Search

Summary: Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant‐eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment‐emergent adverse events. In summary, these findings suggest a benefit of D‐RVd front‐line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd) are commonly used treatment combinations for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). D-Rd and VRd demonstrated superior efficacy relative to lenalidomide and dexamethasone (Rd) in the MAIA and SWOG S0777 trials, respectively, but have not been compared directly in a head-to-head trial. Naïve comparisons of efficacy across the two trials may be biased because MAIA enrolled only TIE patients (median age 73 years), whereas SWOG S0777 enrolled both TIE patients and transplant-eligible patients who chose to defer/refuse frontline stem cell transplantation (median age 63 years). The present study compared progression-free survival (PFS) in TIE patients with NDMM treated with D-Rd versus VRd based on an adjusted indirect treatment comparison (ITC) that leveraged individual patient-level data from MAIA and SWOG S0777. Methods: Harmonized inclusion/exclusion criteria (including age ≥ 65 years as a proxy for transplant ineligibility) and propensity-score weighting were used to balance the trial populations on measured baseline characteristics. After differences in trial populations were adjusted for, an anchored ITC was performed wherein within-trial PFS hazard ratios (HRs) for D-Rd versus Rd and VRd versus Rd were estimated and used to make indirect inference about PFS for D-Rd versus VRd. Results: PFS HRs were 0.52 (95% confidence interval [CI] 0.41–0.67) for D-Rd versus Rd based on MAIA data, 0.88 (95% CI 0.63–1.23) for VRd versus Rd based on SWOG S0777 data, and 0.59 (95% CI 0.39–0.90) for the Rd-anchored ITC of D-Rd versus VRd. Sensitivity and subgroup analyses produced results consistent with the primary results. Conclusion: This anchored ITC demonstrated a greater PFS benefit for D-Rd versus VRd in TIE patients with NDMM. In the absence of head-to-head trials comparing D-Rd and VRd, the present trial may help inform treatment selection in this patient population. Plain Language Summary: Multiple drug combinations can be used to treat patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for a stem cell transplant. Two of these combinations—daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd)—have each been studied in clinical trials (MAIA and SWOG S0777) against the combination of lenalidomide plus dexamethasone (Rd), but D-Rd and VRd have not been compared directly in a head-to-head clinical trial. Our study used data from the MAIA and SWOG S0777 trials to indirectly compare outcomes observed with D-Rd and VRd. For this indirect comparison between D-Rd and VRd, we first made adjustments to the patient populations of each trial to make them more similar to each other; this helped to make sure any differences we saw in treatment outcomes between D-Rd and VRd would not be because of differences in the characteristics of the patients who participated in the trials. After we made these adjustments to the patient populations of each trial, both D-Rd and VRd lowered the risk of disease progression or death compared with Rd alone. However, when indirectly compared in our study, D-Rd lowered the risk of disease progression or death by 41% compared with VRd. As data directly comparing treatment outcomes for D-Rd and VRd are not available, this indirect comparison can contribute to the information used to make treatment decisions for patients with NDMM who are not eligible for a stem cell transplant. [ABSTRACT FROM AUTHOR]

There are significant disparities with regards to incidence, timely diagnosis, access to treatment, clinical trial participation and health care utilization that negatively impact outcomes for African American patients with multiple myeloma. Health care providers have a role in ameliorating these disparities with thoughtful consideration of historical, sociocultural, individual and disease characteristics that influence the care provided to African American patient population. This review by a group of experts committed to health disparity in multiple myeloma provides a snapshot of disparities at both biologic and non-biologic levels, barriers to clinical care, and best practices to ensure that African American patients receive the best care available. [ABSTRACT FROM AUTHOR]

The plasma cell cancer multiple myeloma (MM) varies significantly in genomic characteristics, response to therapy, and long-term prognosis. To investigate global interactions in MM, we combined a known protein interaction network with a large clinically annotated MM dataset. We hypothesized that an unbiased network analysis method based on large-scale similarities in gene expression, copy number aberration, and protein interactions may provide novel biological insights. Applying a novel measure of network robustness, Ollivier-Ricci Curvature, we examined patterns in the RNA-Seq gene expression and CNA data and how they relate to clinical outcomes. Hierarchical clustering using ORC differentiated high-risk subtypes with low progression free survival. Differential gene expression analysis defined 118 genes with significantly aberrant expression. These genes, while not previously associated with MM, were associated with DNA repair, apoptosis, and the immune system. Univariate analysis identified 8/118 to be prognostic genes; all associated with the immune system. A network topology analysis identified both hub and bridge genes which connect known genes of biological significance of MM. Taken together, gene interaction network analysis in MM uses a novel method of global assessment to demonstrate complex immune dysregulation associated with shorter survival. [ABSTRACT FROM AUTHOR]

