Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma.

B-cell maturation antigen (BCMA)-targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 x BCMA bispecific antibody (BsAb), 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy-naïve patients. Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and one of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from one patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen.

Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma.

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017-March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

Comparison of infectious complications with BCMA-directed therapies in multiple myeloma.

B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25-0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31-3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05-3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21-0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17-0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.

Unscheduled healthcare interactions in multiple myeloma patients receiving T cell redirection therapies.

Outcomes for relapsed/refractory multiple myeloma (RRMM) patients have dramatically improved following the development and now growing utilization of B cell maturation antigen targeted chimeric antigen receptor (CAR) T cell therapy and bispecific antibody (BsAb) therapy. However, healthcare utilization as a quality-of-life metric in these growing populations has not been thoroughly evaluated. We performed a retrospective cohort study evaluating the frequency and cause of unscheduled healthcare interactions (UHIs) among RRMM patients responding to B-cell maturation antigen targeted BsAbs and CAR T cell therapies (N = 46). This included analysis of remote UHIs including calls to physicians' offices and messages sent through an online patient portal. Our results showed that nearly all (89%) RRMM patients receiving these therapies required a UHI during the first 125 days of treatment, with a mean of 3.7 UHIs per patient. RRMM patients responding to BsAbs were significantly more likely to remotely contact their physicians' offices (1.8-fold increase, p = 0.038) or visit an urgent care center (>3-fold increase, p = 0.012) than RRMM patients responding to CAR T cell therapies. This was largely due to increased reports of mild upper respiratory tract infections in BsAb patients. Our results underscore the need to develop preemptive management strategies for commonly reported symptoms that RRMM patients experience while receiving CAR T cell or BsAb therapies. This preemptive management may significantly reduce unnecessary healthcare utilization in this vulnerable patient population.

Patterns of CRS with teclistamab in relapsed/refractory multiple myeloma with or without prior T-cell redirection therapy.

ABSTRACT: Teclistamab (Tec) is a first-in-class BCMA × CD3 bispecific T-cell engager antibody approved for treating multiple myeloma progressing after at least 4 lines of therapy. The objective of this study was to evaluate the rate of cytokine release syndrome (CRS) in patients who were treated with commercial Tec and had prior exposure to other T-cell redirection therapies. A retrospective chart review was performed to identify patients who completed the Tec step-up dosing phase between November 2022 and November 2023. Patients were divided into 2 cohorts based on prior exposure to T-cell redirection therapy (cohort 1: T-cell redirection therapy experienced; cohort 2: T-cell redirection therapy naïve). The primary objective was to compare the differences in the rates of CRS between the 2 cohorts. Univariate and multivariate logistic regression analyses were performed to assess the association between CRS rates with Tec and prior treatment with T-cell redirection therapy. A total of 72 patients were included in the analysis (27 in cohort 1 and 45 in cohort 2). The CRS rates were significantly lower in cohort 1 (37%, n = 10) compared with cohort 2 (80%, n = 36; P = .0004). Based on multivariate logistic regression analysis, patients without prior exposure to T-cell redirection therapy (cohort 2) had about a fourfold increase in the incidence of CRS (95% confidence interval, 1.40-14.90; P = .0002) with Tec. In our study, prior exposure to T-cell redirection therapy reduced the risk of CRS with Tec during the step-up dosing phase. This observation will allow for the optimization of CRS prophylactic strategies for Tec.

Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma.

SUMMARY: While the current approach to precursor hematologic conditions is to "watch and wait," this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit-risk assessment.

Dietary risk factors for monoclonal gammopathy of undetermined significance in a racially diverse population.

ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma, is associated with shorter lifespan and cardiac, renal, neurologic, and immune-related comorbidities. There is little known about modifiable risk factors for this condition. To determine whether the risk of MGUS is associated with dietary factors in a racially diverse population, we conducted a US population-based case-control study from the National Health and Nutrition Examination Survey (1988-2004), which included 373 individuals with MGUS and 1406 matched controls. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. Unconditional multivariable logistic regressions were used to model associations between intake of several food groups and MGUS, with odds ratios (ORs) and 95% confidence intervals (CIs) reported for the highest relative to the lowest quantile of intake. Daily gram intake of several food and beverage groups were significantly associated with MGUS. MGUS was inversely associated with whole-grain bread, oats, and rice (OR, 0.70; 95% CI, 0.48-1.00; P < .05), fruits (excluding juice) and vegetables (OR, 0.69; 95% CI, 0.52-0.93; P = .02), vegetables (OR, 0.75; 95% CI, 0.56-0.99; P < .05), tomatoes (OR, 0.72; 95% CI, 0.51-1.00; P < .05), and cruciferous vegetables (OR, 0.44; 95% CI, 0.26-0.74; P < .01). Direct associations were observed for sugar-sweetened beverages (OR, 1.34; 95% CI, 1.00-1.78; P < .05), sugar-sweetened soft drinks (OR, 1.41; 95% CI, 1.01-1.96; P = .04), and artificially sweetened soft drinks (OR, 1.55; 95% CI, 1.04-2.33; P = .03). Our study shows that diet is potentially a modifiable risk factor for MGUS.

