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Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G ± P). Chemomobilization (CM) can be used as a salvage regimen after G ± P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefits. At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell (PC) burden or MM-related biomarkers. Given the lack of efficacy of non-ICM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary PC leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G ± P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n = 45; hyper-CVAD-based, n = 16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved free light chains. Among those evaluated with longitudinal peripheral blood flow cytometry (n = 8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34 + cells (10.8 versus 10.2 × 10⁶/kg, P = .018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (hazard ratio [HR] 0.30, 95% CI 0.14 to 0.67, P = .003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, P = .2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, P < .001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, P < .001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, P = .031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, P = .018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, P = .018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, P = .012). ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (T PHEX ), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ + T PHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ + T PHEX . We also observed IFN-γ + T PHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19 + leukemia cells. An IFN-γ + T PHEX gene signature was recapitulated in T EX cells from human cancers, including myeloma and lymphoma. Here, we characterize a T EX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional T EX found in chronic viral infections. Thus, IFN-γ + T PHEX represent a potential target for immunotherapy of blood cancers.

Abstract: Autologous stem cell transplantation (ASCT) is the standard of care consolidation therapy for eligible patients with myeloma but most patients eventually progress, an event associated with features of immune escape. Novel approaches to enhance antimyeloma immunity after ASCT represent a major unmet need. Here, we demonstrate that patient-mobilized stem cell grafts contain high numbers of effector CD8 T cells and immunosuppressive regulatory T cells (Tregs). We showed that bone marrow (BM)-residing T cells are efficiently mobilized during stem cell mobilization (SCM) and hypothesized that mobilized and highly suppressive BM-derived Tregs might limit antimyeloma immunity during SCM. Thus, we performed ASCT in a preclinical myeloma model with or without stringent Treg depletion during SCM. Treg depletion generated SCM grafts containing polyfunctional CD8 T effector memory cells, which dramatically enhanced myeloma control after ASCT. Thus, we explored clinically tractable translational approaches to mimic this scenario. Antibody-based approaches resulted in only partial Treg depletion and were inadequate to recapitulate this effect. In contrast, a synthetic interleukin-2 (IL-2)/IL-15 mimetic that stimulates the IL-2 receptor on CD8 T cells without binding to the high-affinity IL-2Ra used by Tregs efficiently expanded polyfunctional CD8 T cells in mobilized grafts and protected recipients from myeloma progression after ASCT. We confirmed that Treg depletion during stem cell mobilization can mitigate constraints on tumor immunity and result in profound myeloma control after ASCT. Direct and selective cytokine signaling of CD8 T cells can recapitulate this effect and represent a clinically testable strategy to improve responses after ASCT., (© 2024 American Society of Hematology. Published by Elsevier Inc. 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.)

Cattaneo et al. report a unique case of a multiple myeloma patient with elevated B-cell maturation antigen (BCMA) surface density, potentially due to genetic alterations in the gamma-secretase protease complex-responsible for BCMA cleavage from plasma cells. No mutations in the BCMA gene were detected, but there was partial deletion of PSEN1 and amplification of PSEN2 (components of the gamma-secretase complex), which may explain the lack of response to the gamma-secretase inhibitor DAPT. This case, along with recent published literature, underscores the significance of gamma secretase in modulating BCMA density and the potential impact of its genetic alterations. Commentary on: Cattaneo et al. Genetic defects of gamma-secretase genes in a multiple myeloma patient with high and dysregulated BCMA surface density: A case report. Br J Haematol 2024;204:571-575., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

The use of granulocyte colony-stimulating factor (G-CSF) after autologous stem cell transplantation (ASCT) has been shown to reduce the time to neutrophil engraftment, as well as the duration of hospitalization post-transplantation. However, prior studies have focused on inpatient-based ASCT, where patients are routinely admitted for conditioning and frequently remain hospitalized until signs of neutrophil recovery. Given improvements in post-transplantation care, an increasing number of patients, particularly those receiving ASCT for multiple myeloma, are now undergoing transplantation in an outpatient setting. We hypothesized that the routine use of G-CSF for outpatient-based ASCT might not result in the same benefit with respect to a reduced duration of hospitalization and thus should be reconsidered in this setting. We performed a retrospective cohort study of 633 consecutive patients with multiple myeloma (MM; n = 484) or non-Hodgkin lymphoma (NHL; n = 149) who underwent ASCT between September 2018 and February 2023. Outpatient ASCT comprised 258 (53%) of combined MM and NHL cases. Starting in September 2021, post-transplantation G-CSF was incorporated into the supportive care regimen for all ASCTs. A total of 410 patients (309 with MM, 101 with NHL) underwent ASCT during the pre-G-CSF policy period and 223 (175 with MM, 48 with NHL) did so in the post-G-CSF policy period. The primary outcome focused on the duration of hospitalization within the first 30 days following graft infusion. As expected, after implementation of the G-CSF policy, the time to neutrophil engraftment was reduced in the patients with MM (mean, -2.8 days; P < .0001) and patients with NHL (mean, -2.9 days; P < .0001). However, among the patients with MM, roughly one-half of whom underwent outpatient-based ASCT, the inpatient duration during the first 30 days was not reduced after G-CSF implementation (P = .40). Comparatively, the inpatient duration (mean, -1.8 days; P = .030) was reduced among patients with NHL, all of whom were electively admitted for ASCT. For patients with MM at an outpatient-based transplant center, incorporation of G-CSF post-ASCT resulted in reduced time to neutrophil engraftment but did not significantly reduce the time spent in the inpatient setting through day +30., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response., (© 2023. Springer Nature Limited.)

