Checkpoint Inhibition in Myeloma: Opportunities and Challenges

Abstract

Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. Blockade of such inhibitory immune receptors (termed as “immune checkpoints”) including PD-1/PD-L1 has led to impressive tumor regressions in several cancers. Preclinical studies suggest that these immune checkpoints may also play a role in regulating tumor immunity in MM. Indeed, myeloma was among the first tumors wherein therapeutic efficacy of blockade of PD-1 axis was demonstrated in preclinical models. Expression of PD-L1 on tumor and immune cells also correlates with the risk of malignant transformation. However, early clinical studies of single agent PD-1 blockade have not led to meaningful tumor regressions. Immune modulatory drugs (IMiDs) are now the mainstay of most MM therapies. Interestingly, the mechanism of immune activation by IMiDs also involves release of inhibitory checkpoints, such as Ikaros-mediated suppression of IL-2. Combination of PD-1 targeted agents with IMiDs led to promising clinical activity, including objective responses in some patients refractory to IMiD therapy. However, some of these studies were transiently halted in 2017 due to concern for a possible safety signal with IMiD-PD1 combination. The capacity of the immune system to control MM has been further reinforced by recent success of adoptive cell therapies, such as T cells redirected by chimeric-antigen receptors (CAR-Ts). There remains an unmet need to better understand the immunologic effects of checkpoint blockade, delineate mechanisms of resistance to these therapies and identify optimal combination of agonistic signaling, checkpoint inhibitors as well as other therapies including CAR-Ts, to realize the potential of the immune system to control and prevent MM.

Immunotherapy in Multiple Myeloma

“…Malignancies have exploited these pathways to evade the host T-cell immune response, hence escape from immune surveillance is recognized as a hallmark of cancer [125]. Examples of immune checkpoints relevant to oncology include CTLA4, LAG3, TIM3, TGIT and programmed death receptor 1 (PD-1) [126]. The PD-1/PD-1 ligand (PDL-1) pathway is critical to the normal regulation of T-cell mediated immunity [127].…”

“…A phase 1b study of single agent nivolumab, a PD-1 inhibitor, in 27 relapsed refractory MM patients showed a best response of stable disease, suggesting that single agent activity is limited [132]. Similarly, the single agent activity of the PD-1 inhibitor pembrolizumab was modest in the relapsed refractory setting, as well as when used as consolidation post-ASCT [126,133]. Lenalidomide has been shown to down regulate PD-1 expression on T and NK cells while reducing expression of PD-L1 in MM cells in vitro [134].…”

“…Unexpectedly, both trials showed a higher mortality in the pembrolizumab arms with no significant difference in terms of disease response. This led to the FDA temporarily halting recruitment to several clinical trials of anti PD-1/PD-L1 therapy in MM [126]. It is noteworthy that the median age, incidence of renal impairment and high risk cytogenetics was higher in the pembrolizumab arm of the KEYNOTE-185 trial [137].…”

“…It is noteworthy that many of the clinical trials investigating anti PD-1 therapy in MM used them in combination with steroids [126,130]. It is well known that steroids affect T-cell mediated immunity and have been proposed to adversely affect immune checkpoint inhibitor therapy [139].…”

Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma

“…Combination of immune checkpoint inhibitors and P(BCMA) B*18 using cells of MM patients induced peptide-specific T cells with anti-myeloma activity Next, we aimed to overcome the reported profound immune defects (including impaired function of immune effector cells) in MM 22 , and therefore evaluate the potential of P(BCMA) B*18 to induce de novo functional T-cell Fig. 1 Identification of BCMA-derived peptides and validation of P(BCMA) B*18 using a synthetic isotope-labeled peptide.…”