Prevalence and impact of diabetes on survival of patients with multiple myeloma in different racial groups.

ABSTRACT: Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1-/-/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1-/-/MKR mice and grew more rapidly in the Rag1-/-/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1-/-/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored.

Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.

Pre-Diagnosis Dietary Patterns and Risk of Multiple Myeloma in the NIH-AARP Diet and Health Study.

Background: Despite patient interest in knowing whether diet is linked to multiple myeloma (MM), there is limited research on dietary patterns and MM risk. Two studies have assessed this risk, albeit with a small number of MM cases. The EPIC-Oxford cohort and Oxford Vegetarian study (65 MM cases) showed that fish eaters, vegetarians and vegans had significantly reduced MM risk compared to meat eaters. The Nurses' Health Study and Health Professionals Follow-up Study (478 MM cases) showed a significantly increased MM risk in men with Empirical Dietary Inflammatory Pattern. Methods: The NIH-AARP Diet and Health study is a prospective cohort of 567,169 persons who completed a food frequency questionnaire in 1995-1996 and were followed until December 2011. Healthy Eating Index-2015 (HEI-2015), Healthy Diet Score (HDS), alternate Mediterranean Diet (aMED) and healthful Plant-based Diet Index (hPDI) scores were calculated using a priori defined methods and grouped into quartiles, with higher scores reflecting healthier eating patterns. We prospectively evaluated the association between pre-diagnosis dietary patterns and MM incidence in this cohort. Hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated using multivariate Cox proportional hazards models adjusted for age at study entry, sex, race, body mass index, education, and total energy intake (by residual method). Sensitivity analysis was conducted to assess reverse causality by excluding MM cases diagnosed within one year of follow-up. Results: Among 392,589 participants (after exclusions), a total of 1,366 MM cases (59% males; 92% non-Hispanic whites) were identified during the follow-up period. Analysis revealed a significant association between hPDI scores and reduced MM risk (highest vs lowest quartile, HR 0.85; 95%CI 0.73-1.0; p=0.043) (Table). In sensitivity analysis (1,302 MM cases), the association was no longer significant (HR 0.87; 95%CI 0.74-1.03; p 0.09) but trended in the same direction. This may be due to small sample size, given MM is a rare disease. HEI-2015, HDS and aMED scores were not associated with MM risk. Conclusions: A healthful plant-based diet was associated with reduced MM risk in the NIH-AARP cohort. These results will help oncologists and patients make informed choices about their diet. To our knowledge, this is the largest epidemiologic study to date assessing pre-diagnosis dietary patterns and MM risk.

Personal and Planetary Health-The Connection With Dietary Choices.

This Viewpoint offers strategies to help shift to plant-based diets to reduce climate change and promote individual health by encouraging patients, incorporating the environmental impact of food choices in national dietary guidelines, and adding plant-based nutrition training in medical schools.

Imaging modalities for measuring body composition in patients with cancer: opportunities and challenges.

Body composition assessment (ie, the measurement of muscle and adiposity) impacts several cancer-related outcomes including treatment-related toxicities, treatment responses, complications, and prognosis. Traditional modalities for body composition measurement include body mass index, body circumference, skinfold thickness, and bioelectrical impedance analysis; advanced imaging modalities include dual energy x-ray absorptiometry, computerized tomography, magnetic resonance imaging, and positron emission tomography. Each modality has its advantages and disadvantages, thus requiring an individualized approach in identifying the most appropriate measure for specific clinical or research situations. Advancements in imaging approaches have led to an abundance of available data, however, the lack of standardized thresholds for classification of abnormal muscle mass or adiposity has been a barrier to adopting these measurements widely in research and clinical care. In this review, we discuss the different modalities in detail and provide guidance on their unique opportunities and challenges.

