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Introduction: Patients with triple-class refractory (TCR) multiple myeloma (MM) often need cytoreductive chemotherapy for rapid disease control. Bendamustine is an outpatient-administered, bifunctional alkylator and isatuximab is an anti-CD38 monoclonal antibody with unique cytotoxicity characteristics. We hypothesized that isatuximab-bendamustine-prednisone would be well-tolerated regimen in TCR MM, and conducted single-center, phase Ib, investigator-initiated study., Patients/methods: Patients had TCR MM and last daratumumab exposure ≥ 6 weeks. This study was conducted as a 3 + 3 design to establish the maximally tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Isatuximab 10 mg/kg IV was administered weekly (cycle 1), and every 2 weeks thereafter. Bendamustine was administered on days 1 and 2 at 3 dose levels (DL): 50, 75, and 100 mg/m 2 . Methylprednisolone was administered as 125 mg on day 1 and prednisone 60 mg days 2-4. Common definitions were used for DLTs, adverse events (CTCAE v 5.0), and disease response., Results: Fifteen patients were treated (3 DL1, 6 DL2, 6 DL3). Median age was 71, 53% had high-risk cytogenetics, and 34% had prior BCMA-targeting therapy. One DLT was observed at DL2 (Grade 3 thrombocytopenia plus bleeding). There were no Grade 5 treatment-related AEs. The MTD was not reached. The overall response rate was 20% (3/15) including one stringent complete response. The median PFS was 2.5 months (95% CI 0.9-4.1 months)., Conclusion: We demonstrated the safety and tolerability of isatuximab-bendamustine-prednisone. Toxicities were mild and manageable with limited intervention. The study was discontinued due to slow accrual. However, we observed responses even among highly refractory patients., Clinical Trial Registration: This study was registered on clinicaltrials.gov as NCT04083898 on 9/6/2019., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients., (© 2024. The Author(s).)

Persons with myeloma were randomized to receive an anti-TIGIT (T cell immunoreceptor) or anti-LAG3 (lymphocyte activation gene) antibody followed by combination with pomalidomide and dexamethasone ( NCT04150965 ). Primary and secondary endpoints were safety and efficacy, respectively. Therapy was well tolerated without dose-limiting toxicity. Durable clinical responses were observed in both the anti-TIGIT(three of six participants) and the anti-LAG3 (two of six participants) arms. Anti-LAG3 responders had higher naive cluster of differentiation 4 (CD4)-positive T cells and lower programmed cell death protein 1-positive effector T cells. Anti-TIGIT responders had higher CD226 expression, natural killer cell activation and lower CD112 expression. These data demonstrate the clinical activity of TIGIT-LAG3 blockade and identify pathway-specific response correlates in myeloma., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option., (© 2024. The Author(s).)

Purpose: Financial toxicity is a contributor to the psychosocial burden of cancer care. There is no consensus measure of financial toxicity; however, recent studies have adopted the Comprehensive Score for Financial Toxicity (COST). Despite its growing popularity, data on the responsiveness to change of the COST instrument are lacking. To address this gap in the literature, we performed a sequential mixed-methods study of people with multiple myeloma., Materials and Methods: In the quantitative phase of the study, we collected COST scores at two time points approximately 8 weeks apart from 72 patients. In the qualitative phase, we conducted semistructured interviews with a subset of 12 patients who reported the largest changes in scores. The qualitative data were analyzed using a deductive coding scheme developed using the Framework Method in the context of a commonly cited conceptual model of financial toxicity., Results: The median absolute change in COST scores was four points (IQR, 2-6). Only 13% of the sample had the same COST scores at both assessments; 38% had an improved score and 50% had a worsened score. Only, seven of the 12 patients (58%) interviewed reported changes to one or more of the constructs in the conceptual model of financial toxicity. Most commonly, changes to out-of-pocket medical costs were reported (5/12). Changes to nonmedical expenses (n = 2) and subjective financial distress without changes to objective financial burden (n = 2) were also reported., Conclusion: Additional research is needed to explicate changes in COST scores over time.

