Phase II Study of the Bortezomib-Melphalan-Prednisolone Induction Therapy Followed By Lenalidomide-Plus-Dexamethasone Consolidation and Lenalidomide Maintenance in Non-Transplant Eligible Patients with Newly Diagnosed Symptomatic Multiple Myeloma (CANDLE trial)

Background

Bortezomib-melphalan-prednisolone (VMP) is a standard therapy for newly diagnosed multiple myeloma (NDMM) patients either ≧65 years of age, or not candidates for autologous stem cell transplantation (ASCT). However, the Japanese phase II study of VMP for NDMM using the same protocol of VISTA trial revealed that the duration of treatment was shorter (median 4.5 cycles vs 9 cycles) and the discontinuation rate was higher (39% vs 32%) than those of VISTA (Cancer Sci 104: 912, 2013). Therefore, we evaluated the efficacy and feasibility of reduced intensity VMP therapy (5 cycles) as induction followed by lenalidomide plus dexamethasone (Rd) consolidation (6 cycles) and lenalidomide maintenance therapy (until progression).

Patients and methods

In total, 83 pts with NDMM were recruited in this trial from 27 Japanese centers between October 2012 and August 2014. VMP included the IV or SQ administration of weekly bortezomib 1.3 mg/m² on days 1, 8, 15, and 22 in combination with oral melphalan 6 mg/m² and prednisone 60 mg/m² on days 1-4 of a 35-day cycle. Rd treatment consisted of lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly of a 28-day cycle. Lenalidomide maintenance therapy consisted of lenalidomide 10 mg daily on days 1-21 of a 28-day cycle. The responses were assessed according to the IMWG criteria after each cycle. The primary endpoint was median progression-free survival (PFS). Secondary endpoints included overall survival (OS) and overall response rate (ORR). Here, we presented the analysis of the PFS, OS and ORR data from the trial.

Results

Median age was 73 years (range, 61-84), and 36.1% of the patients were 75 years of age or older. As for International Staging System (ISS), 29.3% had stage I, 50.0% had stage II, and 20.7% had ISS stage III. FISH analysis revealed that 18.3% (15/82) had t(4;14), 8.5% (7/82) had del 17p, and 41.5% (34/82) had +1q21. Twelve patients (14.6%) had both t(4;14) and +1q21, 6 patients (7.3%) had both del 17p and +1q21, and only one patient (1.2%) had all of t(4;14), del 17p, and +1q21. The rates of partial response (PR) or better were 86.4% including sCR (22.2%), CR (9.9%), VGPR (21%), and PR (33.3%). The median PFS was 28.0 months and the 2-year OS was 82.6%. The median PFS of the patients who had t(4;14) and/or del-17p (n=21) was 28.6 months. Interestingly, the median PFS of the patients with t(4;14) and/or del-17p and/or 1q-gain (n=38) was short (20.5 months). However, there was no difference in OS between the two groups. The most commonly observed grade 3 or higher adverse events during VMP therapy were anemia (30%), neutropenia (16%), thrombocytopenia (5%), and GI toxicity (6%). Grade 3/4 adverse events during Rd therapy were white blood cell count decrease (7.0%), rash (5.3%), hyperglycemia (5.3%), and anemia (3.5%).

Summary

Treatment with 5 cycles of reduced intensity VMP followed by 6 cycles of Rd and lenalidomide maintenance induced longer PFS (28 months vs 26 month) and deeper response (≧CR: 32.1%, ≧VGPR: 53.1%, ORR 86.4% vs ≧CR: 19.8%, ORR: 69.8%) compared with the Japanese phase II VISTA trial. Grade 3 or higher adverse events were few and controllable. Therefore, this treatment approach is one of the optimal therapeutic options for elderly patients with NDMM.

Acknowledgment

This study was supported by ECRIN. We also thank Dr. Junichi Sakamoto for his excellent support.