = 2) had severe RI (CrCl &lt; 30 mL/min). With a median follow-up of 7.4 mos, the median Tx duration was 6.4 mos. The ORR was 83.3%, including VGPRs (12.5%) (n=3) and PRs (70.8%) (n=17). The median TTR was 2.0 mos. Due to the short follow-up DOR, PFS, and OS were not reached at data cutoff. The most common grade 3–4 adverse events (AEs; reported in &gt; 10% of pts) were anemia (19.2%), neutropenia (15.4%), and rash (11.5%). The most frequently reported AEs (≥ 20% incidence) were rash, constipation, anemia, nasopharyngitis, and insomnia. A total of 8 pts (30.8%) discontinued the study: 4 due to AEs, 3 through the investigator’s decision and 1 due to protocol deviation. No deaths, thromboembolic events, or second primary malignancies were reported.
Conclusion: Continuous Rd was effective and well tolerated by Japanese transplant-ineligible NDMM pts. These findings are consistent with those reported in the FIRST trial (Facon, Blood 2013) and support the use of the Rd combination regimen as a first-line Tx for this pt group.

Disclosures
Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Taniwaki:Celgene Corporation: Honoraria, Research Funding. Iida:Celgene K.K.: Honoraria, Research Funding. Matsumura:Celgene: Honoraria. Ogaki:Celgene K.K.: Employment. Midorikawa:Celgene K.K.: Employment. Houck:Celgene Corporation: Employment. Ervin-Haynes:Celgene Corporation: Employment.