Second autologous hematopoietic cell transplantation (AHCT2) is a useful therapeutic modality for fit patients with multiple myeloma who have durable remission after upfront AHCT. Retrospective studies have suggested a significant benefit of incorporating maintenance therapy post-AHCT2, but prospective data on specific regimens are lacking. The purpose of this study was to investigate the use of elotuzumab, pomalidomide, and dexamethasone (EPd) as salvage therapy prior to and maintenance after AHCT2 for relapsed multiple myeloma. This prospective single-arm phase II trial investigating the use of EPd in combination with AHCT2 in patients with relapsed multiple myeloma was conducted at 2 academic centers in North America. The primary outcome was 1-year progression-free survival (PFS). Twenty-five patients were enrolled on the study. Sixteen patients received EPd induction; six patients (38%) progressed during salvage therapy and were removed from the trial prior to AHCT2. Following a planned safety analysis, the protocol was amended, and EPd induction was removed from the study schema. An additional 9 patients underwent induction off-study and were enrolled on trial for AHCT2 and EPd maintenance. A total of 18 patients underwent AHCT2 and received EPd maintenance. Two patients discontinued treatment because of toxicity, one attributed to elotuzumab and the other to pomalidomide. The 1-year PFS was 72%, and the median PFS was 19 months. The study was closed early owing to poor accrual; 6 patients remained on therapy at time of analysis. EPd maintenance after AHCT2 was safe and tolerable. The 1-year PFS and median PFS were similar to values in previous retrospective reports of outcomes following AHCT2. Further studies are needed to define the optimal use of and protocol for AHCT2 in fit patients with relapsed multiple myeloma., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Multiple myeloma (MM), as well as some treatments for MM, increase the risk of venous thromboembolism (VTE). Prior literature suggests carfilzomib, lenalidomide, and dexamethasone (KRd) may have a higher incidence of thromboembolic events compared with bortezomib, lenalidomide, and dexamethasone (VRd). We aimed to evaluate VTE risk with KRd induction compared to VRd at a large academic medical center in the United States., Materials and Methods: We retrospectively reviewed patients with newly diagnosed MM presenting at a single institution. Patients were followed for objectively diagnosed VTE events for 6 months following the start of induction therapy., Results: A total of 209 patients were included, with 69 (33%) receiving KRd and 140 (67%) receiving VRd. Overall, 18 patients (9%) had a VTE event, with 5 (7%) in the KRd cohort and 13 (9%) in the VRd cohort (P = .80). Treatment with KRd was not associated with an increased risk of VTE compared to VRd (HR 0.74; 95% CI 0.26-2.08; P = .57)., Conclusion: In this cohort, KRd was not associated with an increase in VTE risk compared to VRd, contrary to prior literature., Competing Interests: Disclosure Angela Vickroy has consulted for Janssen Advisory Board. Mark Schroeder has received consultancy fees or honoraria from Advarra, Incyte, StemLine, and GSK. Ravi Vij has received consultancy fees or honoraria from Oncopeptides, Janssen, Takeda, BMS, GSK, Sanofi, Beigene, and Adaptive Biotechnologies. Sanofi. Kristen Sanfilippo has received research funding and loan repayment from NHLBI NIH, research funding from ACS-IRG, consultancy from Health Services Advisory Group, and expert case review from Quinn Johnston and Covington & Burling LLP., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We performed a systematic review of the literature investigating the demographic and insurance-related factors linked to disparities in multiple myeloma (MM) care patterns in the United States from 2003 to 2021. Forty-six observational studies were included. Disparities in MM care patterns were reported based on patient race in 76% of studies (34 out of 45 that captured race as a study variable), ethnicity in 60% (12 out of 20), insurance in 77% (17 out of 22), and distance from treating facility, urbanicity, or geographic region in 62% (13 out of 21). A smaller proportion of studies identified disparities in MM care patterns based on other socioeconomic characteristics, with 36% (9 out of 25) identifying disparities based on income estimate or employment status and 43% (6 out of 14) based on language barrier or education-related factors. Sociodemographic characteristics are frequently associated with disparities in care for individuals diagnosed with MM. There is a need for further research regarding modifiable determinants to accessing care such as insurance plan design, patient out-of-pocket costs, preauthorization criteria, as well as social determinants of health. This information can be used to develop actionable strategies for reducing MM health disparities and enhancing timely and high-quality MM care., Competing Interests: Disclosure All authors declare no relevant conflicts of interest related to this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Multiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel unsupervised integrative multi-omic analysis was performed using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples from patients receiving Atezo monotherapy or Atezo+Dara. A similarity network fusion (SNF) algorithm was applied to preprocessed data. Eighty-five patients were enrolled. Treatment-emergent deaths occurred in 2 patients; both deaths were considered unrelated to study treatment. ORRs ranged from 11.1% (Atezo+Len cohorts, n=18) to 83.3% (Atezo+Dara+Pom cohort, n=6). High-dimensional multi-omic profiling of the tumor microenvironment and integrative SNF analysis revealed novel correlations between cellular and molecular features of the tumor and immune microenvironment, patient selection criteria, and clinical outcome. Atezo monotherapy and SoC combinations were safe in this patient population and demonstrated some evidence of clinical efficacy. Integrative analysis of high dimensional genomics and immune data identified novel clinical correlations that may inform patient selection criteria and outcome assessment in future immunotherapy studies for myeloma., Competing Interests: SW declares Consultancy for Amgen and Dren Biosciences; Research Support from BMS, Caelum, Fortis, Genentech, GSK, Janssen; Membership on Sanofi’s Board of Directors or Advisory Committees. HH, AR, and RS were employed by Genentech. LC declares Honoraria/Research Funding from Amgen Celgene; Research Funding from Janssen, AbbVie, Karyopharm, Therapeutics, BMS; Honoraria from Sanofi. NN declares Research Funding from Janssen and Glaxo Smith Kline. RV declares Honoraria/Research funding from Celgene, BMS, Takeda; HonorariaAmgen, Janssen, Karyopharm, and Jazz Pharmaceuticals. TN and EW-F were employed by Roche. HC was employed by The Multiple Myeloma Research Foundation and declares Research Support from BMS, Genentech, and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from F. Hoffmann-La Roche Ltd. In addition, F. Hoffmann-La Roche Ltd. and the Principal Investigator (H.J Cho) designed the clinical study, performed data collection and analysis, and jointly made the decision to publish these data. F. Hoffmann-La Roche Ltd. funded the medical writing support., (Copyright © 2023 Wong, Hamidi, Costa, Bekri, Neparidze, Vij, Nielsen, Raval, Sareen, Wassner-Fritsch and Cho.)

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., (© 2023. The Author(s).)

Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy., Significance: Single-cell transcriptomic profiling and multiomic cross-validation to uncover therapeutic targets identifies 38 myeloma marker genes, including 11 transcribing surface proteins with previously uncharacterized potential for targeted antitumor therapy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction/background: People with multiple myeloma are at risk for financial toxicity due to the high cost of treatment and prolonged treatment duration. However, little data exist regarding financial toxicity among people with myeloma., Patients and Methods: In this study, a cohort of 135 patients were recruited from an ongoing observational trial to complete the Comprehensive Score for financial Toxicity (COST). Participants were sent follow-up surveys at 3, 6, and 12 months., Results: The median age was 68 years; the majority were non-Hispanic whites (88%), male (63%), held a college degree (61%), and had left the workforce (70%). The median time from myeloma diagnosis was 28 months. The median COST score was 27; 48% of participants had a score below 27 and considered to have financial toxicity. The only characteristic associated with financial toxicity was a college degree. After controlling for other covariates, those with a college education were 69% less likely to have financial toxicity. Of the 108 participants who completed a follow-up survey, 34% reported changes in their financial toxicity status at a subsequent time point. Transitioning from not having financial toxicity to having financial toxicity was more common than the reverse., Conclusion: Because financial toxicity is a dynamic process, which patients are experiencing it at any given time is difficult to predict. Focusing the research agenda on improved detection and intervention may be warranted., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34 + hematopoietic stem and progenitor cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 10 6 CD34 + cells kg -1 within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12-201.33, P < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36-549.35, P < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34 + HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529., (© 2023. The Author(s).)

