Background: Carfilzomib (K)-based combinations have been established as effective frontline and relapse regimens in pts with multiple myeloma (MM).
Aims: In this randomized phase II trial we evaluated the impact of either Revlimid (R) or Thalidomide (T) as combination partner for K and dexamethasone (KRd or KTd) on outcome in pts with newly diagnosed MM (NDMM) not eligible for autologous transplantation (TNE). Further, we evaluated the role of one year K maintenance therapy compared to observation.
Methods: One hundred twenty two pts have been enrolled (ITT population). Median age was 75 yrs, ISS stage I/II/III: 29 (23.8%)/48 (39.3%)/45 (36.9%), ECOG stage 0/1: 64 (52.5%) / 58 (47.5%). t(4;14) ± del17p was noted in 15 (16.3%) of 92 pts with results available. Pts were randomized to 9 cycles of KRd or KTd, and 107 pts received at least one full cycle. Carfilzomib (K) was started with 20mg/m2 at d 1 of cycle 1, and was continued with 27mg/m2 for the first 2 cycles (d 1 + 2, 8 + 9, 15 + 16 schedule); followed by K administration at 57mg/m2 once weekly for a 28 d cycle. Thalidomide 100mg/d (50mg in pts >75 yrs of age), d 1-28, or Revlimid 25mg/d (15mg in pts 375 yrs of age) d 1-21. Dexamethasone 40mg (20mg in pts 375 yrs of age) once/week. After induction, pts with 3SD were randomized to K maintenance (d 1 and 15) for 12 cycles or observation. MRD was assessed by NGF with a sensitivity of 10-6 in pts with ≥VGPR. Survival estimates were calculated according to Kaplan-Meier and survival curves were compared with the log-rank test. PFS and OS results presented are given for the ITT population. This trial is registered on clinicaltrials.gov (NCT02891811).
Results: Median follow-up was 25.3 mos, 15 pts discontinued therapy within the first cycle due to patient (3) or investigator (1) decision, AE/toxicity (8), death or progressive disease (2) or other reason (1). Overall response rate was 91.3% in the entire group with available data (n=115). Results for sCR, CR, VGPR, PR, and ORR for KRd and KTd were similar between both groups (7.3%/10.0%, 27.3%/33.3%, 38.2%/35.0%, 14.5/16.7%, 87.3%/95.0%, respectively). Minor response was noted in 4 (3.5%), stable disease in 5 (4.3%) and progressive disease in 1 (0.8%) pts.
PFS (median 26.9 and 23.5 mos, p=0.832) and OS (not reached vs 52.2 mos, p=0.398) were similar between the KRd and KTd group, respectively. The OS rate at 36 mos was 82% in both groups. MRD testing was performed in 57 pts at time of CR/VGPR. Of those, 43.9%, (20.5% of the ITT group) pts were found to be MRDneg. PFS was significantly longer in MRDneg vs. MRDpos pts (p=0.003). Seventy six pts were randomized to K maintenance therapy or observation. Median PFS was numerically higher in the pts with K maintenance treatment (median 33.0 vs 24.0, p=0.714), but the difference was not statistically significant. Data on OS are not mature yet (only 9 events).
Grade 3/4 hematologic AEs were anemia (4.1%), leukopenia (0.8%), thrombocytopenia (7.4%), while non-hematologic grade 3/4 AEs were infection (20.5%), GI-disorders (7.4%), hypertension (7.4%), renal and cardiac impairment/failure (6.6% and 8.2% respectively).
Summary/Conclusion: Our data show similar high efficacy of KRd and KTd in elderly NTE NDMM pts, including no difference in ORR (KRd and KTd, 87.3% and 95%, respectively), PFS and OS. Overall survival rate at 3 yrs was 82%. Median PFS was significantly longer in MRDneg pts. PFS was numerically, but not statistically longer in pts on K maintenance vs observation. Treatment was associated with an acceptable tolerance profile.