Cilta-cel, a BCMA-targeting chimeric antigen receptor T-cell therapy for multiple myeloma, was approved in USA on 28 February 2022, for patients with relapsed or refractory disease who have received ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Approval in the EU followed for patients with ≥3 prior therapies. At median 28-month follow-up, the pivotal CARTITUDE-1 trial showed a 98% response rate (83% stringent complete response); median progression-free survival had not been reached, and adverse events could be managed with supportive therapy. Cilta-cel efficacy and safety in earlier lines of therapy, and its optimal sequencing in a complex treatment landscape are important areas of investigation. [ABSTRACT FROM AUTHOR]

Introduction: Extrapolating long-term overall survival (OS) from shorter-term clinical trial data is key to health technology assessment in oncology. However, extrapolation using conventional methods is often subject to uncertainty. Using ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy for multiple myeloma, we used a flexible Bayesian approach to demonstrate use of external longer-term data to reduce the uncertainty in long-term extrapolation. Methods: The pivotal CARTITUDE-1 trial (NCT03548207) provided the primary efficacy data for cilta-cel, including a 12-month median follow-up snapshot of OS. Longer-term (48-month median follow-up) survival data from the phase I LEGEND-2 study (NCT03090659) were also available. Twelve-month CARTITUDE-1 OS data were extrapolated in two ways: (1) conventional survival models with standard parametric distributions (uninformed), and (2) Bayesian survival models whose shape prior was informed from 48-month LEGEND-2 data. For validation, extrapolations from 12-month CARTITUDE-1 data were compared with observed 28-month CARTITUDE-1 data. Results: Extrapolations of the 12-month CARTITUDE-1 data using conventional uninformed parametric models were highly variable. Using informative priors from the 48-month LEGEND-2 dataset, the ranges of projected OS at different timepoints were consistently narrower. Area differences between the extrapolation curves and the 28-month CARTITUDE-1 data were generally lower in informed Bayesian models, except for the uninformed log-normal model, which had the lowest difference. Conclusions: Informed Bayesian survival models reduced variation of long-term projections and provided similar projections as the uninformed log-normal model. Bayesian models generated a narrower and more plausible range of OS projections from 12-month data that aligned with observed 28-month data. Trial Registration: CARTITUDE-1 ClinicalTrials.gov identifier, NCT03548207. LEGEND-2 ClinicalTrials.gov identifier, NCT03090659, registered retrospectively on 27 March 2017, and ChiCTR-ONH-17012285. [ABSTRACT FROM AUTHOR]

Background: Ki‐67 is an index of proliferative activity and is an established predictive and prognostic marker in multiple malignancies. However, its prognostic relevance in multiple myeloma (MM) is unclear. We investigated the relationship between Ki‐67 expression and survival outcomes in MM in the era of novel therapies. Methods: We interrogated our database to identify patients with MM, newly diagnosed between July 1, 2013 and December 31, 2020, with Ki‐67 expression assessed by immunohistochemistry (IHC) on bone marrow biopsies. Using an established threshold of 5% we defined Ki‐67low (≤5%) and Ki‐67high (>5%) subgroups for association with progression‐free survival (PFS) and overall survival (OS). Results: Of 167 patients included: 53 (31.7%) had Ki‐67high and 114 had Ki‐67low. More patients with R‐ISS 3 had Ki‐67high (22.2% vs. 9.7%). The gain of 1q21 was overrepresented in the Ki‐67high group (28% vs. 8%). Median PFS in the Ki‐67low group was 3.1 years, and in the Ki‐67high group 1.6 years (log‐rank p <.001, HR: 1.9). Median OS was not reached in the Ki‐67low vs. 4.8 years in the Ki‐67high cohort (HR: 1.9; log‐rank test: p =.018). In the multivariable modeling, after adjusting for other risk factors, HR for Ki‐67high versus Ki‐67low was 2.4 (p <.001) for PFS and 2.1 (p =.026) for OS. Conclusions: Our results demonstrate that a high Ki‐67 index (>5%) is an independent prognostic marker associated with worse OS and PFS in newly diagnosed MM. IHC staining for Ki‐67 on bone marrow biopsies could be easily adopted as a prognostic biomarker for MM in economically constrained healthcare settings. [ABSTRACT FROM AUTHOR]