Background: Zaccaria and colleagues recently proposed a new risk score to identify patients at high risk for relapse within 18 months of diagnosis (ER18), the Score for Early Relapse in Multiple Myeloma (S-ERMM). We performed external validation of the S-ERMM using data from the CoMMpass study., Patients and Methods: Clinical data was obtained from the CoMMpass study. Patients were assigned S-ERMM risk scores and risk categories by the three iterations of the International Staging System (ISS): ISS, R-ISS and R2-ISS. Patients with missing data or early mortality in remission were excluded. Our primary endpoint was the relative predictive ability of the S-ERMM versus other risk scores for ER18 as assessed by area-under-the-curve (AUC)., Results: 476 patients had adequate data to assign all four risk scores. 65%, 25% and 10% were low, intermediate and high risk by S-ERMM. 17% experienced ER18. All four risk scores stratified patients by risk for ER18. S-ERMM (AUC: 0.59 [95% CI 0.53-0.65]) was similar to R-ISS (0.63 [95% CI 0.58-0.69]) and statistically inferior to ISS (0.68 [95% CI 0.62-0.75]) and R2-ISS (0.66 [95% CI 0.61-0.72]) for prediction of ER18. Sensitivity analyses were performed and did not significantly impact results., Conclusion: The S-ERMM risk score is not superior to existing risk stratification systems for predicting early relapse in NDMM and further studies are needed to identify the optimal approach., Competing Interests: Conflict of Interest Statement All authors declare no relevant conflicts of interest related to this manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Survival is poor among patients with triple-class-exposed relapsed and refractory multiple myeloma. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, previously led to deep, durable responses in patients with heavily pretreated relapsed and refractory multiple myeloma., Methods: In this international, open-label, phase 3 trial involving adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab) and who had disease refractory to the last regimen, we randomly assigned patients in a 2:1 ratio to receive either ide-cel (dose range, 150×10 6 to 450×10 6 CAR-positive T cells) or one of five standard regimens. The primary end point was progression-free survival. Key secondary end points were overall response (partial response or better) and overall survival. Safety was assessed., Results: A total of 386 patients underwent randomization: 254 to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class-refractory disease, and 95% had daratumumab-refractory disease. At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, as compared with 4.4 months in the standard-regimen group (hazard ratio for disease progression or death, 0.49; 95% confidence interval, 0.38 to 0.65; P<0.001). A response occurred in 71% of the patients in the ide-cel group and in 42% of those in the standard-regimen group (P<0.001); a complete response occurred in 39% and 5%, respectively. Data on overall survival were immature. Adverse events of grade 3 or 4 occurred in 93% of the patients in the ide-cel group and in 75% of those in the standard-regimen group. Among the 225 patients who received ide-cel, cytokine release syndrome occurred in 88%, with 5% having an event of grade 3 or higher, and investigator-identified neurotoxic effects occurred in 15%, with 3% having an event of grade 3 or higher., Conclusions: Ide-cel therapy significantly prolonged progression-free survival and improved response as compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma who had received two to four regimens previously. The toxicity of ide-cel was consistent with previous reports. (Funded by 2seventy bio and Celgene, a Bristol-Myers Squibb company; KarMMa-3 ClinicalTrials.gov number, NCT03651128.)., (Copyright © 2023 Massachusetts Medical Society.)

