T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations.

Multiple myeloma (MM) is an incurable blood cancer that primarily affects older adults. Several frailty tools have been developed to address the heterogeneity of aging in this population. Uptake of these measures has been variable, leading to a gap in knowledge regarding the proportion of enrolled trial participants considered frail and uncertainty in the treatment-related effects and outcomes among this high-risk population. We performed a systematic review of therapeutic interventional MM clinical trials reporting on frailty. We included 43 clinical trials (24 randomized controlled trials and 19 non-randomized trials) which met eligibility criteria. Frailty was increasingly incorporated in studies in more recent years with 41.9% of included studies being reported in the last two years. Commonly used frailty tools included the International Myeloma Working Group (IMWG) frailty index (41.8%), and the simplified frailty score (39.5%). Frailty status was categorized with 3 levels as (frail, intermediate fit, or fit) in 51.2% of the studies and dichotomized (frail, non-frail) in 18.6% of studies. Frailty prevalence greatly varied across trials ranging from 17.2% to 73.6% of the cohort. Of the included studies, 72.0% conducted subgroup analysis (planned or post-hoc) based on frailty status. Most studies demonstrated a consistent benefit of MM interventions among the frail and non-frail populations, however in general, frail patients had worse outcomes compared to the fit. Although frailty is increasingly being incorporated in MM clinical trials, due to the variation in both the definition and categorization of frailty, there remains heterogeneity in the prevalence of frailty and its potential associated impact on outcomes.

Multiple myeloma (MM) is a cancer of older adults and those who are more frail are at high risk of poor outcomes. Current tools for identifying and categorizing frail patients are often static and measured only at the time of diagnosis. The concept of dynamic frailty (i.e. frailty changing over time) is largely unexplored in MM. In our study, adults with newly-diagnosed MM who received novel drugs between the years 2007–2014 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Using a previously published cumulative deficit approach, a frailty index score was calculated at diagnosis and each landmark interval (1-yr, 2-yr, 3-yr post diagnosis). The association of frailty with overall survival (OS) both at baseline and at each landmark interval as well as factors associated with worsening frailty status over time were evaluated. Overall, 4617 patients were included. At baseline, 39% of the patients were categorized as moderately frail or severely frail. Among those who had 3 years of follow-up, frailty categorization changed post diagnosis in 93% of the cohort (78% improved and 72% deteriorated at least at one time point during the follow up period). In a landmark analysis, the predictive ability of frailty at the time of diagnosis decreased over time for OS (Harrell’s C Statistic 0.65 at diagnosis, 0.63 at 1-yr, 0.62 at 2-yr, and 0.60 at 3-yr) and was inferior compared to current frailty status at each landmark interval. Our study is one of the first to demonstrate the dynamic nature of frailty among older adults with MM. Frailty may improve or deteriorate over time. Current frailty status is a better predictor of outcomes than frailty status at time of diagnosis, indicating the need for re-measurement in this high-risk patient population.

Hematologic malignancy outcomes have remarkably improved in the past decade with further advancement expected in future years. However, the detrimental effects of financial toxicity (FT) on patients with hematologic malignancies, because of both diagnoses and subsequent treatments, have not been studied comprehensively. We performed a systematic review of all studies reporting FT as a primary or secondary outcome among adult or pediatric patients with hematological malignancies. A total of 55 studies met the inclusion criteria for analysis. Across studies, 20–50% of patients reported some form of FT, including loss of work productivity, food and transportation costs, and depletion of savings. Younger age, lower-income level, unemployment, and rural residence were the most commonly identified risk factors for FT. Two studies looked at survival outcomes, with one reporting improvement in survival with a decrease in financial toxicity. However, significant heterogeneity in FT definitions was found between countries and payor systems. Only half of the studies (51%, n = 28) used validated survey instruments such as the COST assessment. The present systematic review identified that FT is common in patients with hematological malignancies and may be associated with poorer outcomes. However, studies of FT generally use non-standardized methods with cross-sectional analyses rather than longitudinal, prospective assessments. Further work is needed to standardize FT reporting and investigate measures to alleviate FT among patients with hematologic malignancies.

Teclistamab, a BCMAxCD3-directed bispecific antibody, has shown high response rates and durable remissions in triple-class-exposed patients with relapsed/refractory multiple myeloma. We performed a retrospective study evaluating the efficacy and safety of teclistamab in 210 patients treated at 9 academic centers from five countries within the IMWG Immunotherapy Working Group Committee. Patients were heavily pretreated, with 83% having triple-class refractory disease and 44% with prior BCMA-targeted therapy. With a median follow-up of 5.3 months, the overall response rate (ORR) was 67% in 188 response-evaluable patients, including 55% with a very good partial response or better. The 6-month progression-free survival (PFS) and overall survival rates were 53% (95% CI, 46–61%) and 73% (67–80%), respectively. Patients who received prior BCMA-directed therapy compared to BCMA-treatment-naïve patients had a lower ORR (58.3 vs 74.0%; P = 0.03) and PFS (6-month PFS 43% [95% CI, 33–55%] vs 63% [54–73%]; logrank P = 0.004). Step-up dosing occurred in an outpatient setting for 23% of patients. CRS occurred in 54% of patients, and infections were reported in 56.2% of patients, with 22% having grade ≥3 infections. In this multicenter real-world study, we found that teclistamab can lead to rapid responses in heavily pretreated myeloma patients with comparable efficacy and safety profiles, as demonstrated in MajesTEC-1.

Quadruplet regimens (anti-CD38 monoclonal antibodies [mAbs] with proteasome inhibitor [PI] and immunomodulatory drugs [IMiDs]) are increasingly being investigated in newly diagnosed multiple myeloma (NDMM). The objective of our study was to conduct a systematic review and meta-analysis to measure the efficacy and toxicity of quadruplet regimens used in NDMM. Embase, MEDLINE, Web of Science, Cochrane Library, clinical trial registries, and meeting libraries from inception to 24 January 2024, in addition to American Society of Clinical Oncology conference abstracts 2024, were searched using terms reflecting multiple myeloma and components of the quadruplet regimen. Included studies were randomized controlled trials (RCTs) that compared backbone regimens consisting of a PI and IMiD vs the same regimen plus an anti-CD38 mAb in NDMM. We identified 7 RCTs including 3716 patients. Compared with triplets, quadruplets increase the overall response rate (ORR; relative risk [RR], 1.03; 95% confidence interval [CI], 1.01-1.05) and progression-free survival (PFS; hazard ratio [HR], 0.55; 95% CI, 0.46-0.66). Quadruplets increase the rates of minimal residual disease (MRD) negativity at 10–5 (RR, 1.39; 95% CI, 1.23-1.58) and 10–6 (RR, 1.62; 95% CI, 1.36-1.94). Quadruplets improve overall survival (OS; HR, 0.65; 95% CI, 0.53-0.79). There was a slight increase in the rates of grade 3 to 4 infections (RR, 1.22; 95% CI, 1.07-1.39) noted with quadruplets compared with triplets. Overall, in this meta-analysis, quadruplets were associated with improved efficacy including ORR, MRD negativity, PFS, and OS, with a slight increase in infection rates. Quadruplet regimens represent a new standard of care, particularly in transplant-eligible NDMM.