Lenalidomide and dexamethasone with bortezomib (VRd) or carfilzomib (KRd) are commonly used induction regimens in the U.S. This single-center, retrospective study evaluated outcomes and safety of VRd and KRd. Primary endpoint was progression-free survival (PFS). Of 389 patients with newly diagnosed multiple myeloma, 198 received VRd and 191 received KRd. Median PFS was not reached (NR) in both groups; 5-year PFS was 56% (95%CI, 48–64%) for VRd and 67% (60–75%) for KRd (P = 0.027). Estimated 5-year EFS was 34% (95%CI, 27–42%) for VRd and 52% (45–60%) for KRd (P < 0.001) with corresponding 5-year OS of 80% (95%CI, 75–87%) and 90% (85–95%), respectively (P = 0.053). For standard-risk patients, 5-year PFS was 68% (95%CI, 60–78%) for VRd and 75% (65–85%) for KRd (P = 0.20) with 5-year OS of 87% (95%CI, 81–94%) and 93% (87–99%), respectively (P = 0.13). For high-risk patients, median PFS was 41 months (95%CI, 32.8–61.1) for VRd and 70.9 months (58.2-NR) for KRd (P = 0.016). Respective 5-year PFS and OS were 35% (95%CI, 24–51%) and 69% (58–82%) for VRd and 58% (47–71%) and 88% (80–97%, P = 0.044) for KRd. Overall, KRd resulted in improved PFS and EFS with a trend toward improved OS compared to VRd with associations primarily driven by improvements in outcome for high-risk patients. [ABSTRACT FROM AUTHOR]

There are disparities in outcomes for patients with multiple myeloma (MM). We evaluated the influence of sociodemographic factors on global disparities in outcomes for patients with MM. This rapid evidence assessment (PROSPERO, CRD42021248461) followed PRISMA-P guidelines and used the PICOS framework. PubMed and Embase® were searched for articles in English from 2011 to 2021. The title, abstract, and full text of articles were screened according to inclusion/exclusion criteria. The sociodemographic factors assessed were age, sex, race/ethnicity, socioeconomic status, and geographic location. Outcomes were diagnosis, access to treatment, and patient outcomes. Of 84 articles included, 48 were US-based. Worldwide, increasing age and low socioeconomic status were associated with worse patient outcomes. In the US, men typically had worse outcomes than women, although women had poorer access to treatment, as did Black, Asian, and Hispanic patients. No consistent disparities due to sex were seen outside the US, and for most factors and outcomes, no consistent disparities could be identified globally. Too few studies examined disparities in diagnosis to draw firm conclusions. This first systematic analysis of health disparities in patients with MM identified specific populations affected, highlighting a need for additional research focused on assessing patterns, trends, and underlying drivers of disparities in MM. [ABSTRACT FROM AUTHOR]

These results indicate that corticosteroid tapering does not diminish DARA SC monotherapy efficacy, as patients who received DARA SC with/without tapering achieved similar efficacy [[3], [15]]. No patients evaluable for daratumumab immunogenicity were positive for anti-daratumumab antibodies, indicating a low risk for immunogenicity for DARA SC with corticosteroid tapering. All patients experienced >=1 TEAE; 21 (50.0%) patients reported a grade >=3 TEAE, and 16 (38.1%) patients experienced a serious TEAE. [Extracted from the article]

The ECOG performance status was higher at the extremes of BMI; 68% of underweight patients and 58% of severely obese patients had ECOG >= 1 compared to 43-51% in normal weight, overweight, or moderately obese patients. The study in US veterans showed that overweight and obese patients had lower MM mortality compared to healthy weight patients, whereas underweight patients had higher MM mortality. The authors of that study found that obese patients with MM experienced superior survival, except those with substantial weight loss in the year prior to diagnosis and those who were underweight at diagnosis (BMI < 18.5) [[10]]. [Extracted from the article]

Magrolimab is a monoclonal antibody that blocks CD47, a 'do not eat me' signal overexpressed on tumor cells. CD47 is overexpressed in multiple myeloma (MM), which contributes to its pathogenesis. Preclinical studies have shown that CD47 blockade induces macrophage activation, resulting in elimination of myeloma cells, and that there is synergy between magrolimab and certain anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This phase II study investigates magrolimab in combination with commonly used myeloma therapies in patients with relapsed/refractory MM and includes a safety run-in phase followed by a dose-expansion phase. Primary end points include the incidence of dose-limiting toxicities and adverse events (safety run-in) and the objective response rate (dose expansion). Magrolimab is a therapy that blocks a 'do not eat me' signal overexpressed by certain cancers, including multiple myeloma (MM) cells. Studies have shown that blocking this signal leads to destruction of myeloma cells and that this cancer-killing effect may be increased by combining magrolimab with certain additional anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This study is investigating magrolimab in combination with commonly used myeloma therapies in patients with MM who have persistent disease despite prior treatment. Goals of the trial include assessing safety and response to treatment. Clinical Trial Registration:NCT04892446 (ClinicalTrials.gov) This phase II study investigates safety and treatment response to #magrolimab, an antibody that enhances phagocytosis of cancer cells, combined with commonly used therapies in patients with #multiplemyeloma. [ABSTRACT FROM AUTHOR]