There remains an unmet need for molecularly targeted imaging agents for multiple myeloma (MM). The integrin very late antigen 4 (VLA4), is differentially expressed in malignant MM cells and in pathogenic inflammatory microenvironmental cells. [ 64 Cu]Cu-CB-TE1A1P-LLP2A ( 64 Cu-LLP2A) is a VLA4-targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated the safety and human radiation dosimetry of 64 Cu-LLP2A for potential use in MM patients. Methods: A single-dose [ nat Cu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed on CD-1 (Hsd:ICR) male and female mice. 64 Cu-LLP2A was synthesized in accordance with good-manufacturing-practice-compliant procedures. Three MM patients and six healthy participants underwent 64 Cu-LLP2A-PET/CT or PET/MRI at up to 3 time points to help determine tracer biodistribution, pharmacokinetics, and radiation dosimetry. Time-activity curves were plotted for each participant. Mean organ-absorbed doses and effective doses were calculated using the OLINDA software. Tracer bioactivity was evaluated via cell-binding assays, and metabolites from human blood samples were analyzed with analytic radio-high-performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry. Results: A 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level). Time-activity curves from human imaging data showed rapid tracer clearance from blood via the kidneys and bladder. The effective dose of 64 Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and the spleen had the highest organ uptake, 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated the highest residence time. Image quality analysis supports an early imaging time (4-5 h after injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all human studies (82.42% ± 13.47%). Blood metabolism studies confirmed a stable product peak (>90%) up to 1 h after injection of the radiopharmaceutical. No clinical or laboratory adverse events related to 64 Cu-LLP2A were observed in the human participants. Conclusion: 64 Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Patients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant IgH clonotypes between the tumors were observed in 5 paired MM/B-ALL samples. Across all 17 B-ALL samples, 14 (83%) had a TP53 variant detected. Three MM samples with sufficient sequencing depth (>500×) revealed rare cells (average of 0.6% variant allele frequency, or 1.2% of cells) with the same TP53 variant identified in the subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL samples shows that B-ALL developed as a second malignancy arising from a founding population of cells that likely represented unrelated clonal hematopoiesis caused by a TP53 mutation. The recurrent variants in TP53 in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53 variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53 variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study., Methods: Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion., Results: As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively., Conclusion: ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation., Competing Interests: Anita D'SouzaConsulting or Advisory Role: Pfizer, Janssen, Akcea Therapeutics, Bristol Myers Squibb/Celgene, ProthenaResearch Funding: Takeda (Inst), Sanofi (Inst), TeneoBio (Inst), Prothena (Inst), Caelum Biosciences (Inst), Janssen Oncology, Regeneron, AbbVie,Travel, Accommodations, Expenses: Imbrium Therapeutics Nina ShahEmployment: AstraZenecaStock and Other Ownership Interests: AstraZenecaConsulting or Advisory Role: Indapta Therapeutics, Sanofi, Oncopeptides, Karyopharm Therapeutics, Genentech/Abbvie, GlaxoSmithKline, Amgen, CareDXResearch Funding: Janssen Oncology, Regeneron, AbbVieTravel, Accommodations, Expenses: Imbrium Therapeutics Cesar RodriguezConsulting or Advisory Role: Janssen, ArtivaSpeakers' Bureau: Bristol-Myers Squibb/Celgene, Sanofi Peter M. VoorheesConsulting or Advisory Role: Oncoptides, Karyopharm Therapeutics, Bristol Myers Squibb, Secura Bio, Pfizer, Sanofi, Janssen, GlaxoSmithKlineResearch Funding: AbbVie (Inst), Janssen (Inst), GlaxoSmithKline (Inst), TeneoBio (Inst)Travel, Accommodations, Expenses: SanofiUncompensated Relationships: GlaxoSmithKline Katja WeiselHonoraria: Amgen, Bristol Myers Squibb, Janssen-Cilag, GlaxoSmithKline, Adaptive Biotechnologies, Karyopharm Therapeutics, Takeda, Sanofi, AbbVie, GlaxoSmithKline, Novartis, Pfizer, Amgen (Inst), Bristol Myers Squibb/Celgene (Inst), Celgene, Janssen (Inst), GlaxoSmithKline (Inst), Oncopeptides, Roche, Sanofi (Inst)Consulting or Advisory Role: Amgen, Adaptive Biotechnologies, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen-Cilag, Karyopharm Therapeutics, Sanofi, Takeda, Oncopeptides, RocheResearch Funding: Amgen (Inst), Celgene (Inst), Sanofi (Inst), Janssen-Cilag (Inst), Bristol Myers Squibb/Celgene (Inst), GlaxoSmithKline (Inst)Travel, Accommodations, Expenses: Amgen, Celgene, Bristol Myers Squibb, Janssen-Cilag, GlaxoSmithKline, Takeda Orlando F. BuenoEmployment: AbbVieStock and Other Ownership Interests: AbbVieResearch Funding: AbbVieTravel, Accommodations, Expenses: AbbVie Rajvineeth K. PothacamuryEmployment: AbbVieStock and Other Ownership Interests: AbbVie Kevin J. FreiseEmployment: AbbVieStock and Other Ownership Interests: AbbVie Susan YueEmployment: AbbVie, Atara BiotherapeuticsStock and Other Ownership Interests: AbbVie, Atara Biotherapeutics Jeremy A. RossEmployment: AbbVieStock and Other Ownership Interests: AbbVie Akshanth R. PolepallyEmployment: AbbVieStock and Other Ownership Interests: AbbViePatents, Royalties, Other Intellectual Property: pending patent application Chetasi TalatiEmployment: AbbVieStock and Other Ownership Interests: AbbVie Shane LeeEmployment: AbbVie/Pharmacyclics, RegeneronStock and Other Ownership Interests: Abbvie/Pharmacyclics Ziyi JinEmployment: AbbVieStock and Other Ownership Interests: AbbVie Ben BuelowEmployment: Teneobio, Ancora Biotech, IncLeadership: Teneobio, Ancora Biotech, IncStock and Other Ownership Interests: Teneobio, Ancora Biotech, IncPatents, Royalties, Other Intellectual Property: Co-patent holder of some Teneobio patents Ravi VijConsulting or Advisory Role: Sanofi, CareDX, Legend Biotech, GlaxoSmithKline, Oncopeptides, Harpoon, Adaptive Biotechnologies, Pfizer, Bristol Myers Squibb/Celgene,Research Funding: Takeda (Inst), Bristol Myers Squibb (Inst), Sanofi (Inst)Travel, Accommodations, Expenses: Celgene, Bristol Myers Squibb, Sanofi, Janssen, Dava Oncology, Karyopharm Therapeutics, Amgen, Takeda, AbbVie, Shaji KumarHonoraria: BeiGene, GLH Pharma, Secura BioConsulting or Advisory Role: Takeda (Inst), Janssen Oncology (Inst), Amgen (Inst), AbbVie (Inst), Celgene (Inst), Genentech/Roche (Inst), AbbVie (Inst), Oncopeptides, Kite, a Gilead company (Inst), Genecentrix, Molecular Partners, Bluebird BioResearch Funding: Celgene (Inst), Takeda (Inst), AbbVie (Inst), Novartis (Inst), Sanofi (Inst), Janssen Oncology (Inst), Merck (Inst), Kite, a Gilead company (Inst), Medlmmune (Inst), Roche/Genentech (Inst), TeneoBio (Inst), CARsgen Therapeutics (Inst)No other potential conflicts of interest were reported.

As part of the Multiple Myeloma Research Foundation (MMRF) immune atlas pilot project, we compared immune cells of multiple myeloma bone marrow samples from 18 patients assessed by single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to understand the concordance of measurements among single-cell techniques. Cell type abundances are relatively consistent across the three approaches, while variations are observed in T cells, macrophages, and monocytes. Concordance and correlation analysis of cell type marker gene expression across different modalities highlighted the importance of choosing cell type marker genes best suited to particular modalities. By integrating data from these three assays, we found International Staging System stage 3 patients exhibited decreased CD4 + T/CD8 + T cells ratio. Moreover, we observed upregulation of RAC2 and PSMB9 , in natural killer cells of fast progressors compared with those of nonprogressors, as revealed by both scRNA-seq and CITE-seq RNA measurement. This detailed examination of the immune microenvironment in multiple myeloma using multiple single-cell technologies revealed markers associated with multiple myeloma rapid progression which will be further characterized by the full-scale immune atlas project., Significance: scRNA-seq, CyTOF, and CITE-seq are increasingly used for evaluating cellular heterogeneity. Understanding their concordances is of great interest. To date, this study is the most comprehensive examination of the measurement of the immune microenvironment in multiple myeloma using the three techniques. Moreover, we identified markers predicted to be significantly associated with multiple myeloma rapid progression., Competing Interests: S.K. Kumar reports other from Abbvie, Amgen, BMS, Janssen, Roche-Genentech, Takeda, AstraZeneca, Bluebird Bio, Epizyme, Secura Biotherapeutics, Monterosa therapeutics, Trillium, Loxo Oncology, K36, Sanofi, ArcellX; personal fees from ncopeptides, Beigene, Antengene, GLH Pharma; and grants from Abbvie, Amgen, Allogene, AstraZeneca, BMS, Carsgen, GSK, Janssen, Novartis, Roche-Genentech, Takeda, Regeneron, Molecular Templates outside the submitted work. H.J. Cho reports other from The Multiple Myeloma Research Foundation during the conduct of the study; grants from BMS and Takeda outside the submitted work. A.H. Rahman reports grants from Multiple Myeloma Research Foundation during the conduct of the study; grants from Celgene/BMS and personal fees from Fluidigm outside the submitted work. D. Avigan reports other from BMS, Chugai, Sanofi, Merk, and Paraexel; and grants from MMRF outside the submitted work. S. Gnjatic reports grants from Multiple Myeloma Research Foundation during the conduct of the study; grants from Regeneron, Boehringer Ingelheim, BMS, Genentech, Jannsen R&D, Takeda, and EMD Serono outside the submitted work. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models., (© 2022. The Author(s).)

