A phase Ib trial of isatuximab, bendamustine, and prednisone in relapsed/refractory multiple myeloma.

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/m2. 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.

Somatic mutation phasing and haplotype extension using linked-reads in multiple myeloma.

Somatic mutation phasing informs our understanding of cancer-related events, like driver mutations. We generated linked-read whole genome sequencing data for 23 samples across disease stages from 14 multiple myeloma (MM) patients and systematically assigned somatic mutations to haplotypes using linked-reads. Here, we report the reconstructed cancer haplotypes and phase blocks from several MM samples and show how phase block length can be extended by integrating samples from the same individual. We also uncover phasing information in genes frequently mutated in MM, including DIS3, HIST1H1E, KRAS, NRAS, and TP53, phasing 79.4% of 20,705 high-confidence somatic mutations. In some cases, this enabled us to interpret clonal evolution models at higher resolution using pairs of phased somatic mutations. For example, our analysis of one patient suggested that two NRAS hotspot mutations occurred on the same haplotype but were independent events in different subclones. Given sufficient tumor purity and data quality, our framework illustrates how haplotype-aware analysis of somatic mutations in cancer can be beneficial for some cancer cases.

Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses.

Outcomes are poor in triple-class-exposed (TCE) relapsed/refractory multiple myeloma (RRMM). In the phase 3 KarMMa-3 (clinicaltrials.gov; NCT03651128) trial, patients with TCE RRMM and 2-4 prior regimens were randomized 2:1 to idecabtagene vicleucel (ide-cel) or standard regimens (SRs). An interim analysis (IA) demonstrated significantly longer median progression-free survival (PFS; primary endpoint; 13.3 vs 4.4 months; P<.0001) and higher overall response rate (ORR) with ide-cel vs SRs. At final PFS analysis (median follow-up, 30.9 months), ide-cel further improved median PFS vs SRs (13.8 vs 4.4 months; hazard ratio (HR), 0.49; 95% confidence interval (CI), 0.38-0.63). PFS benefit with ide-cel vs SRs was observed regardless of number of prior lines of therapy, with greatest benefit after 2 prior lines (16.2 vs 4.8 months, respectively). ORR benefit was maintained with ide-cel vs SRs (71% vs 42%; complete response, 44% vs 5%). Patient-centric design allowed crossover from SRs (56%) to ide-cel upon progressive disease, confounding overall survival (OS) interpretation. At IA of OS, median (95% CI) was 41.4 (30.9-not reached [NR]) vs 37.9 (23.4-NR) months with ide-cel and SRs, respectively (HR, 1.01; 95% CI 0.73-1.40); median OS in both arms was longer than historical data (9-22 months). Two prespecified analyses adjusting for crossover showed OS favoring ide-cel. This trial highlighted the importance of individualized bridging therapy to ensure adequate disease control during ide-cel manufacturing. Ide-cel improved patient-reported outcomes vs SRs. No new safety signals were reported. These results demonstrate the continued favorable benefit-risk profile of ide-cel in early-line and TCE RRMM. NCT03651128.

Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes.

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.

Clinical response and pathway-specific correlates following TIGIT-LAG3 blockade in myeloma: the MyCheckpoint randomized clinical trial.

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.

IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma.

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.

LINC01432 binds to CELF2 in newly diagnosed multiple myeloma promoting short progression-free survival to standard therapy.

Multiple Myeloma (MM) is a highly prevalent and incurable form of cancer that arises from malignant plasma cells, with over 35,000 new cases diagnosed annually in the United States. While there are a growing number of approved therapies, MM remains incurable and nearly all patients will relapse and exhaust all available treatment options. Mechanisms for disease progression are unclear and in particular, little is known regarding the role of long non-coding RNAs (lncRNA) in mediating disease progression and response to treatment. In this study, we used transcriptome sequencing to compare newly diagnosed MM patients who had short progression-free survival (PFS) to standard first-line treatment (PFS < 24 months) to patients who had prolonged PFS (PFS > 24 months). We identified 157 differentially upregulated lncRNAs with short PFS and focused our efforts on characterizing the most upregulated lncRNA, LINC01432. We investigated LINC01432 overexpression and CRISPR/Cas9 knockdown in MM cell lines to show that LINC01432 overexpression significantly increases cell viability and reduces apoptosis, while knockdown significantly reduces viability and increases apoptosis, supporting the clinical relevance of this lncRNA. Next, we used individual-nucleotide resolution cross-linking immunoprecipitation with RT-qPCR to show that LINC01432 directly interacts with the RNA binding protein, CELF2. Lastly, we showed that LINC01432-targeted locked nucleic acid antisense oligonucleotides reduce viability and increases apoptosis. In summary, this fundamental study identified lncRNAs associated with short PFS to standard NDMM treatment and further characterized LINC01432, which inhibits apoptosis.

