ABSTRACT
A better understanding of the roles of the adaptive and innate immune systems in the oncogenesis of cancers including multiple myeloma (MM) has led to the development of novel immune-based therapies. B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D) and Fc receptor-like protein 5 (FcRL5, also known as FcRH5) are cell-surface transmembrane proteins expressed by plasma cells, and have been identified as prominent immunotherapeutic targets in MM, with promising activity demonstrated in patients with heavily pretreated relapsed and/or refractory disease. Indeed, since 2020, antibody-drug conjugates, bispecific T cell engagers and autologous chimeric antigen receptor T cells targeting BCMA or GPRC5D have been approved for the treatment of relapsed and/or refractory MM. However, responses to these therapies are not universal, and acquired resistance invariably occurs. In this Review, we discuss the various immunotherapeutic approaches targeting BCMA, GPRC5D and FcRL5 that are currently either available or in clinical development for patients with MM. We also review the mechanisms underlying resistance to such therapies, and discuss potential strategies to overcome these mechanisms and improve patient outcomes.
Subject(s)
B-Cell Maturation Antigen , Multiple Myeloma , Receptors, G-Protein-Coupled , Humans , Multiple Myeloma/immunology , Multiple Myeloma/therapy , Multiple Myeloma/drug therapy , B-Cell Maturation Antigen/immunology , B-Cell Maturation Antigen/antagonists & inhibitors , Receptors, G-Protein-Coupled/immunology , Receptors, G-Protein-Coupled/metabolism , Immunotherapy/methods , Receptors, Fc/immunology , Molecular Targeted Therapy/methods , Membrane Proteins/immunologyABSTRACT
Multiple myeloma (MM) is a haematological lymphoid malignancy involving tumoural plasma cells and is usually characterized by the presence of a monoclonal immunoglobulin protein. MM is the second most common haematological malignancy, with an increasing global incidence. It remains incurable because most patients relapse or become refractory to treatments. MM is a genetically complex disease with high heterogeneity that develops as a multistep process, involving acquisition of genetic alterations in the tumour cells and changes in the bone marrow microenvironment. Symptomatic MM is diagnosed using the International Myeloma Working Group criteria as a bone marrow infiltration of ≥10% clonal plasma cells, and the presence of at least one myeloma-defining event, either standard CRAB features (hypercalcaemia, renal failure, anaemia and/or lytic bone lesions) or biomarkers of imminent organ damage. Younger and fit patients are considered eligible for transplant. They receive an induction, followed by consolidation with high-dose melphalan and autologous haematopoietic cell transplantation, and maintenance therapy. In older adults (ineligible for transplant), the combination of daratumumab, lenalidomide and dexamethasone is the preferred option. If relapse occurs and requires further therapy, the choice of therapy will be based on previous treatment and response and now includes immunotherapies, such as bi-specific monoclonal antibodies and chimeric antigen receptor T cell therapy.
Subject(s)
Multiple Myeloma , Multiple Myeloma/therapy , Multiple Myeloma/physiopathology , Multiple Myeloma/diagnosis , Multiple Myeloma/epidemiology , Humans , Dexamethasone/therapeutic use , Lenalidomide/therapeutic use , Antibodies, Monoclonal/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Melphalan/therapeutic use , Thalidomide/therapeutic use , Thalidomide/analogs & derivatives , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Recent data highlight genomic events driving antigen escape as a recurring cause of chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engager (TCE) resistance in multiple myeloma (MM). Yet, it remains unclear if these events, leading to clonal dominance at progression, result from acquisition under treatment selection or selection of pre-existing undetectable clones. This differentiation gains importance as these immunotherapies progress to earlier lines of treatment, prompting the need for innovative diagnostic testing to detect these events early on. By reconstructing phylogenetic trees and exploring chemotherapy mutational signatures as temporal barcodes in 11 relapsed refractory MM patients with available whole genome sequencing data before and after CART/TCE treatment, we demonstrated that somatic antigen escape mechanisms for BCMA- and GPRC5D-targeting therapies are acquired post-diagnosis, likely during CART/TCE treatment. Longitudinal tracking of these mutations using digital PCR in 4 patients consistently showed that genomic events promoting antigen escape were not detectable during the initial months of therapy but began to emerge nearly 1 year post therapy initiation. This finding reduces the necessity for a diagnostic panel to identify these events before CART/TCE. Instead, it underscores the importance of surveillance and identifying patients at higher risk of acquiring these events.