Background: In the single-arm, phase 1b/2 CARTITUDE-1 study, ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen chimeric antigen receptor T-cell (CAR-T) therapy, showed encouraging efficacy in US patients with multiple myeloma (MM) who previously received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody (triple-class exposed)., Patients and Methods: A dataset of US patients refractory to an anti-CD38 monoclonal antibody (MAMMOTH) was used to identify patients who would meet eligibility for CARTITUDE-1 and received subsequent non-CAR-T therapy. The intent-to-treat (ITT) population in CARTITUDE-1 included patients who underwent apheresis (N = 113); the modified ITT (mITT) population was the subset who received cilta-cel (n = 97). Corresponding populations were identified from the MAMMOTH dataset: ITT population (n = 190) and mITT population of patients without progression/death within 47 days (median apheresis-to-cilta-cel infusion time) from onset of therapy (n = 122). Using 1:1 nearest neighbor propensity score matching to control for selected baseline covariates, 95 and 69 patients in CARTITUDE-1 ITT and mITT populations, respectively, were matched to MAMMOTH patients., Results: In ITT cohorts of CARTITUDE-1 vs. MAMMOTH, improved overall response rate (ORR; 84% vs. 28% [P < .001]) and longer progression-free survival (PFS; hazard ratio [HR], 0.11 [95% confidence interval (CI), 0.05-0.22]) and overall survival (OS; HR, 0.20 [95% CI, 0.10-0.39]) were observed. Similar results were seen in mITT cohorts of CARTITUDE-1 vs. MAMMOTH (ORR: 96% vs. 30% [P < .001]; PFS: HR, 0.02 [95% CI, 0.01-0.14]; OS: HR, 0.05 [95% CI, 0.01-0.22]) and with alternative matching methods., Conclusion: Cilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0-1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1-20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2-36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9-5.6) and 12.4 months (95% CI: 10.3-NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action., (© 2022. The Author(s).)

Multiple myeloma (MM) is a cancer of bone marrow (BM) plasma cells, which is increasingly treatable but still incurable. In 90% of MM patients, severe osteolysis results from pathological interactions between MM cells and the bone microenvironment. Delineating specific molecules and pathways for their role in cancer supportive interactions in the BM is vital for developing new therapies. Very Late Antigen 4 (VLA4, integrin α 4 β 1 ) is a key player in cell-cell adhesion and signaling between MM and BM cells. We evaluated a VLA4 selective near infrared fluorescent probe, LLP2A-Cy5, for in vitro and in vivo optical imaging of VLA4. Furthermore, two VLA4-null murine 5TGM1 MM cell (KO) clones were generated by CRISPR/Cas9 knockout of the Itga4 (α 4 ) subunit, which induced significant alterations in the transcriptome. In contrast to the VLA4 +  5TGM1 parental cells, C57Bl/KaLwRij immunocompetent syngeneic mice inoculated with the VLA4-null clones showed prolonged survival, reduced medullary disease, and increased extramedullary disease burden. The KO tumor foci showed significantly reduced uptake of LLP2A-Cy5, confirming in vivo specificity of this imaging agent. This work provides new insights into the pathogenic role of VLA4 in MM, and evaluates an optical tool to measure its expression in preclinical models., (© 2022. The Author(s).)

Cancer patients undergo detrimental toxicities and ineffective treatments especially in the relapsed setting, due to failed treatment attempts. The development of a tool that predicts the clinical response of individual patients to therapy is greatly desired. We have developed a novel patient-derived 3D tissue engineered bone marrow (3DTEBM) technology that closely recapitulate the pathophysiological conditions in the bone marrow and allows ex vivo proliferation of tumor cells of hematologic malignancies. In this study, we used the 3DTEBM to predict the clinical response of individual multiple myeloma (MM) patients to different therapeutic regimens. We found that while no correlation was observed between in vitro efficacy in classic 2D culture systems of drugs used for MM with their clinical efficacious concentration, the efficacious concentration in the 3DTEBM were directly correlated. Furthermore, the 3DTEBM model retrospectively predicted the clinical response to different treatment regimens in 89% of the MM patient cohort. These results demonstrated that the 3DTEBM is a feasible platform which can predict MM clinical responses with high accuracy and within a clinically actionable time frame. Utilization of this technology to predict drug efficacy and the likelihood of treatment failure could significantly improve patient care and treatment in many ways, particularly in the relapsed and refractory setting. Future studies are needed to validate the 3DTEBM model as a tool for predicting clinical efficacy., (© 2021. The Author(s).)

Background: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM., Methods: FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders., Results: Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores., Conclusion: The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach., Trial Registration: This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015., (© 2021. The Author(s).)

T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, such as poor pharmacokinetics and the ability to target only one antigen on the cancer cells. In multiclonal diseases, these therapies confer the development of antigen-less clones, causing tumor escape and relapse. In this study, we developed nanoparticle-based bispecific T-cell engagers (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies (mAbs) targeting T cells, and mAbs targeting the cancer antigen. We also developed a nanoparticle that targets multiple cancer antigens by conjugating multiple mAbs against multiple cancer antigens for T-cell engagement (nanoMuTEs). NanoBiTEs and nanoMuTEs have a long half-life of about 60 h, which enables once-a-week administration instead of continuous infusion, while maintaining efficacy in vitro and in vivo. NanoMuTEs targeting multiple cancer antigens showed greater efficacy in myeloma cells in vitro and in vivo, compared to nanoBiTEs targeting only one cancer antigen. Unlike nanoBiTEs, treatment with nanoMuTEs did not cause downregulation (or loss) of a single antigen, and prevented the development of antigen-less tumor escape. Our nanoparticle-based immuno-engaging technology provides a solution for the major limitations of current immunotherapy technologies., (© 2021. The Author(s).)

