Carfilzomib or bortezomib with lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): Long-term follow-up of the ECOG-ACRIN ENDURANCE phase 3 trial.

7540 Background: The combination of a proteasome inhibitor (PI) with lenalidomide (R) and dex (d) has been a common initial therapy for newly diagnosed myeloma (NDMM). We designed a randomized phase 3 trial to examine if carfilzomib (K), a next generation PI, improved progression free survival (PFS) compared with bortezomib (V) when either is combined with Rd for initial treatment of NDMM. Initial analysis at a median follow up of 15.3 months (mos) showed comparable PFS for both triplets. We present the long-term results of the trial with ~70 months median follow up. Methods: Patients (Pts) with NDMM, were randomized 1:1 to receive VRd or KRd for 36 weeks followed by a 2 nd randomization (1:1) to indefinite versus 2 yrs of R maintenance. Pts without del17p, t(14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included V 1.3 mg/m 2 on days(d) 1, 4, 8, and 11 (d1, 8 for cycles 9-12), R 25 mg d1-14, and d 20 mg d1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received K 36 mg/m 2 d1, 2, 8, 9, 15, 16 with R 25 mg daily on d1-21 and d 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance used 15 mg R d1-21 q4 wks. Results: The study accrued 1087 pts (VRd=542, KRd=545). Median age was 65y; baseline characteristics including intent to transplant were similar across the arms. Median induction duration (mos; IQR) was 7.2 (3.4-8.9) and 8.4 (5.1-9.1) for VRd and KRd, respectively; 59.8% in VRd and 45.3% in KRd did not proceed to Step 2. Median PFS (mos) was VRd=41.9 and KRd=44.6; HR = 0.89 (0.76-1.04). Toxicity data, PFS sensitivity analyses and OS probabilities are as in the table. Conclusions: In this randomized trial, with median follow up of nearly 6 years, KRd and VRd had comparable PFS and OS in an intent to treat analysis. While similar numbers proceeded to SCT in the 2 arms, more did so during induction in the VRd arm while more patients in the KRd arm went to SCT later. VRd remains a standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations. Clinical trial information: NCT01863550 . N (%) VRd(n=527) KRd(n=526) SCT anytime 186 (34.3) 183 (33.6) SCT without Step 2 registration 146 112 Median Time to SCT (mos; range) 7.7 (3.5-83.9) 10.6 (3.7-70.6) Grade 3-4 Treatment-Related Toxicity 315 (59.8) 344 (65.4) Grade 5 Treatment-Related Toxicity 2 (0.4) 9 (1.7) Grade 5 All Events 11 (2.1) 20 (3.8) Survival outcomes HR Median (95% CI) Median (95% CI) PFS Primary: PD or death within 3 months of last evaluation as events 0.89(0.76-1.04) 41.9(35.7, 50.3) 44.6(38.2, 51.9) PFS Sensitivity: All deaths as events, 0.87(0.75-1.02) 39.5(34.9, 46.0) 42.8(37.4, 49.7) PFS Sensitivity: Censor at alternate Rx 0.83(0.69-0.99) 35.0(31.3, 42.6) 38.7(34.7, 49.0) PFS Sensitivity: Event at alternate Rx 0.84(0.73-0.97) 18.0(14.2, 23.0) 24.4(20.9, 27.9) Overall survival 0.92(0.75-1.12) 119(100, NE) 118(103-NE)