This study used the latest available data cuts from the CARTITUDE-1 and KarMMa clinical trials to update previously published matching-adjusted indirect treatment comparisons (MAICs) assessing the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the FDA-approved idecabtagene vicleucel (ide-cel) dose range of 300 to 450 × 106 CAR-positive T-cells in the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed). MAICs were performed with the latest available individual patient data for cilta-cel (CARTITUDE-1) and published summary-level data for ide-cel (KarMMa). The analyses included treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was assessed for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p <.0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.65 [95% CI: 2.51, 12.69; p <.0001]; RR: 2.23), DoR (hazard ratio [HR]: 0.52 [95% CI: 0.30, 0.88; p =.0152]), PFS, (HR: 0.38 [95% CI: 0.24, 0.62; p <.0001]), and OS (HR: 0.43 [95% CI: 0.22, 0.88; p =.0200]) compared with ide-cel. These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes over longer follow-up and highlight its therapeutic potential in triple-class exposed RRMM patients. [ABSTRACT FROM AUTHOR]

At last follow-up, 5 (50%) patients remained on maintenance lenalidomide, and 5 (50%) patients received a subsequent line of therapy (note: three patients, in the absence of PD, continued on daratumumab beyond the six cycles). It is plausible that in standard-risk patients there may be a stable MRD clone without clinical consequence, leading to clinician and patient preferences to avoid interventions in the absence of a clinical relapse. Despite the improved complete response (CR) rates in multiple myeloma with newer therapies, most patients still relapse [[1]]. Although there was a third patient that converted to bone marrow MRD-negativity, this patient had serologic progressive disease (PD) at the time of response assessment and was deemed not to have achieved the primary end point. [Extracted from the article]

Objective: In the absence of head-to-head trials, indirect treatment comparisons (ITCs) between ciltacabtagene autoleucel (cilta-cel; in CARTITUDE-1) and treatments used in real-world clinical practice (physician's choice of treatment [PCT]), were previously conducted. We conducted multiple meta-analyses using available ITC data to consolidate the effectiveness of cilta-cel versus PCT for patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM). Methods: Five ITCs were assessed for similarity to ensure robust comparisons using meta-analysis. Effectiveness outcomes were overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR). A robust variance estimator was used to account for the use of CARTITUDE-1 in each pairwise ITC. Analyses were conducted in both treated and enrolled populations of CARTITUDE-1. Results: Four ITCs were combined for evaluation of OS. Results were statistically significantly in favor of cilta-cel versus PCT in treated patients (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.22–0.26). Three ITCs were combined for evaluation of PFS and TTNT. Cilta-cel reduced the risk of progression and receiving a subsequent treatment by 80% (HR: 0.20 [95% CI: 0.06, 0.70]) and 83% (HR: 0.17 [95% CI: 0.12, 0.26]), respectively. Three ITCs were combined for evaluation of ORR. Cilta-cel increased the odds of achieving an overall response by 86-times versus PCT in treated patients. Findings were consistent in the enrolled populations and across sensitivity analyses. Conclusions: Evaluating multiple indirect comparisons, cilta-cel demonstrated a significantly superior advantage over PCT, highlighting its effectiveness as a therapy in patients with triple-class exposed RRMM. [ABSTRACT FROM AUTHOR]

CANDOR compared the safety/efficacy of carfilzomib with dexamethasone and daratumumab (KdD) to carfilzomib with dexamethasone (Kd) in adults with relapsed/refractory multiple myeloma (RRMM). This CANDOR subgroup analysis evaluated outcomes based on cytogenetic risk. Overall response rates (KdD vs. Kd) were 81% versus 56% in high‐risk and 87% versus 79% in standard‐risk groups. Median progression‐free survival was 11.2 versus 7.4 months in high‐risk (hazard ratio, 0.56 [95% CI, 0.34, 0.93]) and not reached versus 16.6 months in standard‐risk groups (0.56 [95% CI, 0.39, 0.80]). These data support the efficacy of KdD in RRMM treatment, including in patients with high‐risk cytogenetics. [ABSTRACT FROM AUTHOR]

