Cereblon-Targeting Ligase Degraders in Myeloma: Mechanisms of Action and Resistance.

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.

BCMA- or GPRC5D-targeting bispecific antibodies in multiple myeloma: efficacy, safety, and resistance mechanisms.

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.

Integrated epigenetic and transcriptional single-cell analysis of t(11;14) multiple myeloma and its BCL2 dependency.

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.

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma.

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.

Current use of bispecific antibodies to treat multiple myeloma.

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.

Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma.

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.

The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients.

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.

Monoclonal Gammopathy of Undetermined Significance in Patients With Transthyretin Amyloidosis (ATTR): Analysis Using the iStopMM Criteria.

INTRODUCTION: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin amyloid (ATTR). We used the iStopMM study revised reference ranges for serum free light-chain (sFLC) corrected for eGFR to identify ATTR patients with light-chain MGUS (LC-MGUS). Characteristics and frequencies of the ATTR cohort with underlying MGUS was compared to a cohort of MGUS patients without ATTR. PATIENTS AND METHODS: A retrospective analysis of ATTR and MGUS patients evaluated at our center between January 2014 to December 2021. A total of 149, predominantly male (87.5%) ATTR patients with a median age of 82 were included. This cohort was compared to 228 MGUS patients. RESULTS: Of the 149 ATTR patients, 27 (18.1%) had coexisting MGUS. Among ATTR patients with MGUS, 12/27 (44%) had LC-MGUS based on sFLC abnormalities assessed using the iStopMM reference ranges. Of the MGUS only cohort, 44/228 (19.3%) met criteria for LC-MGUS. Utilizing the iStopMM reference ranges, 6 ATTR patients did not meet criteria for abnormal sFLCs, uncovering a 20% false-positive rate. CONCLUSION: We noted higher rates of MGUS, particularly LC-MGUS, among ATTR patients when compared to our MGUS only cohort. The high prevalence remained after utilizing the iStopMM sFLC corrected for eGFR reference ranges. Additionally, 6 ATTR patients with renal-dysfunction would have met MGUS criteria if not evaluated using the iStopMM revised measures. These findings emphasize careful interpretation of sFLC abnormalities and encourage providers to keep ATTR on the differential when work-up uncovers sFLC aberrations.

Real-world Outcomes With Cumulative Bortezomib Dose and Efficacy in the Treatment of Transplant-ineligible Multiple Myeloma With Cyclophosphamide, Bortezomib, and Dexamethasone.

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.

Impact of COVID-19 on the Diagnosis and Management of Multiple Myeloma: Experience from a Canadian Center.

BACKGROUND: The impact of coronavirus disease-19 on the management of multiple myeloma (MM) has been recognized. However, the real effect on clinical outcomes remains poorly understood. OBJECTIVE: We describe a local experience of the management of MM patients and report their outcomes during the current pandemic. METHODS: All consecutive symptomatic MM patients seen at our center since 03/20 were evaluated. RESULTS: A cohort of 156 patients diagnosed from 01/19 to 12/20 was analyzed to interrogate differences in presentation patterns. A total of 553 MM patients were seen and/or treated at Tom Baker Cancer Center in the year of 2020. From those, 47.1% (n = 261) were tested for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Sixteen patients tested positive and data are presented. In addition, a decrease of 21.7% in the rate of new smoldering MM/MM diagnosis was observed in 2020 as compared to 2019. Further, an increase in deaths was also observed in 2020. CONCLUSIONS: Our study confirms an increase lethality for MM patients infected with SARS-CoV-2. A balance between safety and need for cancer control should be emphasized.

Cyclophosphamide, Bortezomib and Methylprednisolone (CyBorMe) for the Treatment of AL Amyloidosis: Initial Experience From a Single Center.

The use of cyclophosphamide, bortezomib and dexamethasone (CyBorD) is widely accepted in the treatment of AL amyloidosis (AL). Recently, the substitution of dexamethasone by methylprednisolone (CyBorMe) appeared to improve response rates and survival outcomes. All consecutive newly diagnosed AL amyloidosis treated with CyBorMe from 01/19 to 08/20 were evaluated. A historic cohort of patients treated with CyBorD was used for comparison (01/13-08/20). Methylprednisolone was given IV at 500 mg weekly for 4 weeks in the CyBorMe group. 43 patients were treated with CyBorD and 14 with CyBorMe. After a median of 4 cycles of CyBorD and 3 cycles of CyBorMe, Hematological Response was seen in 90.6% and 92.8% of cases, including CR in 28.5% and 35.7%, VGPR in 33.3% and 35.7% and PR in 30.9% and 21.4% for CyBorD and CyBorMe, respectively. Time to first response was faster in the CyBorMe group (4 vs. 6 weeks) and cardiac response was observed in 44% and 31% of patients treated with CyBorMe and CyBorD, respectively. CyBorMe appeared to be efficacious and well tolerated in patients with AL amyloidosis. Prospective studies with CyBorMe in the stage III/IV group are warranted aiming to minimize toxicity.