Competing Interests: Scott R. GoldsmithConsulting or Advisory Role: Wugen Inc Ravi VijConsulting or Advisory Role: Bristol Myers Squibb, Sanofi, Karyopharm Therapeutics, Takeda, BeiGene, CareDX, Legend Biotech, GlaxoSmithKlineResearch Funding: Takeda, Bristol Myers Squibb, SanofiTravel, Accommodations, Expenses: Celgene, Bristol Myers Squibb, Sanofi, Janssen, DAVA Oncology, Karyopharm Therapeutics, Amgen, Takeda, AbbVieNo other potential conflicts of interest were reported.

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect "B cell-featured" plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options.

Carfilzomib, a next-generation proteasome inhibitor, improves outcomes in patients with multiple myeloma (MM); however, a proportion of those treated develop renal failure due to adverse event, comorbidity, or myeloma progression. The rate of renal failure and associated risk factors remains unknown in real-world populations. Adults with relapsed/refractory MM who received carfilzomib between the years 2013 and 2016 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Renal failure was defined using the corresponding International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnostic codes and procedure codes for dialysis. Patients with a pre-existing diagnosis of renal failure were excluded to distinguish an adverse event from comorbidity. Multivariate cox regression analysis was performed to identify the variables independently associated with the development of renal failure among MM patients utilizing carfilzomib. A total of 1950 patients were included in the analysis. Renal failure developed in 22% of patients during the study period. The median time to development of renal failure from first carfilzomib administration was 1.6 months (range < 0.1-23.3). Increasing age (adjusted hazard ratio [aHR] 1.01 per year, p = 0.018), pre-existing heart failure (aHR 1.50, p = 0.005), and pre-existing chronic kidney disease (aHR 2.00, p < 0.001) were associated with a higher risk of developing renal failure. Renal failure occurred in up to 22% of patients on carfilzomib therapy. The exact cause and mechanism of renal failure cannot be determined from our study and may be multifactorial. Future studies are needed to further understand the cause of renal failure among patients on carfilzomib and devise strategies to mitigate the risk.

Purpose: In multiple myeloma, drug-resistant cells underlie relapse or progression following chemotherapy. Cell adhesion-mediated drug resistance (CAM-DR) is an established mechanism used by myeloma cells (MMC) to survive chemotherapy and its markers are upregulated in residual disease. The integrin very late antigen 4 (VLA4; α 4 β 1 ) is a key mediator of CAM-DR and its expression affects drug sensitivity of MMCs. Rather than trying to inhibit its function, here, we hypothesized that upregulation of VLA4 by resistant MMCs could be exploited for targeted delivery of drugs, which would improve safety and efficacy of treatments., Experimental Design: We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMCs, alone or with stroma, and immunocompetent mice with orthotopic multiple myeloma were used to track delivery of NPs and response to treatments., Results: V-NPs selectively delivered their payload to MMCs in vitro and in vivo , and chemotherapy increased their uptake by surviving MMCs. V-CP, alone or in combination with melphalan, was well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association with suboptimal dosing without increasing overall toxicity., Conclusions: V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer., (©2020 American Association for Cancer Research.)

This phase 2 study evaluated isatuximab as monotherapy or combined with dexamethasone in relapsed/refractory multiple myeloma (RRMM). Patients had RRMM refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI) or had received ≥3 prior lines of therapy incorporating an IMiD and PI. Patients received isatuximab either as monotherapy (20 mg/kg on days 1, 8, 15, and 22 [once weekly] of cycle 1 followed by 20 mg/kg on days 1 and 15 of subsequent cycles; Isa group) or in combination with dexamethasone (40 mg/d [20 mg/d in patients aged ≥75 years] once weekly; Isa-dex group). Treated patients (N = 164) had received a median of 4 (range, 2-10) prior treatment lines. Patients received a median of 5 (1-24) and 7 (1-22) treatment cycles; at data cutoff, 13 (11.9%) of 109 and 15 (27.3%) of 55 patients remained on treatment in the Isa and Isa-dex arms, respectively. Overall response rate (primary efficacy end point) was 23.9% in the Isa arm and 43.6% in the Isa-dex arm (odds ratio, 0.405; 95% confidence interval, 0.192-0.859; P = .008). Median progression-free survival and overall survival were 4.9 and 18.9 months for Isa, and 10.2 and 17.3 months for Isa-dex. Infusion reactions (mostly grade 1/2) and hematologic abnormalities were the most common adverse events. There was a similar incidence of grade 3 or higher infections in both groups (22.0% and 21.8%). In conclusion, addition of dexamethasone to isatuximab increased response rates and survival outcomes with no detrimental effect on safety. This trial was registered at www.clinicaltrials.gov as #NCT01084252., (© 2021 by The American Society of Hematology.)

Background: Multiple myeloma (MM) with the translocation t(11;14) may have inferior outcomes in comparison with other standard-risk MM, and it has been suggested to portend a worse prognosis in African Americans in comparison with Whites. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of t(11;14) on the clinical outcomes of patients with MM of African American and White descent., Methods: This study evaluated 3538 patients who underwent autologous hematopoietic cell transplantation (autoHCT) for MM from 2008 to 2016 and were reported to the CIBMTR. Patients were analyzed in 4 groups: African Americans with t(11;14) (n = 117), African Americans without t(11;14) (n = 968), Whites with t(11;14) (n = 266), and Whites without t(11;14) (n = 2187)., Results: African Americans with t(11;14) were younger, had lower Karnofsky scores, and had more advanced stage MM with a higher Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). Fewer African Americans with t(11;14) (21%) had a coexistent high-risk marker in comparison with Whites with t(11;14) (27%). In a multivariate analysis, race and t(11;14) had no association with progression-free survival. However, overall survival was superior among African Americans with t(11;14) in comparison with Whites with t(11;14) (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P = .03). Survival was also associated with female sex, stage, time from diagnosis to transplant, a low HCT-CI, and receipt of maintenance., Conclusions: Race may have a differential impact on the survival of patients with t(11;14) MM who undergo autoHCT and needs to be further studied., (© 2020 American Cancer Society.)