Background Patients with high-risk, newly diagnosed multiple myeloma (HR-NDMM) who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment options. Recent meta-analyses evaluating the impact of incorporating daratumumab in the backbone regimen on progression-free survival (PFS) have found mixed results in these patients. Materials and Methods A pooled analysis of patient-level data for ASCT-ineligible patients with HR-NDMM [ie, del(17p), t(4;14), t(14;16)] from the MAIA and ALCYONE trials; stratified by study identifier and adjusting for cytogenetic abnormality subtype, baseline performance status, International Staging System stage, myeloma type, and renal impairment; was conducted. Impact of daratumumab on PFS and rates of complete response or better (≥CR), minimal residual disease (MRD)-negative CR, very good partial response or better (≥VGPR), and overall response (ORR) was compared to control. Results Among 101 patients in the daratumumab and 89 patients in the control cohort, median follow-up was 43.7 months. Daratumumab reduced the risk of progression or death by 41% (adjusted hazard ratio for PFS [95% confidence interval (CI)] = 0.59 [0.41-0.85]) versus control. At 36 months, the estimated proportion of patients who did not progress and were still alive was 41.3% in the daratumumab and 19.9% in the control cohort. Rates of ≥CR (41.6% vs. 22.5%), MRD-negative CR (24.8% vs. 5.6%), ≥VGPR (75.2% vs. 46.1%), and ORR (92.1% vs. 74.2%) were higher for daratumumab versus control. Conclusion These findings demonstrate that incorporation of daratumumab in frontline treatment regimens reduced the risk of progression or death and improved response rates among ASCT-ineligible HR-NDMM patients. [ABSTRACT FROM AUTHOR]

With recent advances in myeloma therapy, patients can achieve long-term remissions, but eventually relapses will occur. Triple-class refractory myeloma (disease that is refractory to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody) and penta-refractory myeloma (disease that is refractory to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 antibody) are associated with a particularly poor prognosis, and novel treatments are desperately needed for these patients. Targeting B cell maturation antigen (BCMA), which is ubiquitously expressed on plasma cells, has emerged as a well-tolerated and highly efficacious strategy in patients with relapsed and refractory myeloma. Several mechanisms of targeting BCMA are currently under investigation, including antibody–drug conjugates, bispecific antibodies, and chimeric antigen receptor T cells and natural killer (NK) cells, all with unique side effect profiles. Early phase clinical trials showed unprecedented response rates in highly refractory myeloma patients, leading to the recent approvals of some of these agents. Still, many questions remain with regard to this target, including how best to target it, how to treat patients who have progressed on a BCMA-targeting therapy, and whether response rates will deepen if these agents are used in earlier lines of therapy. In this review, we examine the rationale for targeting BCMA and summarize the data for several agents across multiple classes of BCMA-targeting therapeutics, paying special attention to the diverse mechanisms and unique challenges of each therapeutic class. [ABSTRACT FROM AUTHOR]

Extramedullary involvement (or extramedullary disease, EMD) represents an aggressive form of multiple myeloma (MM), characterized by the ability of a clone and/or subclone to thrive and grow independent of the bone marrow microenvironment. Several different definitions of EMD have been used in the published literature. We advocate that true EMD is restricted to soft-tissue plasmacytomas that arise due to hematogenous spread and have no contact with bony structures. Typical sites of EMD vary according to the phase of MM. At diagnosis, EMD is typically found in skin and soft tissues; at relapse, typical sites involved include liver, kidneys, lymph nodes, central nervous system (CNS), breast, pleura, and pericardium. The reported incidence of EMD varies considerably, and differences in diagnostic approach between studies are likely to contribute to this variability. In patients with newly diagnosed MM, the reported incidence ranges from 0.5% to 4.8%, while in relapsed/refractory MM the reported incidence is 3.4 to 14%. Available data demonstrate that the prognosis is poor, and considerably worse than for MM without soft-tissue plasmacytomas. Among patients with plasmacytomas, those with EMD have poorer outcomes than those with paraskeletal involvement. CNS involvement is rare, but prognosis is even more dismal than for EMD in other locations, particularly if there is leptomeningeal involvement. Available data on treatment outcomes for EMD are derived almost entirely from retrospective studies. Some agents and combinations have shown a degree of efficacy but, as would be expected, this is less than in MM patients with no extramedullary involvement. The paucity of prospective studies makes it difficult to justify strong recommendations for any treatment approach. Prospective data from patients with clearly defined EMD are important for the optimal evaluation of treatment outcomes. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a blood cancer characterized by clonal proliferation of plasma cells in the bone marrow. In recent years, several new drugs have been added to the therapeutic landscape of multiple myeloma, which have contributed to increased survival rates. However, while the use of therapeutics has evolved, there is still a group of high-risk patients who do not benefit from current treatment strategies. Risk stratification and risk-adapted treatment are crucial to identify the group of patients with urgent need for novel therapies. Gene expression profiling has been introduced as a tool for risk stratification in multiple myeloma based on the genetic make-up of myeloma cells. In this review we discuss the challenge of defining the high-risk multiple myeloma patient. We focus on the standardized analysis of myeloma cancer cells by gene expression profiling and describe how gene expression profiling provides additional insights for optimal risk-adapted treatment of patients suffering from multiple myeloma. [ABSTRACT FROM AUTHOR]