Plain language summary of the KarMMa-3 study of ide-cel or standard of care regimens in people with relapsed or refractory multiple myeloma.

What is this summary about? This plain language summary describes the results of a Phase 3 study called KarMMa-3. In this ongoing study, researchers looked at a relatively new treatment for people with multiple myeloma, a type of blood cancer, whose cancer got worse despite treatment (refractory) or had cancer that at first improved with treatment, but eventually stopped responding (relapsed).How was this study conducted? In the KarMMa-3 study, people with relapsed or refractory multiple myeloma received either a one-time infusion of a new treatment, named ide-cel, or one of the standard of care regimens currently available for patients with this cancer. People were treated with the standard of care regimens in weekly or monthly cycles until the cancer got worse, there were unacceptable side effects, or the person withdrew from the study.What were the results? The results of this study showed that people receiving the one-time infusion of ide-cel lived longer without the cancer getting worse and had a greater reduction in cancer cells than patients receiving the standard of care regimen. A higher percentage of patients receiving ide-cel responded to treatment than patients receiving the standard of care regimen, and the response to treatment was better with idecel. These results show that ide-cel is a promising treatment for this challenging disease.Clinical Trial Registration: NCT03651128 (KarMMa-3 study).

Mixed-Methods Study on the Responsiveness of the Comprehensive Score for Financial Toxicity Among People With Multiple Myeloma.

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.

Epigenetic regulation during cancer transitions across 11 tumour types.

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1-4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

Continuous Elotuzumab, Pomalidomide, and Dexamethasone Maintenance Following Second Autologous Transplantation for Multiple Myeloma: Results of a Prospective Phase 2 Multicenter Trial.

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.

Disparities in Multiple Myeloma Treatment Patterns in the United States: A Systematic Review.

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.

Phase I-II Trial of Early Azacitidine after Matched Unrelated Donor Hematopoietic Cell Transplantation.

Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic cell transplantation (allo-HCT). The hypomethylating agent azacitidine (AZA) has been shown to be effective in preclinical and clinical studies for the prevention of acute GVHD (aGVHD). We sought to determine the maximum tolerated dose (MTD) of AZA when given on days 1 to 5 of a 28-day cycle for 4 cycles, starting on day +7 after allo-HCT, as well as its impact on aGVHD and chronic GVHD (cGVHD), relapse, and overall survival (OS) in patients undergoing matched unrelated donor allo-HCT. This study was a single-arm, single-center, open-label phase I-II study with a total of 15 and 38 patients enrolled in the phase I and II portions of the trial, respectively. A standard 3+3 study design was used in phase I, and all patients in phase II received AZA at the MTD determined in phase I. The MTD of AZA starting at day +7 post-transplantation was 45 mg/m2. Phase II of the study was halted after enrolling 38 of the planned 46 patients following an interim analysis that suggested futility. Overall, AZA at 45 mg/m2 exhibited a side effect profile consistent with prior reports and had a minimal impact on engraftment. The cumulative incidence of clinically significant aGVHD by day +180 was 39.9% (95% confidence interval [CI], 22% to 53.7%). The incidence of all-grade cGVHD was 61.4% (95% CI, 40.3% to 75%). At 1 year, OS was 73.7% (95% CI, 60.9% to 89.1%), and the disease relapse rate was 11.4% (95% CI, .2% to 21.3%). Our results suggest that early post-allo-HCT AZA has limited efficacy in preventing aGVHD and cGVHD but could have a beneficial effect in preventing disease relapse.

Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM.

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.

Venous Thromboembolism Risk in Patients With Newly Diagnosed Multiple Myeloma Treated with Carfilzomib or Bortezomib in Combination With Lenalidomide and Dexamethasone.

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.

Dynamic frailty risk assessment among older adults with multiple myeloma: A population-based cohort study.

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.

Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial.

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 × 106 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.

Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma.

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, 150×106 to 450×106 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.).

The Dynamics of Financial Toxicity in Multiple Myeloma.

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.

Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma.

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.