Previously, the landmark improvements in myeloma treatment included, chronologically, the introduction of high-dose melphalan and autologous stem cell transplantation (ASCT), followed by the identification of the prototype immunomodulatory derivative (IMiD) thalidomide and the discovery of bortezomib as the first-in-class proteasome inhibitor (PI). The last decade has witnessed the widespread use of better IMiDs such as lenalidomide and pomalidomide as well the availability of the next-generation PIs carfilzomib and oral ixazomib. Data describing the utility of these newer PIs when used in three- and four-drug regimens in the setting of newly diagnosed, as well as relapsed disease, were reported at the 2018 ASH meeting. In addition, the results with fixed-duration ixazomib maintenance after ASCT (compared with placebo) and the long-term administration of carfilzomib with lenalidomide after ASCT increase the options available for post-transplant therapy.
However, this ASH meeting primarily brought into focus the newest era myeloma therapy – immunotherapy. Although initial enthusiasm for PD-1 (programmed cell death protein 1) and PD-L1 (programmed death-ligand 1) inhibitors in myeloma was severely dampened by toxicity concerns, the use of monoclonal antibodies and cellular therapy directed at the tumour cell has proven much more encouraging. Randomized trials of the “naked” anti-CD38 monoclonal antibody daratumumab included the MAIA study which randomized newly diagnosed transplant-ineligible patients to lenalidomide plus dexamethasone (Rd) with or without daratumumab. Patients in the Rd-daratumumab arm manifest a higher response rate and longer progression-free survival, and this regimen will likely be widely adopted if/when funding is secured; the outcome of patients with high-risk features, when available, will be of considerable interest to Canadian clinicians. In addition, the early results when daratumumab is used in transplant-eligible patients, in combination with bortezomib, lenalidomide, and dexamethasone (VRd) or bortezomib, thalidomide, and dexamethasone (VTd), are promising, and Canadian physicians will likely be advocating for the integration of anti-CD38 monoclonal antibodies in this patient group, depending on the final results of ongoing trials. Future opportunities might include use of such antibodies with regimens other than VRd or VTd (i.e., CyBor-D) and/or as part of post-transplant maintenance therapy.
In the setting of more advanced disease, the fact that multiple oral presentations were devoted to pre-clinical and phase I trials of CAR (chimeric antigen receptor) T-cell therapy in myeloma attests to the tremendous interest in this technology, after initial proof-of-principle of its efficacy was recently reported. The majority of CAR T-cell platforms that were reported targeted BCMA (B-cell maturation antigen) on plasma cells. Many trials reported preliminary outcomes and included relatively few patients, but they illustrate the directions in which the field is quickly moving beyond the first-generation constructs in order to decrease toxicity, such as cytokine release syndrome (CRS) and neurotoxicity, and to improve CAR T-cell efficacy and durability. Efforts to improve BCMA CAR T-cell therapy include the use of a humanized single chain variable fragment to minimize CAR T-cell immunogenicity (Mailankody et al., abstract 957), attempts to enhance tumour cell kill by using CAR T cells recognizing two epitopes of BCMA (Zhao et al., abstract 955), inclusion of truncated epidermal growth factor components to provide a “safety switch” (Lui et al., abstract 956; Mailankody et al., abstract 959), infusion of CAR T cells with a defined composition of CD8+ and CD4+ cells (Green et al., abstract 1011), and measures to enhance the bb2121 BCMA CAR T-cell platform by the addition of a phosphoinositide 3 kinase inhibitor during ex vivo culture to enrich the product for T cells displaying a memory-like phenotype. Gregory et al. (abstract 1012) reported the results of an entirely different CAR T-cell construct, P-BCMA-101, which incorporates several unique features. First, it does not use the typical antibody-based binder to BCMA, but rather the anti-BCMA Centyrin™. Its production utilizes the piggyBac™ DNA modification system rather than a viral vector, and lastly, it is comprised primarily of early memory T cells.
Although most of the CAR T-cell trials in myeloma have targeted BCMA on plasma cells, Smith et al. (abstract 589) described progress on the development of CAR T cells targeting GPRC5D that could potentially be combined with BCMA CAR T-cell therapy. In an alternative strategy, Lulla et al. (abstract 1014) generated multiantigen-targeted T cells by culturing patient-derived PBMCs (peripheral blood mononuclear cells) with autologous dendritic cells loaded with peptides representing five target antigens (PRAME, SSX2, MAGEA4, NY-ESO-1, and survivin).
Despite the excitement regarding CAR T-cell therapy, challenges include its technical complexity and high cost. The bi-specific T-cell engagers (BITEs) represent an alternative to CAR T-cell therapy and afford an “off the shelf” immunotherapy that brings myeloma cells (via an anti-BCMA arm) in close proximity to cytotoxic T cells (via an anti-CD3 arm). Phase I trial results of the short-acting BITE AMG 420 were presented at ASH, and this agent showed considerable activity with a response rate of 70% in the small cohort treated with the minimal residual disease of 400 ug/day for four weeks by continuous infusion, followed by two weeks off the drug. Toxicities observed in this study included CRS, infections, and peripheral neuropathy. The efficacy in advanced myeloma has led to FDA “fast track designation” for this agent.
The presentations at ASH indicate that immunotherapy has already produced improvements in myeloma patient outcomes. In addition, they highlight the rapid evolution of efforts to refine CAR T-cell therapy in this malignancy. Future efforts to define and optimize the use of both CAR T cells and BITEs are underway worldwide, and selected Canadian centres are participating in ongoing/upcoming industry-sponsored trials as well as developing “made in Canada” CAR T-cell platforms for patients with myeloma.