Tradeoff between vaccine-induced immunity and depth of response following autologous stem cell transplantation in multiple myeloma

Abstract Introduction: Immunizations are routinely administered to confer protection against vaccine-preventable infections during both early and late phases following autologous stem cell transplantation (ASCT). Our prior work demonstrated that maintenance therapy with immunomodulatory drug (IMiD), with or without proteasome inhibitor (PI), does not impair the acquisition of protective immunity to the pneumococcal conjugate vaccine (PCV) in patients with multiple myeloma (MM) post-ASCT. Induction therapy, which commonly includes PI, IMiD, corticosteroids, and increasingly anti-CD38 monoclonal antibodies, may negatively affect immune cell compartments and reduce patient's ability to mount robust vaccine responses. Methods: Patients with MM undergoing standard-of-care ASCT were enrolled in an IRB approved study. Demographic, disease characteristics and disease status data were collected. Patients received PCV13 at 6, 8 and 12 months (mo) post-ASCT. Serotype-specific pneumococcal antibody levels and circulating memory B-cell subsets (immature IgD+, mature IgD- resting CD21+CD95-or CD21-CD95+ activated) were quantified at 2, 6mo post-ASCT, prior to vaccination, and again at 8, 12, and 14mo thereafter. Minimal residual disease (MRD) status (10-6 sensitivity) and bone marrow plasma cell subsets (short-lived CD19+CD56+, long-lived CD19-CD56+/-, long lived CD19+CD56+) were assessed by flow cytometry at 2mo post-ASCT. Associations between the number of induction regimens, exposure to daratumumab, and depth of response post-ASCT, and the serological response to PCV vaccination were evaluated. Protective antibody titers were defined as ≥ 1.3mcg/mL for non-invasive pneumococcal disease and ≥ 0.35mcg/mL for invasive pneumococcal disease. Results Seventy-two patients were enrolled (median age 60 years, range 35-76) of whom, 30% female), 29% identified as African American. Twenty-one patients (29.2%) received more than one induction therapy, 49 (68%) received daratumumab-containing regimen. Post-ASCT 48 patients (66.6%) achieved CR/sCR, and 35% were MRD negative. By 14mo post-ASCT, 90.5% of patients acquired complete protective immunity against invasive pneumococcal disease, while only 20% against non-invasive disease. Notably, 25% of patients exhibited a recall-like response to the first PCV dose, achieving protective titers (≥ 0.35mcg/mL) after only one PCV13 dose. This early response was significantly associated with humoral immunity retention (p=0.0025), higher circulating memory B cell prevalence at 6mo post-ASCT (p=0.0502), and increased CD19+CD56+ long-lived plasma cells in the bone marrow at 2mo (p=0.0286). At 8mo, prior to booster vaccination, early vaccine responders also showed greater memory B cell activation (p=0.0025). Cox regression analysis revealed that female patients acquired protective immunity earlier than males for both invasive (HR 1.25, 95% CI 0.55-2.72) and non-invasive disease (HR 7.78, 95% CI 2.13-38.46) and, were 3 times more likely to achieve full protection against non-invasive disease by 14mo (p=0.0052). In contrast, patients treated with daratumumab-containing induction (HR 0.22, 95% CI 0.02-1.43) or who achieved MRD negativity (HR 0.40, 95% CI 0.09-1.52) had delayed acquisition of protective immunity. These groups were also 2-3 times less likely to achieve full protection against non-invasive disease by 14mo (daratumumab: p=0.0048; MRD-negative: p<0.1), and showed significantly reduced CD19+CD56+ long-lived plasma cell content at 2mo post-ASCT (daratumumab-naïve vs. treated: 0.0024% vs. 0.0006%, p=0.0005; MRD-positive vs. negative: 0.0023% vs. 0.0014%, p<0.1). Conclusions: Our study suggests that while most patients developed protective immunity against invasive pneumococcal disease following PCV vaccination post-ASCT, more intensive induction regimens, particularly those including daratumumab, may impair vaccine responsiveness. Retention of humoral memory post-ASCT was associated with stronger vaccine responses but also correlated with detectable MRD. In contrast, loss of humoral memory or CD19+CD56+ long-lived plasma cells, partly linked to daratumumab exposure, were associated with reduced acquisition of protective immunity against non-invasive disease. These findings highlight a potential tradeoff between achieving deeper disease responses and maintaining effective vaccine-induced immunity post-ASCT. Validation in larger cohorts across other acellular vaccines is warranted.