Bortezomib (VEL) Based Regimens in Multiple Myeloma (MM) Patients with Renal Impairment (RI): A Preliminary Retrospective Italian Multicenter Study
Authors: Gentile Massimo , Ciolli Stefania , Petrucci Maria Teresa , Galimberti Sara , Mele Giuseppe , Casulli Antonio Francesco , Mannina Donato , Piro Eugenio , Pinotti Graziella , Palmieri Salvatore , Catalano Lucio , Callea Vincenzo , Offidani Massimo , Musto Pellegrino , Bringhen Sara , Baldini Luca , Tosi Patrizia , Di Raimondo Francesco , Boccadoro Mario , Palumbo Antonio , Cavo Michele , Morabito Fortunato 
Published: October 2019

Abstract
RI is a common and severe complication throughout the course of MM. Vel, either as single agent or combined with other drugs, has been shown to be highly active in MM pts with varying degrees of RI. We retrospectively analyzed the outcome of 105 pts with RI (CrCl<80 ml/min), who were treated with Vel-based regimens between November 2003 and June 2008. Of these 105 pts, 26 were previously untreated, while the remaining 79 were either relapsed (49 pts) or refractory (30 pts) to a median single line of prior therapy (range 1–5). Median age was 64 years (range 39–82); 43% were female. Isotypes were IgG in 37%, light chain only in 32%, IgA in 29%, IgD in 2%. Vel-based regimens were the following: Vel alone in 10 patients, Vel plus Dex (Vel/Dex) in 41, Vel/Dex plus Thal in 13, Vel/Dex plus liposomal doxorubicin (either Caelyx® or Myocet®) in 11 patients, Vel/Dex plus liposomal doxorubicin plus Thal in 8, Vel plus Mel plus Pdn (VMP) in 14, Vel plus Mel plus Pdn plus Thal (VMPT) in 3, and Vel/Dex plus cyclophosfamide in 5. The median Vel dosage was 1.3 mg/m2 (range 0.8–1.3) for 4 doses per cycle, administered on days 1, 4, 8 and 11 every 3 weeks in all schedules but VMPT and VMP (Vel on days 1, 8, 15 and 22 every 5 weeks). For the purpose of this analysis pts were pooled into 2 major groups: (group 1, 51 pts treated with Vel or Vel/Dex) (group 2, 54 pts who received Vel/Dex or Vel/Pdn combined with other agents). RI was evaluated by CrCl, using the Cockcroft–Gault formula; pts were clustered into 3 subgroups based on CrCl values of 51–80, 30–50 and <30 ml/min, corresponding to mild (12 pts, 11.4%), moderate (22 pts, 21%) and severe (71 pts, 67.6%) RI, respectively. Twelve patients required dialysis. A total of 532 cycles of Vel were administered, with a median number of 5 cycles/pt. 10 pts (9.5%, 7 refractory, 2 relapsed and 1 previously untreated) necessitated early discontinuation of therapy due to WHO grade 4 neuropathy (5 pts), diarrhoea (1), pneumonia (1), cardiotoxicity (1) and stroke (1), while the last pt due to sepsis. The rate of Vel discontinuation in pts with severe, moderate and mild RI was 13%, 5% and 0%, respectively (p=ns). Twenty patients (19%, of whom 12 with severe, 6 with moderate and 2 with mild RI) required Vel dose reduction. Overall, 85 episodes of WHO grade III/IV toxicity were observed: 25 were non-hematological (stroke in 1 case, neuropathy in 6 cases, gastrointestinal in 5, infections in 11 and cardiotoxicity in 2), and 68 were haematological (anemia in 21 pts, neutropenia in 16 and thrombocytopenia in 31). A higher rate of hematological SAEs were observed in pts with severe RI as compared to those with moderate and mild RI (72% vs 50% vs 50%; p=0.035). At least a PR was documented 74/101 evaluable pts (74%), including CR (19%), nCR (10%) and VGPR (15%). The ORR was similar across both renal subgroups (severe vs moderate vs mild RI: 67.5% vs 77% vs 75%; p=ns) and treatment subgroups (group 1 vs group 2: 74.5% vs 76% p=ns). Reversal of RI was documented in 43% of pts after a median of 2.2 months (range 0.5–7.9) and occurred more frequently among previously untreated pts (61.5% vs 37% refractory/relapsed pts; p=0.039) and those with mild to moderate RI (67% and 77%, respectively, vs 28% for pts with severe RI; p<0.0001). No differences in terms of RI recovery rate were observed across treatment subgroups (group 1 vs group 2: 40% vs 60%; p=ns). In 3/12 pts on dialysis, renal replacement therapy was discontinued after 1, 1 and 4 months of Vel-including therapy. After a median follow-up of 12 months, 27 patients died. 2-year estimate of PFS and OS was 51% and 56%, respectively. In conclusion, Vel-based regimens are safe and highly active in MM pts with RI, effecting a high ≥PR rate (74%, including 44% ≥VGPR) and prompt reversal of RI in approximately 50% of cases. Thus, Vel-based regimens should be considered appropriate treatment options for MM pts with any RI degree, including those requiring dialysis.