Subject(s)
Artificial Intelligence , Multiple Myeloma , Humans , Multiple Myeloma/diagnosis , AlgorithmsABSTRACT
Cereblon-targeting degraders, including immunomodulatory imide drugs lenalidomide and pomalidomide alongside cereblon E3 ligase modulators like iberdomide and mezigdomide, have demonstrated significant anti-myeloma effects. These drugs play a crucial role in diverse therapeutic approaches for multiple myeloma (MM), emphasizing their therapeutic importance across various disease stages. Despite their evident efficacy, approximately 5% to 10% of MM patients exhibit primary resistance to lenalidomide, and resistance commonly develops over time. Understanding the intricate mechanisms of action and resistance to this drug class becomes imperative for refining and advancing novel therapeutic combinations.
Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Lenalidomide/pharmacology , Lenalidomide/therapeutic use , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/therapeutic use , Ubiquitin-Protein Ligases/therapeutic useABSTRACT
ABSTRACT: Bispecific antibodies that engage T cells to target B-cell maturation antigen or G-protein-coupled receptor class C group 5 member D have demonstrated remarkable efficacy in heavily pretreated relapsed or refractory multiple myeloma (MM), leading to the recent accelerated approval of teclistamab, elranatamab, and talquetamab by health agencies. Future challenges, however, remain to define their optimal dosing schedule and duration, sequencing, and integration with established anti-MM therapeutics as well as delineating the biological and clinical mediators of immune escape.
Subject(s)
Antibodies, Bispecific , Multiple Myeloma , Neoplasms, Plasma Cell , Humans , Multiple Myeloma/drug therapy , Antibodies, Bispecific/therapeutic use , B-Cell Maturation Antigen , Receptors, G-Protein-CoupledABSTRACT
Immunomodulatory drugs (IMiD) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance, and the mechanisms are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 coactivators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor binding motifs, including ETV4. Chromatin immunoprecipitation sequencing showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and is upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance. SIGNIFICANCE: We show that IKZF1-bound enhancers are critical for IMiD efficacy and that the factor ETV4 can bind the same enhancers and substitute for IKZF1 and mediate IMiD resistance by maintaining MYC and other oncogenes. These data implicate transcription factor redundancy as a previously unrecognized mode of IMiD resistance in MM. See related article by Welsh, Barwick, et al., p. 34. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.
Subject(s)
Multiple Myeloma , Humans , Bromodomain Containing Proteins , Cell Cycle Proteins , Immunomodulating Agents , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Neoplasm Recurrence, Local , Nuclear Proteins , Proto-Oncogene Proteins c-ets/genetics , Transcription Factors/genetics , Ubiquitin-Protein Ligases/physiology , Ubiquitin-Protein Ligases/therapeutic useABSTRACT
ABSTRACT: The translocation t(11;14) occurs in 20% of patients with multiple myeloma (MM) and results in the upregulation of CCND1. Nearly two-thirds of t(11;14) MM cells are BCL2 primed and highly responsive to the oral BCL2 inhibitor venetoclax. Although it is evident that this unique sensitivity to venetoclax depends on the Bcl-2 homology domain 3- proapoptotic protein priming of BCL2, the biology underlying t(11;14) MM dependency on BCL2 is poorly defined. Importantly, the epigenetic regulation of t(11;14) transcriptomes and its impact on gene regulation and clinical response to venetoclax remain elusive. In this study, by integrating assay for transposase-accessible chromatin by sequencing (ATAC-seq) and RNA-seq at the single-cell level in primary MM samples, we have defined the epigenetic regulome and transcriptome associated with t(11;14) MM. A B-cell-like epigenetic signature was enriched in t(11;14) MM, confirming its phylogeny link to B-cell rather than plasma cell biology. Of note, a loss of a B-cell-like epigenetic signature with a gain of canonical plasma cell transcription factors was observed at the time of resistance to venetoclax. In addition, MCL1 and BCL2L1 copy number gains and structural rearrangements were linked to venetoclax resistance in patients with t(11;14) MM. To date, this is the first study in which both single-cell (sc) ATAC-seq and scRNA-seq analysis are integrated into primary MM cells to obtain a deeper resolution of the epigenetic regulome and transcriptome associated with t(11;14) MM biology and venetoclax resistance.
