IXAZOMIB WITH EITHER DEXAMETHASONE, CYCLOPHOSPHAMIDE-DEXAMETHASONE, THALIDOMIDE-DEXAMETHASONE OR BENDAMUSTINE-DEXAMETHASONE FOLLOWED BY IXAZOMIB MAINTENANCE IN ELDERLY NEWLY DIAGNOSED MYELOMA PATIENTS

Background The proteasome inhibitor (PI) Bortezomib is a backbone of induction regimens for newly-diagnosed multiple myeloma (NDMM) patients (pts), although it is usually administered for a limited number of cycles due to its parenteral administration and risk of peripheral neuropathy. The oral PI Ixazomib is a convenient and tolerable drug for elderly pts. Aims We present a preliminary analysis of the randomized phase II UNITO-EMN10 study of ixazomib in combination with dexamethasone (Id), cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd), followed by Ixazomib maintenance in transplant-ineligible NDMM pts. Methods Transplant-ineligible NDMM pts ≥65 years were enrolled. Treatment consisted of 9 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 or Id plus either Cyclophosphamide 300 mg/m2 orally on days 1,8,15, Thalidomide 100 mg/day or Bendamustine 75 mg/m2 iv on days 1,8; followed by ixazomib maintenance (4 mg on days 1,8,15) for up to 2 years. The primary endpoint was the selection of the most effective regimen considering a 2-year progression-free survival (PFS) ≥65% as satisfactory; secondary endpoints were very good partial response (VGPR), PFS, overall survival (OS) and adverse events (AEs). Results 171 pts (Id 41, ICd 59, ITd 60 and IBd 11) with a median age of 74 years started treatment. The IBd arm was closed due to low enrolment (February 2017); the Id arm, according to predefined stopping rules, was closed due to high risk of inefficacy (March 2018) after the first 41 pts were enrolled. The ICd and ITd arms completed the enrollment. The median follow-up is 18.2 months. Overall, 103 pts (59%) completed the induction phase. After induction, overall response (ORR) and ≥VGPR rates were 57% and 26% with Id, 75% and 49% with ICd, 84% and 46% with ITd and 73% and 27% with IBd; overall, 12/50 pts (24%) achieved a minimal residual disease negativity. The most common reasons for induction discontinuation were progressive disease (PD) in the Id (62%), IBd (50%) and ICd (32%) arms and AEs in the ITd (38%) arm. 103 pts (59%) started maintenance; 50 (29%) were still receiving treatment at the last data cut-off. Maintenance was well tolerated: all-grade (G) non-hematologic AEs occurred in 30% of pts but G3-4 AEs were limited (3%). The main reason for maintenance discontinuation was PD (37%), while only 11% of pts discontinued due to AEs. At 2 years, 37% of pts in the Id, 40% in the ICd, 19% in the ITd and 50% in the IBd arm were alive and free from progression; the median PFS was 10.5 months with Id, 17.5 with ICd, 12.9 with ITd and 22.9 with IBd. The median OS was not reached in all arms; at 2 years, 81%/78%/79%/77% of pts were alive in the Id/ICd/ITd/IBd arms. Early death rate (<60 days from start therapy) was 1%. During induction, 12%/17%/30%/36% of pts experienced at least 1 G≥3 non-hematologic AE in the Id/ICd/ITd/IBd arms, among which the most frequent were dermatological (0/2%/7%/0), gastrointestinal (2%/5%/7%/0) and neurological (7%/7%/13%/9%). Serious AEs (SAEs) were more common in the ITd arm (43%) than in the Id (27%), ICd (36%) and IBd arms (27%). Conclusion Based on the 2-year PFS probability, the primary endpoint of the study was not met. However, Id in a triplet with an alkylating agent or thalidomide was more effective than the doublet Id in elderly NDMM pts, Nevertheless, ITd was burdened by more frequent G3-4 AEs and SAEs resulting in higher treatment discontinuation rates than ICd. Single-agent ixazomib maintenance was well tolerated.