Assessment of Safety and Immunogenicity of PVX-410 Vaccine With or Without Lenalidomide in Patients With Smoldering Multiple Myeloma: A Nonrandomized Clinical Trial.

Importance: Increasing evidence suggests the significance of the role of the immune system in the progression of smoldering multiple myeloma (SMM) to symptomatic multiple myeloma (MM). Boosting the immune system via vaccination in the earlier, asymptomatic SMM stage may provide a novel strategy to prevent or slow progression to active MM. Objective: To determine the safety, tolerability, immunogenicity, and anti-MM activity of the PVX-410 multipeptide vaccine with or without lenalidomide. Design, Setting, and Participants: This 3-cohort phase 1/2a multicenter dose-escalation study accrued 22 adults (≥18 years) with SMM with normal organ/marrow function who were human leukocyte antigen A2-positive and at moderate or high risk of progression to MM. Interventions: Patients received 6 doses of PVX-410 emulsified in Montanide ISA 720 VG, 0.4 mg total (0.1 mg/peptide) (n = 3) or 0.8 mg total (0.2 mg/peptide) (n = 9), biweekly via subcutaneous injection. In the combination cohort (n = 10), patients also received three 21-day cycles of lenalidomide, 25 mg, orally daily every 28 days. All patients received 0.5 mL (1 mg) poly-ICLC (2 mg/mL) via intramuscular injection with each PVX-410 dose. Main Outcomes and Measures: Adverse events (AEs) were evaluated using the Common Terminology Criteria for Adverse Events, version 4.03. PVX-410-specific T lymphocytes by flow cytometry to assess tetramer and interferon (IFN)-γ response. Disease response was assessed by investigators using the International Myeloma Working Group (IMWG) and modified European Group for Bone Marrow Transplantation (EBMT) criteria. Results: Overall, 14 (64%) patients were men and the median age at enrollment was 56 years in the monotherapy and 57 years in the combination cohorts (overall range, 39-82 years). Six of 12 patients in the monotherapy and 9 of 10 in the combination cohorts were at moderate risk. The PVX-410 vaccine was well tolerated. The most common AEs were mild-to-moderate injection site reactions and constitutional symptoms. Of note, PVX-410 was immunogenic as monotherapy (10 of 11 patients) and in combination with lenalidomide (9 of 9 patients), as demonstrated by an increase in percentage of tetramer-positive cells and IFN-γ cells in the CD3+CD8+ cell population. The combination resulted in greater mean fold increases in proportions of CD3+CD8+ T cells that were tetramer-positive and IFN-γ-positive, statistically significant for IFN-γ-positive cells after 2 and 4 vaccinations. An increase and persistence of vaccine-specific effector memory cells was noted. In total, 7 of 12 patients in the PVX-410-alone cohort had stable disease with 2 of 3 (low-dose cohort) and 1 of 9 of the target-dose cohort progressing (median TTP, 36 weeks), whereas 5 of 12 patients in the combination cohort showed, clinical response, with 1 patient progressing (median TTP not reached). Conclusions and Relevance: Overall, these results suggest that the vaccine is safe and immunogenic in this patient population and support continued study of PVX-410 in SMM. Trial Registration: ClinicalTrials.gov identifier: NCT01718899.