Background and Objective: Ciltacabtagene autoleucel (cilta-cel) is a novel agent being investigated in the single-arm CARTITUDE-1 trial (NCT03548207) for patients with relapsed or refractory multiple myeloma who are triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. The objective of this study was to evaluate the comparative efficacy of cilta-cel vs physician's choice of treatment, as no head-to-head trials have been conducted. Methods: An external control arm for CARTITUDE-1 was created from patients in the long-term follow-up for three clinical trials of daratumumab (POLLUX, CASTOR, and EQUULEUS) who satisfied the eligibility criteria of CARTITUDE-1. These patients received physician's choice of treatment following the discontinuation of study drugs. Inverse probability of treatment weighting was used to align the external control and CARTITUDE-1 populations on important baseline characteristics. Overall response rate, complete response or better rate, progression-free survival, time to next treatment, and overall survival were assessed. Several sensitivity analyses were conducted. Results: After propensity score weighting, baseline characteristics were comparable between cohorts. Patients showed improved results with cilta-cel vs physician's choice of treatment: overall response rate (relative risk: 2.95 [95% confidence interval (CI) 2.27, 3.84; p < 0.0001]), complete response or better (relative risk: 111.70 [95% CI 29.08, 429.06; p < 0.0001]), progression-free survival (hazard ratio [HR]: 0.24 [95% CI 0.15, 0.37; p < 0.0001]), time to next treatment (HR: 0.14 [95% CI 0.09, 0.22; p < 0.0001]), and overall survival (HR: 0.21 [95% CI 0.13, 0.35; p < 0.0001]). Results were consistent across all sensitivity analyses. Conclusions: Cilta-cel showed superior efficacy compared with physician's choice of treatment, making it a promising new treatment option for patients with triple-class exposed relapsed or refractory multiple myeloma. [ABSTRACT FROM AUTHOR]

Hispanics and non-Hispanic (NH)-Blacks continue to face numerous health disparities related to multiple myeloma (MM). We aimed to analyze trends of MM-related hospitalizations and incidence of in-hospital mortality with a 10-year cross-sectional analysis of inpatient hospitalizations. The prevalence of MM-related hospitalizations was higher in NH-Blacks compared to NH-Whites (476.0 vs. 305.6 per 100,000 hospitalizations, p <.001). MM-related in-hospital mortality was higher in Hispanics compared to NH-Whites and NH-Blacks (6.2 vs. 5.3%, p <.001). Using average annual percent change (AAPC), we found a statistically significant decline of in-hospital mortality among all MM patients except NH-Blacks (AAPC: −2.2, 95% confidence interval (CI) −4.7, 0.4, p =.47), who had the highest inpatient mortality in recent years. Multivariate analysis showed that NH-Blacks received fewer transplants, more blood product transfusions, fewer palliative care consults, less inpatient chemotherapy, and utilized more intensive care. Disparities in MM care for NH-Blacks and Hispanics continue to persist despite recent advancements in MM therapy. [ABSTRACT FROM AUTHOR]

Keywords: mass spectrometry; multiple myeloma; NGF-MRD EN mass spectrometry multiple myeloma NGF-MRD 6933 6936 4 10/21/21 20211015 NES 211015 GLO:FU4O/15oct21:cam44254-toc-0001.jpg PHOTO (COLOR): . gl AKNOWLEDGEMENTS The authors thank Dr. Hazel O'Connor for providing valuable editing suggestions. To our knowledge, this is the first report comparing MALDI-TOF-MS and LC-MS serum M-protein analyses to bone marrow NGF at different sensitivity thresholds. Bone marrow aspirates were prospectively tested using standardized 2-tubes 8-colors NGF methods, and MRD status was established at three levels of sensitivity: 10 SP -4 sp , 10 SP -5 sp , and 10 SP -6 sp .4 Serum eluates were tested retrospectively by MALDI-TOF-MS and Ig-LC-MS for the presence of a serum M-protein using the same I m i / I z i as defined at baseline. [Extracted from the article]