A Phase 2 dose-finding study evaluated isatuximab, an anti-CD38 monoclonal antibody, in relapsed/refractory multiple myeloma (RRMM; NCT01084252). Patients with ≥3 prior lines or refractory to both immunomodulatory drugs and proteasome inhibitors (dual refractory) were randomized to isatuximab 3 mg/kg every 2 weeks (Q2W), 10 mg/kg Q2W(2 cycles)/Q4W, or 10 mg/kg Q2W. A fourth arm evaluated 20 mg/kg QW(1 cycle)/Q2W. Patients (N = 97) had a median (range) age of 62 years (38-85), 5 (2-14) prior therapy lines, and 85% were double refractory. The overall response rate (ORR) was 4.3, 20.0, 29.2, and 24.0% with isatuximab 3 mg/kg Q2W, 10 mg/kg Q2W/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW/Q2W, respectively. At doses ≥10 mg/kg, median progression-free survival and overall survival were 4.6 and 18.7 months, respectively, and the ORR was 40.9% (9/22) in patients with high-risk cytogenetics. CD38 receptor density was similar in responders and non-responders. The most common non-hematologic adverse events (typically grade ≤2) were nausea (34.0%), fatigue (32.0%), and upper respiratory tract infections (28.9%). Infusion reactions (typically with first infusion and grade ≤2) occurred in 51.5% of patients. In conclusion, isatuximab is active and generally well tolerated in heavily pretreated RRMM, with greatest efficacy at doses ≥10 mg/kg.

This study determined whether 85 patients with multiple myeloma (MM) double-refractory to primary induction therapy with triplet regimens had a homogenous prognosis. The overall response rate (ORR) after the second-line therapy was 51%. Patients who proceeded to immediate autologous stem cell transplantation (ASCT) had better ORR than those who received conventional therapies (62% vs. 31%). The ORR for patients who had ASCT directly after the frontline therapy was higher than for those treated with other regimens as the second line therapy (91% vs. 45%) and offered ASCT as the third-line therapy (91% vs. 55%). The median progression-free survival (PFS) after the second-line therapy and median overall survival were 21.6 months and 35.6 months, respectively. ASCT after the second line treatment (HR = 0.24) was an independent predictor of PFS. Eligible patients with primary refractory MM achieve the most benefit from ASCT, also performed immediately after first line induction therapy.

Drug resistance and dose-limiting toxicities are significant barriers for treatment of multiple myeloma (MM). Bone marrow microenvironment (BMME) plays a major role in drug resistance in MM. Drug delivery with targeted nanoparticles have been shown to improve specificity and efficacy and reduce toxicity. We aim to improve treatments for MM by (1) using nanoparticle delivery to enhance efficacy and reduce toxicity; (2) targeting the tumor-associated endothelium for specific delivery of the cargo to the tumor area, and (3) synchronizing the delivery of chemotherapy (bortezomib; BTZ) and BMME-disrupting agents (ROCK inhibitor) to overcome BMME-induced drug resistance. We find that targeting the BMME with P-selectin glycoprotein ligand-1 (PSGL-1)-targeted BTZ and ROCK inhibitor-loaded liposomes is more effective than free drugs, non-targeted liposomes, and single-agent controls and reduces severe BTZ-associated side effects. These results support the use of PSGL-1-targeted multi-drug and even non-targeted liposomal BTZ formulations for the enhancement of patient outcome in MM.

In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10-5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971., (© 2020 by The American Society of Hematology.)

Objectives: Tremendous progress has been made in the treatment of multiple myeloma; however, the majority of this success has been demonstrated in younger patients. With 36% of patients >80 years-old at diagnosis, it is important to understand if older patients are receiving similar benefits., Materials and Methods: We identified 2155 patients diagnosed with myeloma at age 80 or older in the Surveillance, Epidemiology, and End Results Program (SEER)-Medicare database from 2007 to 2013. A cohort of 2933 similar patients diagnosed with myeloma at age 70-79 was used for comparison using a difference-in-differences design., Results: Only 51% of patients >80 years-old at diagnosis received systemic anti-myeloma treatment. Treatment was associated with a 26% decrease in hazard for death, independent of age, race, gender, poverty, comorbidities, and proxy measures of performance status. In the 70-79 cohort, treatment was associated with a 22% decrease in hazard for death. Based on the difference-in-differences design, there is no statistically significant difference in treatment benefit based on age cohort (p = .610)., Conclusions: Anti-myeloma treatment produces a similar survival benefit among the oldest patients. The population over 80, when myeloma incidence peaks, is projected to triple over the next few decades. It is imperative that we continue to advance our understanding of the needs of this vulnerable subgroup of patients with myeloma., Competing Interests: Declaration of Competing Interest T. Wildes has received research funding from Jannsen. The other authors have no relevant conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Purpose: Multiple myeloma (MM) treatment has changed tremendously, with significant improvement in patient out-comes. One group with a suboptimal benefit is patients with high-risk cytogenetics, as tested by conventional karyotyping or fluorescence in situ hybridization (FISH). Methodology for these tests has been published, but not necessarily standardized., Methods: We address variability in the testing and reporting methodology for MM cytogenetics in the United States using the ongoing African American Multiple Myeloma Study (AAMMS). We evaluated clinical and cytogenetic data from 1,221 patients (1,161 with conventional karyotyping and 976 with FISH) tested between 1998 and 2016 across 58 laboratories nationwide., Results: Interlab and intralab variability was noted for the number of cells analyzed for karyotyping, with a significantly higher number of cells analyzed in patients in whom cytogenetics were normal (P 5.0025). For FISH testing, CD138-positive cell enrichment was used in 29.7% of patients and no enrichment in 50% of patients, whereas the remainder had unknown status. A significantly smaller number of cells was analyzed for patients in which CD138 cell enrichment was used compared with those without such enrichment (median, 50 v 200; P, .0001). A median of 7 loci probes (range, 1-16) were used for FISH testing across all laboratories, with variability in the loci probed even within a given laboratory. Chromosome 13-related abnormalities were the most frequently tested abnormality (n5956; 97.9%), and t(14;16) was the least frequently tested abnormality (n 5 119; 12.2%)., Conclusions: We report significant variability in cytogenetic testing across the United States for MM, potentially leading to variability in risk stratification, with possible clinical implications and personalized treatment approaches.