Monoclonal gammopathy of undetermined significance clinic during the coronavirus disease-19 pandemic: caring for the vulnerable in an academic medical center

Background: Patients with monoclonal gammopathy of undetermined significance (MGUS) have clinical features including older age, presence of medical comorbidities, susceptibility to infections, and thrombotic tendencies which are relevant when assessing their risk during the coronavirus disease (COVID-19) pandemic. Objective: To study the vulnerability of patients with MGUS during the COVID-19 pandemic, we assessed the local management of MGUS patients and their clinical outcomes. Methods: Retrospective chart reviews were performed for all patients with MGUS seen at a university medical center clinic (2014-2020). Results: A total of 228 MGUS patients were included; 211 patients are alive, 7 patients died before the pandemic, and 10 patients died since the pandemic declaration. The mean age and the overall survival (OS) of the patients who died before versus during the pandemic were 83.0 versus 75.2 years, p = 0.4, and OS 40.6 versus 53.2 months, p = 0.3, respectively. One patient died of COVID-19. Nine patients had venous thromboembolisms (VTE), all of which occurred before the pandemic onset. Conclusions: There were no significant differences found in the mean age or OS of the MGUS patients who died before versus after the pandemic onset. An increase in VTE rates was not seen. Study results are limited by small patient numbers.

N-Terminal pro-brain natriuretic peptide (NTproBNP) in patients with symptomatic multiple myeloma: report from a single institution.

Elevated levels of serum cardiovascular markers including natriuretic peptides (NPs) such as amino terminal pro-brain natriuretic peptide (NTproBNP) have been associated with disease severity and survival in cancer patients and more recently in multiple myeloma (MM). In the present study, we retrospectively reviewed 87 consecutive symptomatic TEMM (transplant-eligible) and 126 TIMM (transplant-ineligible) patients treated at our institution that did undergo NTproBNP testing from 2017 to 2020. Median age at diagnosis was 59.3 years and 75.4 years for the TEMM and TIMM groups, respectively (p = 0.0001). NTproBNP ≥ 300 ng/L was used to assess survival outcomes in the group of symptomatic MM. Patients with AL amyloidosis and symptomatic MM were excluded from the study. Median OS for patients with NTproBNP ≥ 300 ng/L was shorter (45.9 months) as compared to those with NTproBNP of < 300 ng/L (non-reached) (p = 0.0001). In addition, OS was shorter for those with CCI > 2, ISS2-3, and high-risk cytogenetics by FISH and ≥ 70 years of age. Multivariate analysis showed that HR cytogenetics and ISS2-3 were independent predictors for OS in the entire cohort of MM patients. When restricted to TIMM, age ≥ 80 years and NTproBNP ≥ 800 ng/L were predictors for OS in univariate and multivariate analyses. In conclusion, NTproBNP appears to be an independent predictor factor for OS in symptomatic TIMM patients. The use of NTproBNP as a frailty marker remains to be elucidated. However, NTproBNP could potentially be used to guide treatment decisions aimed to minimize cardiovascular and renal toxicity for myeloma therapies that potentially do have cardio-renal implications.

Treatment response measurements and survival outcomes in a cohort of newly diagnosed AL amyloidosis.

INTRODUCTION: The assessment of AL amyloidosis response is based on serum free light chains (sFLC) levels, and serum and urine monoclonal protein investigations. Recently, difference between involved and uninvolved free light chains (dFLC), involved free light chain (iFLC) and complete response (CR) has been reported as independent predictor of survival and a refinement of the hematological response criteria has been proposed by several groups. METHODS: In the current study, all consecutive newly diagnosed symptomatic AL amyloidosis patients were evaluated. The primary objective of the study was to assess hematological and organ response after first line of treatment. RESULTS: A cohort of 76 cases with upfront treatment was used for this analysis. After a median of 3 months post-therapy, hematological response was seen in 88% of cases including CR in 26.3%, VGPR in 38.2% and PR in 23.7%. Median OS was longer in patients with dFLC < 10 mg/L at 3 months, iFLC <20 mg/L at 1 and 3 months, and those achieving CR. Multivariate analysis showed presence of CR as the most important independent prognostic factors for survival. CONCLUSIONS: Our study suggests that maximal sFLC response and CR are potential endpoints to define clinical outcomes. Large collaborative studies are required to validate and optimize response criteria.