Bortezomib-Based Therapy Overcomes the Adverse Impact of Renal Impairment in Transplant Eligible Patients: An Analysis of the Prospective Randomized EMN02/HO95 Study

Renal impairment (RI) is a common complication of symptomatic myeloma (MM), and is associated with high risk of early death, infectious and other complications, treatment delays and dose modifications which may adversely affect patients' outcomes. Immediate anti-myeloma therapy and vigorous supportive care may improve renal function in many patients. Bortezomib-based therapy, preferably a triplet, is considered the primary choice for newly diagnosed MM patients with RI, according to IMWG recommendations. High dose melphalan (HDM) with autologous stem cell transplantation (ASCT) is a standard therapy for eligible myeloma patients but, in those with RI, dose reduction for melphalan is required and toxicity is increased; dose modification for moderate / severe RI is also required for oral melphalan. In the current analysis we evaluated the importance of moderate/severe RI in the outcomes of patients that were enrolled in the large prospective EMN02/HO95 study.

The prospective randomized EMN02/HO95 trial compared 4 cycles of bortezomib-melphalan-prednisone (VMP) vs HDM with ASCT (either single or double), as intensification therapy after induction with bortezomib-cyclophosphamide-dexamethasone (VCD) (Cavo et al, ASCO 2016, abstract #8000). A second randomization to consolidation therapy with 2 cycles of VRD vs no consolidation followed intensification with either VMP or HDM (Sonneveld et al ASH 2016, abstract 242), while lenalidomide maintenance (10 mg continuously) was given until progression or toxicity in all patients in both arms. From February 2011 to April 2014, 1510 symptomatic MM patients aged ≤ 65 years were enrolled, of whom 1499 were eligible and of which 1211 were randomized (stratified by ISS stage) to VMP (N=505) or HDM (1 or 2 ASCT) (N=706) and 903 eligible patients were randomized to consolidation (N=459) or no consolidation (N=444) with VRD. Patients on dialysis or with creatinine clearance (CrCl) < 15 ml/min were excluded from enrollment in the study and data for CrCl were available in 1189 patients, of which 136 (11.4%) had a CrCl<50 ml/min.

Median age was 58 (range 29-66). ISS stage was -1 in 41.6%, -2 in 38.3 % and -3 in 20.1%; however, 71.6% of patients with RI had ISS-3 (p<0.001). High risk cytogenetics [defined as presence of t(4;14), t(14;16) or del17p (available in 890 patients)] were present in 24.7% and del1p/amp1q (available in 914 patients) were present in 41.6%. Elevated serum LDH (>ULN) was found in 13.7% of patients at diagnosis and per revised ISS (R-ISS), 28.7% were R-ISS-1, 61.6% R-ISS-2 and 9.6% R-ISS-3.

Patients with RI presented more often with increased serum LDH (25% vs 12%, p<0.001), had similar incidence of t(4;14)/t(14;16) (14.8% s 14.7%, p=0.983) and del17p(14.7% vs 10.1%, p=0.14), however, they had more often del1p36/amp1q21 (55.2% vs 39.8%, p=0.003) than patients with CrCl>50 ml/min. According to R-ISS more patients with RI were rated as stage 3 (34.8% vs 6.1%) and fewer as stage 1 (3.6% vs 27.6%) (p<0.001). Among patients with RI, 54.4% were randomized to receive HDM and 45.6% to VMP (p=0.31) after VCD induction.

The median follow up is 38 months and 3-year PFS is 61% for all patients. For patients that presented with RI, the 3-year PFS is 54% vs 62% for non-RI patients (p=0.059). However, in multivariate analysis, R-ISS stage and HDM vs VMP intensification (HR:0.693, p<0.001) were independently associated with PFS, but not the presence of RI at start of induction therapy (p=0.842).

Thus, in a large number of transplant eligible, symptomatic patients with MM, of which 11.4% presented with moderate to severe renal impairment (CrCI 15-49 ml/min), bortezomib-based induction and intensification therapy overcame the adverse impact of RI.