Personalized Neoantigen Peptide Vaccine with or without Lenalidomide for Patients with Intermediate or High Risk Smoldering Multiple Myeloma (SMM) to Prevent Progression to Multiple Myeloma (MM)

Background: Patients with smoldering multiple myeloma (SMM) with intermediate or high-risk have at least a 50% risk of progression to symptomatic multiple myeloma at 5 years after diagnosis. Cure is the ultimate goal for such patients, however, delaying onset of active myeloma or avoiding irreversible organ damage is imperative for improved quality of life and survival. Tumor-associated neo-antigens (NeoAg) have the potential to be excellent targets for immunoprevention in SMM. Personalized peptide vaccines against NeoAgs require (1) time for T cell -mediated immune anti-tumor responses and (2) immune cells that are functional and robust. Because SMM has an indolent nature with relatively intact immune cells, it makes an ideal disease state to evaluate personalized peptide vaccines as an immunoprevention strategy.

Methods: This is a single center, investigator initiated study of a personalized NeoAg peptide vaccine with or without lenalidomide in patients with SMM to evaluate safety, feasibility, efficacy and immune and microenvironment changes. Patient tumor-associated NeoAg were identified using proteomic, genomic, transcriptomic, and bioinformatic analyses. Tumor sequencing identified patient-specific mutations most highly expressed at the RNA level, and HLA peptide binding prediction algorithms identified mutant peptides most likely to be presented by HLA class I and class II molecules and presented to CD8+ and CD4+ T cells, respectively. Eligible patients with high or intermediate risk SMM defined by the PETHEMA criteria, were enrolled on study from 5/2019 to 12/2022. The first ten patients (cohort 1) received personalized NeoAg peptide vaccine alone while the next 20 (cohort 2) received NeoAg vaccine with lenalidomide to augment the immune response. Vaccines were administered subcutaneously on days 1 and 15 of cycles 1-2 (28 day cycles) followed by day 1 of cycles 3-6 and, for cohort 2, lenalidomide dosing was 25 mg orally on days 1-21. Treatment for both cohorts was limited to 6 cycles. Bone marrow and peripheral blood samples were collected at multiple time points for each patient to evaluate vaccine-specific immune responses and molecular and immunophenotypic profiling over time.

Results: NeoAg peptide vaccines were successfully manufactured and all 30 patients were immunized for all 6 cycles. Each patient received 10 unique NeoAg peptides in total, 7 HLA class I binders and 3 HLA Class II binders. No significant dose limiting toxicity occurred. For cohort 1 patients, best response was stable disease for all 10 patients. 2 patients have progressed to multiple myeloma, while 8 continue on observation with a median follow up of 57 months. For cohort 2, 35% of patients achieved a partial response, 35% a minimal response, and 30% stable disease as best response. 5 patients have progressed to myeloma, 4 patients transitioned to another SMM trial, and 11 patients continue on observation with a median follow up of 21 months. ELISPOT data for cohort 2 patients revealed a strong T cell response for 1 patient and moderate vaccine-induced T cell responses for an additional 9 patients. Based on serial evaluations, responses were observed mainly early in the vaccination regimen and decreased with later dosing, suggesting the induction of tolerance. Additional studies such as cytokine assays, single cell RNA sequencing, and B cell receptor and T cell receptor analysis are currently ongoing for cohort 2 patients.

Conclusions: This study demonstrates the feasibility and safety of a personalized NeoAg peptide vaccine in patients with SMM. Longer follow up is needed to evaluate any improvement in time to active myeloma compared to historical controls. Potential combination therapies or altered immunization schedules could reduce tolerance induction to enhance long term disease control.