Subject(s)
Antineoplastic Agents , Multiple Myeloma , Humans , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Multiple Myeloma/drug therapy , Epigenesis, Genetic , Antineoplastic Agents/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic useABSTRACT
Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance. SIGNIFICANCE: These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM. See related article by Neri, Barwick, et al., p. 56. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.
Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Lenalidomide/pharmacology , Lenalidomide/therapeutic use , Transcription Factor AP-1/therapeutic use , Drug Combinations , Immunomodulating AgentsABSTRACT
Targeted immunotherapy has significantly improved the outcome of patients with hematological malignancies by leveraging the power of the immune system to eliminate tumor cells. In multiple myeloma (MM), bispecific T-cell engagers (BsAb) targeting B-cell maturation antigen (BCMA), G protein-coupled receptor, class C, group 5, member D (GPRC5D), and Fc receptor-like 5 (FcRL5) have already demonstrated remarkable clinical activity in triple-class refractory patients. However, responses to BsAb are not universal, and resistance often emerges while on therapy. Mechanisms mediating resistance are tumor intrinsic or immune dependent. Reported tumor intrinsic factors include antigenic loss (biallelic or functional) through deletions or mutations of target genes, increased soluble BCMA (for BCMA targeting BsAb), high tumor burden, and extramedullary disease. Immune-mediated resistance are largely dependent on T-cell fitness and tolerant immune environment. Understanding these mechanisms will allow the design of optimized BsAb therapy and an informed approach to sequencing and combining these molecules with other anti-MM agents and immune therapies.
Subject(s)
Antibodies, Bispecific , Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/genetics , Antibodies, Bispecific/therapeutic use , B-Cell Maturation Antigen/genetics , Immunotherapy , T-Lymphocytes , Immunotherapy, AdoptiveABSTRACT
B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
Subject(s)
Multiple Myeloma , Receptors, Chimeric Antigen , Humans , Multiple Myeloma/genetics , Multiple Myeloma/therapy , Antigenic Drift and Shift , DNA Copy Number Variations , Neoplasm Recurrence, Local , Immunotherapy , Antibodies , Membrane ProteinsABSTRACT
The spatial organization of the tumor microenvironment has a profound impact on biology and therapy response. Here, we perform an integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize malignant cells in tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, neighboring cellular compositions, and ligand-receptor interactions. We demonstrate that the gene expression profile associated with the LE is conserved across different cancers while the TC is tissue specific, highlighting common mechanisms underlying tumor progression and invasion. Additionally, we find our LE gene signature is associated with worse clinical outcomes while TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biology and interactive spatial atlases ( http://www.pboselab.ca/spatial_OSCC/ ; http://www.pboselab.ca/dynamo_OSCC/ ) that can be foundational for developing novel targeted therapies.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Mouth Neoplasms , Humans , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Transcriptome , Mouth Neoplasms/genetics , Mouth Neoplasms/therapy , Gene Expression Profiling , Tumor Microenvironment/geneticsSubject(s)
Amyloidosis , Immunoglobulin Light-chain Amyloidosis , Humans , Immunoglobulin Light-chain Amyloidosis/drug therapy , Immunoglobulin Light-chain Amyloidosis/genetics , Bortezomib/therapeutic use , Amyloidosis/diagnosis , Amyloidosis/drug therapy , Boronic Acids , Dexamethasone , Treatment OutcomeABSTRACT
Treatment of multiple myeloma (MM) has seen great advances in recent years, and a key contributor to this change has been the effective use of combination therapies, which have improved both the depth and duration of patient responses. Immunomodulatory drug (IMiD) agents (lenalidomide and pomalidomide) have both tumoricidal and immunostimulatory functions, and due to their multiple mechanisms of action have become the backbone of numerous combination treatments in the newly diagnosed and relapsed/refractory settings. Although IMiD agent-based combination regimens provide improved clinical outcomes for patients with MM, the mechanisms underpinning these combinations are not well understood. In this review we describe the potential mechanisms of synergy leading to the enhanced activity observed when IMiD agents and other drug classes are used in combination through interrogation of the current knowledge surrounding their mechanism of actions.
Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Lenalidomide , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , ImmunomodulationABSTRACT
Given the significance of the immune system and the important role of therapies within the context of the immune system in plasma cell disorders, the International Myeloma Society annual workshop convened a session dedicated to this topic. A panel of experts covered various aspects of immune reconstitution and vaccination. The top oral presentations were highlighted and discussed. This is a report of the proceedings.
Subject(s)
Immune Reconstitution , Multiple Myeloma , Humans , Multiple Myeloma/therapy , Vaccination , Immunotherapy, AdoptiveABSTRACT
Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but the immunological mechanism and molecular determinants of primary and acquired resistance to TCEs remain poorly understood. Here, we identify conserved behaviors of bone marrow-residing T cells in multiple myeloma patients undergoing BCMAxCD3 TCE therapy. We show that the immune repertoire reacts to TCE therapy with cell state-dependent clonal expansion and find evidence supporting the coupling of tumor recognition via major histocompatibility complex class I (MHC class I), exhaustion, and clinical response. We find the abundance of exhausted-like CD8+ T cell clones to be associated with clinical response failure, and we describe loss of target epitope and MHC class I as tumor-intrinsic adaptations to TCEs. These findings advance our understanding of the in vivo mechanism of TCE treatment in humans and provide the rationale for predictive immune-monitoring and conditioning of the immune repertoire to guide future immunotherapy in hematological malignancies.
Subject(s)
Antibodies, Bispecific , Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , CD8-Positive T-Lymphocytes , Immunotherapy , Clone Cells/pathology , Antibodies, Bispecific/therapeutic useABSTRACT
BACKGROUND: Higher cumulative dose of bortezomib, a key component of Multiple Myeloma (MM) treatment regimens, has been shown to improve outcomes in MM patients, but must be balanced with toxicities including peripheral neuropathy. In this study, we studied the effect of cumulative bortezomib dose on survival, depth of response, and discontinuation rate in transplant ineligible MM patients. PATIENTS AND METHODS: Data from 70 patients treated with Cyclophsophamide, Bortezomib, and Dexamethasone (CyBorD) in a single Canadian center were grouped according to above vs below median cumulative bortezomib dose and analyzed for progression-free survival (PFS), overall survival (OS), depth of response, and discontinuation rate. RESULTS: There was a trend for lower discontinuation rate (45.7% vs. 68.6%, P = .052) and significantly lower rate of neuropathy-related discontinuation (5.7% vs. 22.9%, P = .035) in patients who received higher than 43.1 mg/m² of bortezomib. The higher-dose group showed a trend for higher rate of complete response (14.3% vs. 5.7%, P = .225) and significantly higher rate of very good partial response or better (77.1% vs. 51.4%, P = .024). There was significantly longer PFS (24.3 vs. 9.1 months, P = .012) and a trend for longer OS (22.4 vs. 61.3 months, P = .061) in the higher-dose group. In landmark analysis after 180 days, PFS (23.5 vs. 24.3 months, P = .941) and OS were similar in both groups. CONCLUSION: Higher cumulative bortezomib dose showed a lower rate of discontinuation, longer survival, and deeper response. Determining risk of treatment intolerance remains important for treatment.