Dietary and microbiome evidence in multiple myeloma and other plasma cell disorders.

Multiple Myeloma (MM) remains an incurable plasma cell neoplasm. Although little is known about the etiology of MM, several metabolic risk factors such as obesity, diabetes mellitus, diet, and the human intestinal microbiome have been linked to the pathogenesis of MM. In this article, we provide a detailed review of dietary and microbiome factors involved in the pathogenesis of MM and their impact on outcomes. Concurrent with treatment advancements that have improved survival in MM, focused efforts are needed to reduce the burden of MM as well as improve MM specific and overall outcomes once MM is diagnosed. The findings presented in this review will provide a comprehensive guide on the evidence available to date of the impact of dietary and other lifestyle interventions on the gut microbiome and on MM incidence, outcomes, and quality of life. Data generated from such studies can help formulate evidence-based guidelines for healthcare providers to counsel individuals at risk such as those with Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) as well as MM survivors with respect to their dietary habits.

Assessment of renal outcome following therapy in monoclonal immunoglobulin deposition disease: Emphasizing the need for a consensus approach.

Monoclonal immunoglobulin deposition disease (MIDD), often associated with plasma cell dyscrasias, predominantly affects the kidneys. In this disease, hematologic response (HR) to treatment can be reliably assessed by International Myeloma Working Group (IMWG) consensus criteria, while uniform criteria for assessing renal response are lacking. We report a retrospective analysis of renal outcomes among 34 patients with MIDD. With most patients treated with bortezomib and autologous stem cell transplantation, 26 of 28 (94%) achieved very good partial HR or better. We demonstrate that both IMWG (based on estimated glomerular filtration rate, eGFR) and amyloid (based on proteinuria) criteria are needed to capture renal response: among 28 evaluable patients, 6 (21%) had isolated proteinuria, while 13 (46%) had isolated decreased eGFR. Using both criteria, which were concordant in patients with both decreased eGFR and proteinuria, 22 of 28 patients (79%) achieved a renal response, including 2 of 7 discontinuing dialyses. All 6 patients (100%) with isolated proteinuria and 7 of 13 (54%) with isolated decreased eGFR achieved renal response, suggesting that isolated proteinuria is an early manifestation of MIDD associated with reversible renal damage. Baseline eGFR predicted renal response (p = .02 by quartile) and survival (p = .02), while HR (CR vs. non-CR) did not, probably because of high HR rate. With a median follow-up of 110 months, the median overall survival was 136 months (95% CI: 79-NR) and median renal survival had not been reached. Prospective studies using uniform renal response criteria are needed to optimize the management of MIDD.

Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration-approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post-CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval [CI], 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell-engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell-engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell-engaging therapies appear to maintain pronounced clinical activity in this setting.

GPRC5D-Targeted CAR T Cells for Myeloma.

BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).

Sustained Minimal Residual Disease Negativity in Multiple Myeloma is Associated with Stool Butyrate and Healthier Plant-Based Diets.

PURPOSE: Sustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma. The gut microbiome is affected by diet, and in turn can modulate host immunity, for example through production of short-chain fatty acids including butyrate. We hypothesized that dietary factors affect the microbiome (abundance of butyrate-producing bacteria or stool butyrate concentration) and may be associated with multiple myeloma outcomes. EXPERIMENTAL DESIGN: We examined the relationship of dietary factors (via a food frequency questionnaire), stool metabolites (via gas chromatography-mass spectrometry), and the stool microbiome (via 16S sequencing - α-diversity and relative abundance of butyrate-producing bacteria) with sustained MRD negativity (via flow cytometry at two timepoints 1 year apart) in myeloma patients on lenalidomide maintenance. The Healthy Eating Index 2015 score and flavonoid nutrient values were calculated from the food frequency questionnaire. The Wilcoxon rank sum test was used to evaluate associations with two-sided P < 0.05 considered significant. RESULTS: At 3 months, higher stool butyrate concentration (P = 0.037), butyrate producers (P = 0.025), and α-diversity (P = 0.0035) were associated with sustained MRD negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (P = 0.009) and sustained MRD negativity (P = 0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins P = 0.01, flavones P = 0.01, and flavanols P = 0.02). CONCLUSIONS: This is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production, and sustained MRD negativity in multiple myeloma, providing rationale to evaluate a prospective dietary intervention.