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PURPOSE Idecabtagene vicleucel (ide-cel) is an autologous B-cell maturation antigen–directed chimeric antigen receptor T-cell therapy approved for relapsed/refractory multiple myeloma (RRMM) on the basis of the phase II pivotal KarMMa trial, which demonstrated best overall and ≥ complete response rates of 73% and 33%, respectively. We report clinical outcomes with standard-of-care (SOC) ide-cel under the commercial Food and Drug Administration label. METHODS Data were retrospectively collected from patients with RRMM who underwent leukapheresis as of February 28, 2022, at 11 US institutions with intent to receive SOC ide-cel. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines and managed according to each institution's policies. Responses were graded on the basis of the International Myeloma Working Group response criteria. RESULTS One hundred fifty-nine of 196 leukapheresed patients received ide-cel by data cutoff. One hundred twenty (75%) infused patients would have been ineligible for participation in the KarMMa clinical trial because of comorbidities at the time of leukapheresis. Any grade and grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 82/3% and 18/6%, respectively. Best overall and ≥ complete response rates were 84% and 42%, respectively. At a median follow-up of 6.1 months from chimeric antigen receptor T infusion, the median progression-free survival was 8.5 months (95% CI, 6.5 to not reached) and the median overall survival was 12.5 months (95% CI, 11.3 to not reached). Patients with previous exposure to B-cell maturation antigen–targeted therapy, high-risk cytogenetics, Eastern Cooperative Oncology Group performance status ≥ 2 at lymphodepletion, and younger age had inferior progression-free survival on multivariable analysis. CONCLUSION The safety and efficacy of ide-cel in patients with RRMM in the SOC setting were comparable with those in the phase II pivotal KarMMa trial despite most patients (75%) not meeting trial eligibility criteria.

Background: Transcriptome studies are gaining momentum in genomic epidemiology, and the need to incorporate these data in multivariable models alongside other risk factors brings demands for new approaches. Methods: Here we describe SPECTRA, an approach to derive quantitative variables that capture the intrinsic variation in gene expression of a tissue type. We applied the SPECTRA approach to bulk RNA sequencing from malignant cells (CD138+) in patients from the Multiple Myeloma Research Foundation CoMMpass study. Results: A set of 39 spectra variables were derived to represent multiple myeloma cells. We used these variables in predictive modeling to determine spectra-based risk scores for overall survival, progression-free survival, and time to treatment failure. Risk scores added predictive value beyond known clinical and expression risk factors and replicated in an external dataset. Spectrum variable S5, a significant predictor for all three outcomes, showed pre-ranked gene set enrichment for the unfolded protein response, a mechanism targeted by proteasome inhibitors which are a common first line agent in multiple myeloma treatment. We further used the 39 spectra variables in descriptive modeling, with significant associations found with tumor cytogenetics, race, gender, and age at diagnosis; factors known to influence multiple myeloma incidence or progression. Conclusions: Quantitative variables from the SPECTRA approach can predict clinical outcomes in multiple myeloma and provide a new avenue for insight into tumor differences by demographic groups. Impact: The SPECTRA approach provides a set of quantitative phenotypes that deeply profile a tissue and allows for more comprehensive modeling of gene expression with other risk factors.

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).

Background/Aim: There exists considerably large interpatient variability in pharmacokinetic exposure of high dose melphalan in multiple myeloma patients with hematopoietic stem-cell transplantation. In this study, we aimed to evaluate the potential impacts of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) variations on pharmacokinetic properties of melphalan and clinical outcomes in multiple myeloma (MM) patients. Patients and Methods: Genotypes of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) were determined by validated gene-specific real-time PCR (RT-PCR) assays using DNA samples from 108 MM patients; plasma concentrations of melphalan at different time points were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/ΜS). Results: CYP3A4*1B/*1B and CYP3A5*3/*3 carriers appeared to have a short median progression-free survival time and a higher maximum melphalan plasma concentration than non-carriers [792 vs. over 950 days, p=0.08; 9.91 (2.67, 34.03) vs. 8.66 (4.46, 17.61) mg/l, p=0.039]. Conclusion: CYP3A4*1B/*1B and CYP3A5*3/*3 variations might influence melphalan therapy in MM patients through yet-to-be-identified mechanisms.