Background: Treatment with novel agents has become the standard of care for newly diagnosed multiple myeloma, but members of racial and ethnic minority groups receive these agents at a lower rate than their peers. Researchers have largely attributed this finding to the higher costs of these drugs in respect to traditional chemotherapies, but data supporting this hypothesis are lacking. We compared the relative bortezomib and lenalidomide utilization in patients with newly diagnosed multiple myeloma, hypothesizing that the disparity between white and African American patients would be greater for lenalidomide as a result of its higher overall and out-of-pocket costs., Methods: We reviewed the utilization patterns of bortezomib and lenalidomide using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database., Results: Bortezomib utilization was 31% less likely for African Americans compared to whites. There was no statistically significant difference in lenalidomide utilization when other factors were controlled., Conclusion: Our findings do not support the hypothesis that higher respective costs are the cause of the racial disparities in novel agent utilization for myeloma treatment. We postulate that travel or logistical issues, structural barriers in the medical system, and preferences and biases among patients and providers may also be involved in the observed treatment disparities., (Copyright © 2020. Published by Elsevier Inc.)

CALGB (Alliance) 100001 was a phase II study evaluating autologous stem cell transplant (ASCT) followed by nonmyeloablative allogeneic stem cell transplant (alloSCT) in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than 1 prior progression event. Conditioning for ASCT was with high-dose melphalan (200 mg/m 2 ). The alloSCT reduced-intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m 2 /d i.v. on days -7 through -3) and cyclophosphamide (1 g/m 2 /d i.v. on days -4 through -3). The primary objective was to determine the 6-month post-alloSCT treatment-related mortality (TRM) rate. Additional objectives included determining the proportion of patients who could complete this tandem ASCT-alloSCT approach in a cooperative group setting, overall response rates, rates of donor chimerism, rates of graft-versus-host disease (GVHD), disease-free survival, and overall survival (OS). Sixty patients were enrolled, of whom 57 (95%) completed ASCT and 49 (82%) completed tandem ASCT-alloSCT. The TRM rate was 2% (1/49; 90% confidence interval, 0.10% to 9.3%). Moderate to severe (grades 2 to 3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of nonprotocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years. Similar to other studies, this study confirmed that tandem ASCT/alloSCT is associated with durable disease control in a subset of patients. This study demonstrated the feasibility of performing tandem ASCT/alloSCT in a cooperative group setting and determined that a fludarabine/cyclophosphamide RIC regimen is associated with a very low TRM rate., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated., Competing Interests: Competing interests: JA: consultant with SWOG, NCI, CIBMTR, received honoraria from Patient Power, Celgene and Janssen, board member Patient Empowerment Network, advisor for Myeloma Crowd; DEA: advisory board for Celgene, Juno, Partners Tx, Karyopharm and Bristol-Myers Squibb, research support from Celgene and Pharmacyclics, consulting for Janssen, Parexel and Takeda; JGB: contracted research for AbbVie, Amgen, Acetylon, Bluebird, Bristol-Myers Squibb, Celgene, Celularity, Constellation, CURIS, EMD Sorono, Genentech, Glenmark, Janssen, Kesios, Eli Lilly, Novartis, Poseida, Sanofi, Takeda, Teva and Vivolux, consulting fees for Takeda, Bristol-Myers Squibb, Karyopharm, CRISPR Therapeutics, Celgene, Kite Pharma, Legend, Servier, Janssen, Amgen, BioClinica, Prothena; IMB: founder and shareholder Wind MIL Therapeutics, consulting for Celgene and Bristol-Myers Squibb; AC: research funding from Pharmacyclics, Seattle Genetics and Janssen; advisory board for Janssen, consulting for Seattle Genetics, Janssen, Karyopharm, Sanofi and OncoPeptides; ADC: consulting for Celgene, Takeda, Janssen, GlaxoSmithKline, Kite Pharma, Oncopeptides, Seattle Genetics, contracted research for Novartis; MD: advisory board for Amgen, Kite, Celgene, Janssen, Lava Therapeutics and Roche; LG: speaker’s bureau for Genetech, IMF Nurse Leadership Board; DG: patents and royalties from Juno Therapeutics and Celgene, advisory board for Juno Therapeutics, Celgene, GSK, Seattle Genetics; AK: consulting for Celgene, advisory board for Sutro and 2Predicta, speaker for Celgene, Amgen and Takeda, stockholder Celgene, grant support from Janssen; YL: research funding from Kite/Gilead, Celgene, BlueBird Bio, Merck, Takeda and Janssen, advisory board for Kite/Gilead, Celgene, Bluebird Bio, Juno, Novartis and Janssen; EM: consulting for Adaptive Biotechnologies, Janssen, Celgene and Sanofi, contracted research for Sanofi, Quest Diagnostics and Merck; NCM: consulting for AbbVie, Adaptive, Amgen, Celgene, Janssen, Takeda, Oncopep, owner and stakeholder Oncopep; AKN: honorarium for participation inadvisory board for Amgen, Celgene, Takeda, Adaptive Janssen, GSK and Spectrum Pharmaceuticals; NS: advisor for Amgen, Bristol-Myers Squibb, Kite, Nkarta, Nektar, Oncopeptides, Karyopharm, Seattle Genetics, Indapta Therapeutics, Surface Oncology and Precision Biosciences, stock owenership Indapta Therapeutics; ELS: patents and royalties Juno and Celgene, consulting for Juno, Celgene, Fate Therapeutics and Precision Biosciences; RV: consulting for Celgene, Bristol-Myers Squibb, Sanofi, Takeda, Genentech, GSK, Securbio and Karyopharm, contracted research for Takeda, Celgen and Bristol-Myers Squibb. KG, APP have nothing to disclose. SITC Staff: AK, LL, RL, and SMW have nothing to disclose., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Multiple myeloma is a plasma cell blood cancer with frequent chromosomal translocations leading to gene fusions. To determine the clinical relevance of fusion events, we detect gene fusions from a cohort of 742 patients from the Multiple Myeloma Research Foundation CoMMpass Study. Patients with multiple clinic visits enable us to track tumor and fusion evolution, and cases with matching peripheral blood and bone marrow samples allow us to evaluate the concordance of fusion calls in patients with high tumor burden. We examine the joint upregulation of WHSC1 and FGFR3 in samples with t(4;14)-related fusions, and we illustrate a method for detecting fusions from single cell RNA-seq. We report fusions at MYC and a neighboring gene, PVT1, which are related to MYC translocations and associated with divergent progression-free survival patterns. Finally, we find that 4% of patients may be eligible for targeted fusion therapies, including three with an NTRK1 fusion.