Peripheral Neuropathy (PN) with Immunomodulatory Drugs in Patients with Multiple Myeloma (MM)

Background: PN is a recognized adverse event (AE) with thalidomide (THAL). Despite similarities between THAL and its analogues (lenalidomide [LEN] and pomalidomide [POM]) that include structural, binding target, and common drug-induced substrates, the result of unshared downstream molecular, cellular, and microenvironment effects among the compounds is a diverse array of biological responses and different efficacy and safety outcomes (Bjorklund CC, et al. Blood Cancer J . 2015;5:e354). This underscores the mechanistic diversity of a family of agents rather than the mechanistic uniformity of a therapeutic class. In untreated patients with MM, low incidence (3%-13%) of symptomatic PN has been reported, while the estimated rate was much higher (40%-60%) for subclinical PN (Kwan JY. Neurol Clin. 2007;25:47-69). Objective: To describe the frequency, severity, and tolerability of PN in patients with MM treated with THAL-, LEN-, and POM-based therapy from Celgene-sponsored pivotal and other registrational studies. Methods: AEs of new and worsening PN were analyzed for THAL-, LEN-, and POM-based therapy in 9 randomized clinical trials in 3518 patients with MM. Eight of the 9 clinical trials included patients with baseline grade 1 PN, while 1 clinical trial excluded all patients with PN. The search for PN used narrow-scope Standardised MedDRA Query "peripheral neuropathy." The AEs were rated per NCI-CTCAE. Results: PN was reported more frequently in patients in the THAL-based pool (36.2%; 460/1272) compared with the LEN-based pool (23.2%; 400/1727) and POM-based pool (12.3%; 64/519). Generally, PN was grade 1/2: 27.2% in the THAL-, 19.9% in the LEN-, and 11.4% in the POM-based pool. The frequency of patients with grade 3/4 PN events was 9.0% in the THAL-, 3.2% in the LEN-, and 1.0% in the POM-based pool. The frequencies of patients with serious AEs (SAEs) of PN were low (≤ 1%) for both THAL- and LEN-based pools; no patient had an SAE of PN in the POM-based pool. PN led to THAL-based therapy discontinuation in 7.0% and dose adjustments (reduction, modification, or interruption) in 16.7% of the patients. PN led to LEN-based therapy discontinuation in 0.6%, dose reduction in 2.5%, and interruption in 1.5% of the patients. PN led to POM-based therapy discontinuation in 0.4%, dose reduction in 0.6%, and interruption/reduction in 0.2% of the patients. Conclusions: The frequency and severity of PN and therapy discontinuation or modification is highest in THAL-treated patients with MM compared with LEN- and POM-treated patients. LEN and POM demonstrate improved safety for PN compared with THAL. Disclosures Mezo: Celgene: Employment, Equity Ownership. Castaneda: Celgene: Employment. Weiss: Celgene: Consultancy, Employment, Equity Ownership. Minton: Celgene: Employment, Equity Ownership. Hirsch: Celgene: Employment, Equity Ownership. Renz: Celgene: Employment. Arunagiri: Celgene: Employment. Brown: Celgene: Employment, Equity Ownership. Gambini: Celgene: Employment, Equity Ownership. Peng: Celgene: Employment. Yu: Celgene: Employment, Equity Ownership. Yu: Celgene: Employment. Freeman: Celgene: Employment.