This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the approved idecabtagene vicleucel (ide-cel) dose range of 300–460 × 106 CAR-positive T-cells for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed) using matching-adjusted indirect treatment comparisons (MAICs). MAICs were performed with individual patient data for cilta-cel (CARTITUDE-1; NCT03548207) and published summary-level data for ide-cel (KarMMa; NCT03361748). Treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa were included in the analyses. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was estimated for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p <.0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.49 [95% CI: 2.47, 12.21; p <.0001]; RR: 2.21), DoR (hazard ratio [HR]: 0.50 [95% CI: 0.29, 0.87; p =.0137]), and PFS (HR: 0.37 [95% CI: 0.22, 0.62; p =.0002]) when compared with ide-cel. For OS, the results were in favor of cilta-cel and clinically meaningful but with a CI overlapping one (HR: 0.55 [95% CI: 0.29, 1.05; p =.0702]). These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes, highlighting its therapeutic potential in patients with triple-class exposed RRMM. [ABSTRACT FROM AUTHOR]

For patients with one prior LOT, the PFS HR (95% CI) was 0-90 (0-48-1-70) for lenalidomide-naive patients, 0-30 (0-10-0-86) for lenalidomide-exposed patients and 0-11 (0-02-0-52) for lenalidomide-refractory patients. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Keywords: cancer; clinical studies; clinical trials; multiple myeloma EN cancer clinical studies clinical trials multiple myeloma 784 788 5 08/18/21 20210815 NES 210815 Bortezomib- and lenalidomide-based therapies have become standard front-line treatment for multiple myeloma (MM),1 resulting in many patients being refractory to bortezomib or lenalidomide at first relapse.2,3 This may negatively impact the efficacy of later lines of therapy (LOT)4 and makes optimal sequencing of MM therapies challenging. [Extracted from the article]

Administration of plerixafor with granulocyte‐colony stimulating factor (G‐CSF) mobilizes CD34+ cells much more effectively than G‐CSF alone, but cost generally limits plerixafor use to patients at high risk of insufficient CD34+ cell collection based on low peripheral blood (PB) CD34+ counts following 4 days of G‐CSF. We analyzed costs associated with administering plerixafor to patients with higher day 4 CD34+ cell counts to decrease apheresis days and explored the use of a fixed split dose of plerixafor instead of weight‐based dosing. We analyzed 235 patients with plasma cell disorders or non‐Hodgkin's lymphoma who underwent progenitor cell mobilization and autologous hematopoietic cell transplantation (AHCT) between March 2014 and December 2017. Two hundred ten (89%) received G‐CSF plus Plerixafor and 25 (11%) received G‐CSF alone. Overall, 180 patients (77%) collected in 1 day, 53 (22%) in 2 days and 2 (1%) in 3 days. Based on our data, we present a probabilistic algorithm to identify patients likely to require more than one day of collection using G‐CSF alone. CD34+ cell yield, ANC and platelet recovery were not significantly different between fixed and standard dose plerixafor. Plerixafor enabled collection in 1 day and with estimated savings of $5000, compared to patients who did not receive plerixafor and required collection for three days. While collection and processing costs and patient populations vary among institutions, our results suggest re‐evaluation of current algorithms. [ABSTRACT FROM AUTHOR]

We report the population pharmacokinetic (PK) and exposure‐response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33‐92 years; weight, 28.6‐147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1‐2, once every 2 weeks for cycles 3‐6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard‐of‐care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough) versus intravenous DARA, with lower maximum concentrations and smaller peak‐to‐trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure‐response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65‐kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800‐mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg. [ABSTRACT FROM AUTHOR]

Gain of chromosome 1q (+1q) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM), occurring in approximately 40% of newly diagnosed cases. Although it is often considered a poor prognostic marker in MM, +1q has not been uniformly adopted as a high-risk cytogenetic abnormality in guidelines. Controversy exists regarding the importance of copy number, as well as whether +1q is itself a driver of poor outcomes or merely a common passenger genetic abnormality in biologically unstable disease. Although the identification of a clear pathogenic mechanism from +1q remains elusive, many genes at the 1q21 locus have been proposed to cause early progression and resistance to anti-myeloma therapy. The plethora of potential drivers suggests that +1q is not only a causative factor or poor outcomes in MM but may be targetable and/or predictive of response to novel therapies. This review will summarize our current understanding of the pathogenesis of +1q in plasma cell neoplasms, the impact of 1q copy number, identify potential genetic drivers of poor outcomes within this subset, and attempt to clarify its clinical significance and implications for the management of patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (Ctrough). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of Ctrough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the Ctrough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03–185.00%) and 148.02% (90% CI, 113.32–193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105 [ABSTRACT FROM AUTHOR]

