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Induction of antibody-mediated immunity against hematologic malignancies requires CD4+ T-cell help, but weak tumor antigens generally fail to induce adequate T-cell responses, or to overcome tolerance. Conjugate vaccines can harness alternative help to activate responses, but memory B cells may then be exposed to leaking tumor-derived antigen without CD4+ T-cell support. We showed previously using lymphoma-derived idiotypic antigen that exposure to “helpless” antigen silences the majority of memory IgG+ B cells. Transfer experiments now indicate that silencing is permanent. In marked contrast to IgG, most coexisting IgM+ memory B cells exposed to “helpless” antigen survive. Confirmation in a hapten (NP) model allowed measurement of affinity, revealing this, rather than isotype, as the determinant of survival. IgM+ B cells had Ig variable region gene usage similar to IgG but with fewer somatic mutations. Survival of memory B cells appears variably controlled by affinity for antigen, allowing a minority of low affinity IgG+, but most IgM+, memory B cells to escape deletion in the absence of T-cell help. The latter remain, but the majority fail to undergo isotype switch. These findings could apply to other tumor antigens and are relevant for vaccination strategies aimed to induce long-term antibody.

Introduction: The introduction of novel agentshas revolutionised the treatment of multiple myeloma, with improvements in survival of newly diagnosed and relapsed/refractory patients. However, despite these advances, the role for allogeneic haematopoietic stem cell transplantation (HSCT) in the treatment of these patients remains in question. Reduced-intensity conditioning (RIC) HSCT with Seattle regimen (30 mg/m2 fludarabine and 2 Gray total-body irradiation, TBI) for multiple myeloma has been reported to be an effective treatment with low upfront toxicity, and the potential for graft-versus-myeloma effect (Niederwieser D et al, Blood, 2003). Its use as part of tandem HSCT (autologous HSCT followed by RIC-HSCT) is associated with a treatment-related mortality (TRM) rate as low as 15% (Björkstrand B et al, J Clin Onc, 2011). However, data on survival following auto-HSCT/RIC-HSCT is inconsistent and no unifying consensus has been reached regarding the optimal timing of RIC-HSCT in the treatment algorithm. In this retrospective multi-centre study, we investigated the safety, tolerability and efficacy of RIC-HSCT in multiple myeloma patients in remission following previous auto-HSCT. Methods: A retrospective series was conducted for early-phase, high-risk myeloma patients who underwent RIC-HSCT following prior auto-HSCT in two tertiary transplant centres in Manchester in North West England, between November 2006 and July 2014. Results: Over the eight-year period, 42 myeloma patients (male n=29, female n=13) underwent Seattle-conditioned RIC-HSCT following prior auto-HSCT. 66.6% (n=28) were performed in tandem. Median age at RIC-HSCT was 52 years (range 41-65), and median β2-microglobulin at diagnosis was 3.1 mg/L (range 1.6-18.0). 16 patients had cytogenetics assessed at the time of diagnosis, of which loss of TP53 and translocation of chromosome 14 were most common. 37 patients (88.1%) had previously been exposed to immunomodulatory agents (IMiDs). 53.3% patients (n=24) were in first remission at RIC-HSCT, whilst 37.8% (n=17) were in second remission. 31.1% (n=14) of RIC-HSCTs were performed after second auto-HSCT following previous relapse and re-induction chemotherapy. 34 patients (55.9%) had achieved at least a very good partial response (VGPR) prior to RIC-HSCT. RIC-HSCT was performed a median of 20 months (range 10-89) from diagnosis. Two patients (4.8%) required re-transplantation for failed engraftment, but subsequently engrafted following in vivo T cell-depleting regimens. Mortality at early and interim time-points was low relative to registry and trial series, with TRM of 2.4% (n =1) and 9.5% (n=4) at day 100 and 365, respectively. 37 patients (82.2%) experienced chronic graft-versus-host disease (GVHD). Chronic skin GVHD was observed in 21 patients (grade 1-2: n=20; grade 3-4: n=1); chronic gastrointestinal GVHD in four patients (grade 1-2: n=1; grade 3-4: n=3); chronic hepatic GVHD in six patients (grade 1-2: n=4; grade 3-4: n=2); chronic oral GVHD in 17 patients (grade 1-2: n=17); and chronic ophthalmic GVHD in five patients (grade 1-2: n=5). There was an association between GVHD and enhanced disease control, as complete response rates increased from 26.5% to 51.5% by day 100 post-RIC-HSCT. However, 22 patients (48.9%) eventually relapsed with a median time to relapse of 6.5 months. 13 patients remain in CR one year post-RIC-HSCT. Relapse was treated with escalating donor lymphocyte infusions (DLI, n=13) or IMiDs (n=16). Response to lenalidomide at relapse was potentiated, despite the majority of patients having prior exposure to IMiDs. The median length of follow-up from diagnosis was 27 months (range 1-90). Median overall survival (OS) has not been reached; OS at two years was 69.2% (Figure 1). Conclusions: In this retrospective series we demonstrate the feasibility of Seattle-conditioned RIC-HSCT in multiple myeloma. We observed a very low early TRM of 9.5% and presence of allo-immune disease control (graft-versus-myeloma effect), thereby augmenting IMiD efficacy. Chronic GVHD was prevalent and relapse occurred in a significant proportion of patients, but salvage with DLI and IMiDs highlighted the efficacy of the graft-versus-myeloma effect elicited by RIC-HSCT. Figure 1. Survival outcomes after RIC-HSCT in myeloma. Median OS has not been reached, two-year OS was 69.2%. Figure 1. Survival outcomes after RIC-HSCT in myeloma. Median OS has not been reached, two-year OS was 69.2%. Disclosures Cavet: Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Speaker. Tholouli:Pfizer: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Gibbs:Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.

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