Treatment at academic cancer centers (ACs) is associated with improved survival across hematologic malignancies, though the benefit in multiple myeloma (MM) has not been examined. This study aims to evaluate survival outcomes at Commission on Cancer accredited ACs compared to non-academic centers (NACs) for patients receiving MM-directed therapy. The National Cancer Database (NCDB) was used to identify demographics and overall survival (OS) of MM patients diagnosed from 2004 to 2017 and to compare outcomes by facility type. Survival analysis was repeated in a propensity score matched cohort, with NACs matched 1:1 to ACs by age, race, comorbidity score, insurance, year of diagnosis, distance traveled, and income. Of 163 375 MM patients, 44.5% were treated at ACs. Patients at ACs were more likely to receive MM-directed therapy compared to NACs (81% vs. 73%, p .001). For patients receiving treatment, median OS at ACs was 71.3 months versus 41.2 months at NACs (p .001). When adjusted for baseline demographics, patients treated at ACs had reduced mortality; hazard ratio (HR) 0.79 (95% CI 0.78-0.81, p .001). The propensity score matched cohort maintained this survival benefit with a median OS of 59.9 months at ACs versus 37.0 months at NACs (p .001), HR of 0.66 (95% CI 0.64-0.67, p .001). ACs treated younger patients with fewer comorbidities and were more likely to treat racial minorities and patients with Medicaid or private insurance, and the uninsured. In this analysis, MM patients treated at ACs have significantly improved survival. While potentially related to access to specialized care, socioeconomic factors that drive facility selection may also contribute.

Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D). Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT) received D-RVd/RVd induction, high-dose therapy and ASCT, D-RVd/RVd consolidation and up to 2 years of lenalidomide maintenance therapy ± D. VTE prophylaxis was recommended (at least aspirin, ≥162 mg daily) in accordance with International Myeloma Working Group guidelines. In the safety population (D-RVd, n = 99; RVd, n = 102), VTEs occurred in 10.1% of D-RVd patients and 15.7% of RVd patients; grade 2-4 VTEs occurred in 9.1% and 14.7%, respectively. Median time to the first onset of VTE was longer for D-RVd versus RVd patients (305 days vs 119 days). Anti-thrombosis prophylaxis use was similar between arms (D-RVd, 84.8% vs RVd, 83.3%); among patients with VTEs, prophylaxis use at time of first VTE onset was 60.0% for D-RVd and 68.8% for RVd. In summary, the addition of daratumumab to RVd did not increase the incidence of VTEs, but the cumulative VTE incidence was relatively high in this cohort and anti-thrombotic prophylaxis use was suboptimal.

Despite treatment advances, multiple myeloma (MM) remains a significant source of morbidity and mortality. We aimed to examine specialist palliative care (SPC) involvement and end-of-life care for patients with MM.We assessed all deceased patients with a diagnosis of MM who received care at a single institution from January 2010 to December 2019 and assessed SPC involvement.We reviewed 456 deceased patients. Overall, 207 patients (45.4%) received SPC visits by clinicians during their disease, and 153 (33.5%) were on MM treatment in the month before death. Median time from SPC consultation to death was 1 month, with 42 (9.2%) of patients receiving SPC visits 6 or more months before death. Amongst the patients for which a place of death was reported (351), 117 (33.3%) died in the acute care setting. Outpatient SPC did not correlate with a reduction of death in the acute care setting. In the group of patients who received outpatient SPC, 22/84 (26.2%) died in an acute care setting, whereas 95/267 (35.5%) patients who did not receive outpatient SPC also died in an acute care setting, (p = .11).In our analysis of the entire trajectory of the MM patient experience from diagnosis to death, we found low rates of SPC involvement and a significant proportion of patients receiving aggressive care at end-of-life. While there is no clear correlation that SPC involvement impacted the rate of acute care deaths or decreased utilization of MM treatment in the last month of life, further prospective research on optimal utilization of SPC is required.

Diagram of predictive modeling.

Scree plot of CoMMpass transcriptome dimensions. To limit overfitting in spectra derivation, we used dimension reduction to focus only on the first k spectra (largest k components of variation), selected using a scree test (Cattell, 1966).

Progression free survival covariates and added predictive values.

Kaplan-Meier curves of overall survival by spectra and UAMS risk-groups in the CoMMpass data. CoMMpass patients were assigned to high and low risk separately using the OS Spectra score and the UAMS score (See Methods, Comparison to the UAMS risk score). Blue and orange lines: both methods agree on patient's risk category. Purple line: Spectra correctly identified high-risk patients (poorer survival) that are misclassified as low risk by UAMS. Green line: Spectra correctly identified low-risk patients (better survival) that are misclassified as high risk by UAMS.

Time to first line treatment failure spectra score. A) Quantile-quantile plot. B) Gaussian mixture modeling to identify patients at high and low risk of early treatment failure. C) Patients in the spectra high-risk TTF (n = 31, 25 events) had median TTF of 9.2 months compared to low-risk patients (n = 736, 344 events) with median TTF of 32.8 months.

