Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study

Abstract

Objectives: This subanalysis of the phase 3 VISTA trial aimed to assess the frequency, characteristics and reversibility of, and prognostic factors for, bortezomib‐associated peripheral neuropathy (PN) in newly diagnosed patients with multiple myeloma ineligible for high‐dose therapy who received bortezomib plus melphalan–prednisone. Methods: Patients received nine 6‐wk cycles of VMP (bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, and days 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2, days 1–4, cycles 1–9; and prednisone 60 mg/m2, days 1–4, cycles 1–9). Results: Overall, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade ≥3 (<1% grade 4). The PN incidence was dose‐related and reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m2. Median time to PN onset was 2.3 months. Bortezomib‐associated PN was reversible; 79% of events improved by at least one NCI CTCAE grade within a median of 1.9 months and 60% completely resolved within a median of 5.7 months, with reversibility similar in responding and non‐responding patients. By multivariate analysis, baseline neuropathy was the only consistent risk factor for any PN [hazard ratio (HR) 1.785, P = 0.0065], grade ≥2 PN (HR 2.205, P = 0.0032), and grade ≥3 PN (HR 2.438, P = 0.023); age, pre‐existing diabetes, International Staging System stage, obesity, and creatinine clearance did not affect the overall rate of PN. Conclusions: Rates of bortezomib‐induced PN in the frontline setting were similar to those in relapsed patients and resolved in most cases. (Clinicaltrials.gov identifier: NCT00111319).

Peripheral neuropathy associated with subcutaneous or intravenous bortezomib in patients with newly diagnosed myeloma treated within the GMMG MM5 phase III trial

“…This is in line with a subanalysis from the VISTA phase III trial of IV bortezomib in combination with melphalan/prednisone in newly diagnosed MM that identified pre-existing PN as the only consistent risk factor for BiPN. 2 In line with the VISTA study, we did not observe that baseline International Staging System (ISS) or creatinine had any effect on the development of PN. However, we observed a trend towards higher baseline body mass index (BMI) in patients with grade II PN or over.…”

“…2 Since subcutaneous (SC) administration reduces rates of bortezomib-induced neuropathy (BiPN), [3][4][5] nowadays bortezomib is mainly given subcutaneously in clinical trials and in general practice. Only limited data are available on risk factors for BiPN in the era of SC bortezomib.…”

Bortezomib in Multiple Myeloma: Systematic Review and Clinical Considerations

“…The publications related to the main studies contributed information about extended follow-up of the original studies 33,45,49,53 , subgroup analyses 34,[39][40][41][42][43][44]48,51,52,55,57,59 , health-related qol 36,47,56,76 , outcome data that were not reported in the original publication 35,37,46,49,54,60,61,64,68,74,78 , and data on toxicity 38,50,62 .…”

The Impact of Bortezomib in Renal Transplantation

“…The most common adverse effects associated with bortezomib are gastrointestinal events, asthenia, hematological toxicity, and peripheral neuropathy [11]. The information related to the bortezomib tolerance mainly comes from the APEX Phase III trial, which compared the efficacy of bortezomib versus dexamethasone in refractory or relapsed multiple myeloma, and from the VISTA trial which compared melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma [12,13].…”