Tumor and Renal Response in Patients with Newly Diagnosed Multiple Mieloma and Renal Failure Treated with Bortezomib and Dexamethasone: Results of a Prospective Phase II Trial from Pethema/GEM

Background: Renal failure (RF) is present in about 20% of patients with newly diagnosed multiple myeloma (MM) and is associated with a poor outcome. Bortezomib-based therapy has shown significant activity in patients with RF, including a higher rate of renal recovery when compared with previous regimens. We report the results of a prospective phase II trial for patients with newly diagnosed MM and RF treated with bortezomib and dexamethasone (VD) (RENVEL: www.clinicaltrials.gov NCT 01084837).

Aim: The primary end-point was efficacy in terms of response rate and secondary end-points were recovery of RF, PFS and OS.

Patients and Methods: Patients with newly diagnosed MM and renal failure from 11 PETHEMA institutions were included. RF was defined as an estimated filtration glomerular rate (eFGR) < 50 ml/min calculated by the MDRD formula. Patients <66 years were treated with 4 cycles of i.v. bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 and dexamethasone 40 mg p.o. on days 1-4 and 9-12 every 3 weeks and those with no other comorbidities than RF were planned to received high-dose melphalan followed by stem cell rescue (ASCT group) . Patients ³66 years or younger with comorbidities not candidates to high-dose therapy received up to 8 cycles of VD. Responding patients with no significant toxicities were given 4 additional cycles at the same dose of bortezomib and dexamethasone 40 mg on days 1-4 at 4-weeks intervals (no ASCT group). Myeloma response was assessed by the IMWG criteria and renal response by the criteria recently proposed (Dimopoulos et al, J Clin Oncol 2010;33:4976-4984).

Results: Between April 9, 2010 and September 13, 2012, 60 patients (42 M, 18F, median age 72 years) were enrolled. The M-protein type was IgG in 14 patients, IgA in 22, light-chain only (Bence-Jones) in 22 and IgD in 2. 85% of the patients had ISS 3 and 19% had high-risk cytogenetics. The median baseline eFGR was 17 ml/min and 40 patients had severe RF defined as eFGR <30 ml/min. Seventeen patients (28%) required initial renal replacement with dialysis. The overall response rate in the overall series was 75% (29%CR, 27% VGPR, 19% PR, 3% MR, 16% refractory disease, 5% early death, 1% non-evaluable).

Eighteen patients (30%) were initially considered candidates to receive ASCT. The overall response rate after 4 induction cycles was 77% (28% CR, 23% VGPR, 28% PR, 5% MR, 16% refractory disease). Seven patients did not proceed to ASCT because of progressive disease (4), renal impairment with poor PS (2) and lost of follow-up (1). The response rate of the 11 patients who underwent to ASCT was CR in 8 patients (73%), VGPR in 1 (9%), PR in 1 (9%) and early death (sepsis) in 1 (9%). Grade 3 toxicity was only observed in 3 patients. No patient developed grade 3-4 neurological toxicity and only 2 patients had grade 2 peripheral neuropathy.

Forty-two patients (70%) were not candidates to receive ASCT. The median number of cycles administered was 7.5. The overall response rate was 71% (29% CR, 29% VGPR, 14% PR, 2% MR, 17% refractory disease, 7% early death, 2% non-evaluable). 15 patients discontinued therapy because of bortezomib-related toxicity and seven were discontinued due to infectious complications. One patient developed grade 3 thrombocytopenia and grade 3 extrahematological toxicity was observed in 4 patients (gastrointestinal, asthenia, Wernicke-Korsakoff and rash one patient each). Peripheral neuropathy was observed in 18 patients (grade 2: 13 patients, grade 3: 5 patients).

Renal response was achieved in 66% of the patients (29% CR, 14% PR, 23% MR). The median time to renal respose was 1.6 months (0.8-2.7). Therteen patients out of 17 (76%) could have been discontinued from dyalisis. The renal response rate was similar in the two groups.

After a median follow-up of 26.7 months, the median PFS in ASCT and no-ASCT groups was 33.3 and 16.3 months, respectively. The estimated OS at 36 months were 82% and 72%, respectively. In both groups the PFS was not significantly different among patients achieving renal response vs. those not achieving renal response. In no-ASCT group the OS was significantly longer in patients achieving renal response compared with patients not achieving renal response (not reached vs. 35.3 months, p=0.03).

Conclusions: VD is a highly effective regimen in patients with newly diagnosed multiple myeloma and severe renal failure, resulting in a high quality tumor responser and a renal response rate of 66% including a 76% of dialysis discontinuation.