Cox regression beta coefficients for overall survival (OS), progression free survival (PFS), and time to treatment failure (TTF). Beta coefficients are by per spectra standard deviation. The quantitative spectra risk score for an outcome is the weighted sum of the spectra retained in its model based on their beta coefficients.

CoMMpass spectra Hallmark pathway GSEA summary. Gene Set Enrichment Analysis (GSEA) results for all spectra using the Hallmark pathway set from MSigDB v7.4. Only pathways with a significant enrichment (p

Progression free survival spectra score. A) Quantile-quantile plot. B) Gaussian mixture modeling to identify patients at high and low risk of progression. C) PFS high-risk patients (n = 60, 50 events) had median survival of 9.7 months. PFS low-risk patients (n = 707, 342 events) had median survival of 35.7 months.

Time to first-line treatment failure covariates and added predictive values.

Hazard ratios of high vs low risk of progression free survival.

Expanded description of the SPECTRA approach.

Supplementary Fig. S1. Therapeutic efficacy of RV and HDACi against cancer B cells; Supplementary Fig. S2. HDACi increase JAM-1 expression without affecting cell viability; Supplementary Fig. S3. RV+HDACi display synergistic anti-myeloma activity; Supplementary Fig. S4. Combination treatment of MCL cells with RV and HDAC inhibitors results in increased cell death, compared to single agent treatments.

Supplementary table 1. Selected early phase clinical trials evaluating Reolysin single-agent and combination treatment regimens. Abbreviations: SD = stable disease, PR = partial response, CR = complete response; ER = endoplasmic reticulum.

supplemental legend

Purpose: Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies.Experimental Design: A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1.Results: There were no dose-limiting toxicities, patients reached the 3 × 1010 TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months.Conclusions: Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers. Clin Cancer Res; 20(23); 5946–55. ©2014 AACR.

Supplementary table 2. Five patients experienced at least grade 2 adverse events. Two of the 5 patients received at least 4 cycles of treatment, and the associated adverse events were noted after cycle 1. All cytopenias resolved prior to the completion of the cycle that adverse event occurred. Abbreviations: DL = dose level, m-protein = monoclonal protein, CXDX = cycle X, day X, NA = not available.

Supplementary figure 1. The top ten worst adverse events include grade 1 - 3 events. Grade 1 events included decreased neutrophil, white blood cell, lymphocyte, and platelet counts, increased aspartate aminotransferase and alkaline phosphatase, and nausea. Grade 2 events included decreased neutrophil, white blood cell, and platelet counts, anemia, and myalgia. Grade 3 events included decreased neutrophil, white blood cell, and platelet counts, and hypophosphatemia.

A color analogy to illustrate the advantages of spectra variables for modeling. a) Individual observations of color. b) Dimension Reduction (additive color theory), all colors can be represented using 3 quantitative RGB variables. c) Standard-use, hierarchical clustering identifies 3 groups. Each sample is categorized into a group (A, B or C). Subsequent modeling uses one categorical variable. d) Multivariable modeling with quantitative spectra variables, multiple spectra integrated directly into a multivariable analysis. Each uncorrelated variable can be assessed separately for its predictive value for an outcome. This implementation retains higher resolution because the variables are quantitative and retain integrity to the initial data. Note, lower-resolution versions of xB and xG can be achieved using hierarchical groups, but the loss of quantification may lose power. xR cannot be captured by any group ordering and associations for this spectrum would be lost using hierarchical groups. Three dimensions shown for visualization purposes; transcriptome data is likely to harbor a higher number of dimensions.

Venous thromboembolism (VTE) is a major complication in all patients with cancer. Compared with the general population, patients with multiple myeloma (MM) have a 9-fold increase in VTE risk, likely because of their malignancy, its treatments, and other additional patient-related factors. In MM, thromboembolism events tend to occur within 6 months of treatment initiation, regardless of treatment regimen; however, the use of immunomodulatory agents such as thalidomide or lenalidomide, especially in combination with dexamethasone or multiagent chemotherapy, is known to create a significant risk for VTE. Currently, official recommendations for VTE prophylaxis in MM outlined in various national guidelines or multidisciplinary society panels are based on expert opinion, because data from randomized controlled trials are scarce. Large studies which have mainly focused on the efficacy of thromboprophylaxis in patients with cancer at higher risk for VTE either had a very low representation of patients with MM, or excluded them all together, limiting our ability to draw evidence-based conclusions on how to effectively protect MM population from VTE. In this brief perspective, we highlight some of the greatest challenges that have hampered the field concerning the availability of high-quality clinical trial data for the formulation of best VTE prophylaxis strategies in patients with newly diagnosed MM, as well as the rationale for the latest updates in the NCCN Guidelines on this topic.

Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We determined whether nonviral sepsis induces differential platelet gene expression and reactivity. Nonviral sepsis upregulated IFN-induced transmembrane protein 3 (IFITM3), an IFN-responsive gene that restricts viral replication. As IFITM3 has been linked to clathrin-mediated endocytosis, we determined whether IFITM3 promoted endocytosis of α-granule proteins. IFN stimulation enhanced fibrinogen endocytosis in megakaryocytes and platelets from Ifitm+/+ mice, but not Ifitm-/- mice. IFITM3 overexpression or deletion in megakaryocytes demonstrated IFITM3 was necessary and sufficient to regulate fibrinogen endocytosis. Mechanistically, IFITM3 interacted with clathrin and αIIb and altered their plasma membrane localization into lipid rafts. In vivo IFN administration increased fibrinogen endocytosis, platelet reactivity, and thrombosis in an IFITM-dependent manner. In contrast, Ifitm-/- mice were completely rescued from IFN-induced platelet hyperreactivity and thrombosis. During murine sepsis, platelets from Ifitm+/+ mice demonstrated increased fibrinogen content and platelet reactivity, which was dependent on IFN-α and IFITMs. Platelets from patients with nonviral sepsis had increases in platelet IFITM3 expression, fibrinogen content, and hyperreactivity. These data identify IFITM3 as a regulator of platelet endocytosis, hyperreactivity, and thrombosis during inflammatory stress.

Use of surrogate end-points such as progression-free survival (PFS) and other time-to-event (TTE) end-points is common in multiple myeloma (MM) clinical trials. This systematic review characterises all published randomised controlled trials (RCTs) in MM using PFS or other TTE end-points between 2005 and 2019 and assesses strength of surrogacy of PFS for overall survival (OS). The association between OS hazard ratios (HRs) and PFS HRs was evaluated with linear regression, and the coefficient of determination with Pearson's correlation. We identified 88 RCTs of which 67 (76%) used PFS as the primary/co-primary end-point. One trial indicated whether progression was biochemical or clinical. Of the variance in OS, 39% was due to variance in PFS. Correlation between PFS and OS was weak (0.62, 95% confidence interval [CI] 0.38–0.78). In newly diagnosed MM, 43% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was weak (0.65, 95% CI 0.30–0.84). In relapsed/refractory MM, 58% of the variance in OS was due to changes in PFS. Correlation between PFS and OS was medium (0.76, 95% CI 0.42–0.91). We demonstrate that PFS and progression characteristics are characterised poorly in MM trials and that PFS is a poor surrogate for OS in MM. First published online: 10 December 2022

Part B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.

Surrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically evaluated the use of surrogate endpoints in multiple myeloma randomized controlled trials over the past 15 years. We searched three databases (Pubmed, Embase, Cochrane) for multiple myeloma randomized controlled trials from January 1, 2005 to December 30, 2019. The primary outcome of our study was the proportion of randomized controlled trials that used overall survival as their primary endpoint. Secondary outcomes included the use of surrogate endpoints, and trends over time, and whether they differed based on study sponsorship. We included 151 randomized controlled trials in our analysis. The primary endpoint was overall survival (OS) in 17 (11.3%) of studies, progression free survival (PFS) or event-defined endpoints in 91 studies (60.3%) and response-based endpoints in 44 studies (29.1%). Quality of life was a primary endpoint in only three studies (2%). The use of OS as a primary endpoint decreased from 28.5% of trials from 2005 to 2009 to 5.5% from 2015 to 2019. There has been a decrease in the clinically meaningful endpoint of OS over the past 15 years in multiple myeloma randomized controlled trials. Use of quality of life as a primary endpoint remains exceedingly low. It remains paramount to recognize that the use of surrogate endpoints is imperfect, and care based upon them requires constant physician and patient re-analysis.

Despite the benign nature of monoclonal gammopathy of undetermined significance (MGUS), mounting data are associating MGUS with the development of organ dysfunction, specifically monoclonal gammopathy of renal significance (MGRS) and monoclonal gammopathy of neurological significance (MGNS), which could be associated with substantial morbidity. Emerging evidence suggests that patients with MGRS and MGNS could benefit from treatments used for myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia, depending on the underlying pathology. However, the treatment of MGRS and MGNS is not standardized, and potentially effective therapies might not be reimbursed because these conditions do not formally meet the criteria for malignant processes. The present review aims at establishing standards for the evaluation and management of MGRS and MGNS, which can facilitate the diagnosis of and provide therapeutic options for treating practitioners and patients affected by these conditions. The careful design and execution of clinical trials for patients with MGRS and MGNS are positively encouraged.