Purpose: The phase III COLUMBA study evaluated daratumumab (DARA) intravenous (IV) and subcutaneous (SC) in patients with relapsed or refractory multiple myeloma. Here, we report patient-reported satisfaction with therapy (SWT) in COLUMBA. Methods: DARA IV or DARA SC was administered weekly (cycles 1–2), every 2 weeks (cycles 3–6), and every 4 weeks (cycles 7 +). Patients completed a modified version of the Cancer Therapy Satisfaction Questionnaire (CTSQ) at weekly (cycles 1–2) and monthly (cycles 3 +) intervals and at the end of treatment. Results for each item and the SWT domain score were summarized using descriptive statistics. The distribution of responses for individual items was calculated for each assessment. The proportion of patients for whom SWT domain score change from first assessment met or exceeded the minimally important difference (MID) of 5.9 points was calculated at each assessment time point. Results: Two-hundred fifty-nine patients were randomized to DARA IV and 263 to DARA SC. Mean scores for SWT domain questions were high and largely positive during treatment. Responses indicating positive perceptions of therapy were given by a numerically greater proportion of patients in the DARA SC group than the DARA IV group for most questions. Changes from the first assessment in SWT domain scores met or exceeded the MID for an average of ~ 40% of patients. Conclusion: In COLUMBA, modified CTSQ results suggest patients in the DARA SC group were more satisfied with their cancer therapy than those in the DARA IV group. Trial registration: ClinicalTrials.gov identifier NCT03277105. Registered September 8, 2107. [ABSTRACT FROM AUTHOR]

Plasma cell disorders (PCDs) are identified in the clinical lab by detecting the monoclonal immunoglobulin (M-protein) which they produce. Traditionally, serum protein electrophoresis methods have been utilized to detect and isotype M-proteins. Increasing demands to detect low-level disease and new therapeutic monoclonal immunoglobulin treatments have stretched the electrophoretic methods to their analytical limits. Newer techniques based on mass spectrometry (MS) are emerging which have improved clinical and analytical performance. MS is gaining traction into clinical laboratories, and has replaced immunofixation electrophoresis (IFE) in routine practice at one institution. The International Myeloma Working Group (IMWG) Mass Spectrometry Committee reviewed the literature in order to summarize current data and to make recommendations regarding the role of mass spectrometric methods in diagnosing and monitoring patients with myeloma and related disorders. Current literature demonstrates that immune-enrichment of immunoglobulins coupled to intact light chain MALDI-TOF MS has clinical characteristics equivalent in performance to IFE with added benefits of detecting additional risk factors for PCDs, differentiating M-protein from therapeutic antibodies, and is a suitable replacement for IFE for diagnosing and monitoring multiple myeloma and related PCDs. In this paper we discuss the IMWG recommendations for the use of MS in PCDs. [ABSTRACT FROM AUTHOR]

Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the ‘efficacy’ of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual’s composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting. [ABSTRACT FROM AUTHOR]

Multiple myeloma(MM) is an incurable plasma cell malignancy. Despite an improvement in OS over the past 2 decades, most patients do experience disease relapse. A subset of patients who experience an early disease relapse within 1‐2 years posttransplant, and considered functional high‐risk. Recent findings implicated high‐risk cytogenetic features and minimal residual disease as negative prognostic factors, each independently associated with early relapse among autologous stem cell transplant recipients(ASCT). The spectrum of disease relapse could range from asymptomatic/biochemical to more aggressive forms such as plasma cell leukemia. Hence, it is imperative that therapy be tailored based on these patterns of relapse upon presentation. The past few years have witnessed an explosion in the armamentarium of second‐line agents for the treatment of relapsed MM. Accordingly, choosing the optimal regimen has become quite challenging for the practicing clinician. In this review, we outline the approach for therapy selection, which takes into account underlying comorbid conditions, duration of response, presence of high‐risk features, etc Due to a better understanding of disease biology coupled with the advances in molecular techniques, the treatment landscape of relapsed MM (posttransplant) will most likely continue to evolve. Novel agents with distinct modes of action, such as immune therapies and novel oral agents are undergoing investigation in the relapsed setting. Once approved, these agents could potentially alter the course of the disease and possibly challenge the role of ASCT. [ABSTRACT FROM AUTHOR]