Background: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma., Methods: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 10 6 CAR T cells, 150 × 10 6 CAR T cells, 300 × 10 6 CAR T cells, and 450 × 10 6 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals., Findings: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 10 6 CAR + cells, and the recommended phase 2 dose was not reached., Interpretations: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials., Funding: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health., Competing Interests: Declaration of interest AJC receives research funding from Juno Therapeutics—a Bristol Myers Squibb company, Nektar, Janssen, Abbvie, Harpoon, Sanofi, Adaptive Biotechologies, and Celgene; is a consultant for Adaptive Biotechnologies, Bristol Myers Squibb, and Abbvie; and receives payment for presentations from Curio Science, DAVA Oncology, and MJH Life Sciences. XS receives research funding from Juno Therapeutics—a Bristol Myers Squibb company. MJP is a consultant for SpringWorks Therapeutics, owns stock or has stock options in Lyell Immunopharma, and is currently employed by CellPoint. CJT receives research funding from Bristol Myers Squibb; has right to receive payments from royalties for inventions licensed to third parties, including Bristol Myers Squibb; is a consultant for Caribou, Myeloid Therapeutics, Precision Biosciences, Arsenal Bio, Century Therapeutics, Allogene, Legend Bio, Nektar, Syncopation Life Sciences, Sobi, Expert Connect, Decheng Capital, Asher Bio, Genentech, and Amgen; has received payment for presentations from St Judes, Malaysian Society for Hematology, Japan Society for Transplantation and Cell Therapy, and Bristol Myers Squibb; and has stock or stock options in Caribou, Myeloid Therapeutics, Precision Biosciences, Arsenal bio, and Eureka Therapeutics. BGT receives research funding from Bristol Myers Squibb; royalties from Mustang Bio; has patents with Mustang Bio; participates on a data safety monitoring board with Mustang Bio and Proteios Technology; and has stock or stock options with Proteios Technology. ENL has research funding from GSK, Celgene, Amgen, Genentech, Beigene, and Seattle Genetics and has received payment for presentations from Curio Science, Janssen, and Pharmacyclics. SAT has stock or stock options in Bristol Myers Squibb and is a current employee of Juno Therapeutics—a Bristol Myers Squibb company. BW has research funding from Amgen, Novartis, Kite, Beam, Wugen, and Biosight and receives payment for lectures from Amgen. MS receives research funding from Mustang Bio, Bristol Myers Squibb, Pharmacyclics, Genentech, Abbvie, TG Therapeutics, BeiGene, AstraZeneca, Genmab, Morphosys, Incyte, and Vincerx; is a consultant for AbbVie, Genentech, AstraZeneca, Pharmacyclices, BeiGene, Bristol Myers Squibb, Morphosys, Incyte, Kite, Eli Lilly, Genmab, Mustang Bio, Regeneron, ADC therapeutics, Fate Therapeutics, Nurix, and MEI Pharma; and receives payment for presentations from AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeiGene, Bristol Myers Squibb, Morphosys, Incyte, Kite, Eli Lilly, Genmab, Mustang Bio, Regeneron, ADC therapeutics, Fate Therapeutics, Nurix, and MEI Pharma. JG receives research funding from Sobi, Juno Therapeutics— a Bristol Myers Squibb company, Celgene—a Bristol Myers Squibb company, and Angiocrine Bioscience; is a consultant for Sobi, Legend Biotech, Janssen, Kite Pharma, and MorphoSys;, and is on an advisory board for Century Therapeutics. DGM receives research funding from Kite Pharma, Juno Therapeutics—a Bristol Myers Squibb company, Celgene, Legend Biotech, and Bristol Myers Squibb; is a consultant for A2 Biotherapeutics, Navan Technologies, Chimeric Therapeutics, Genentech, Bristol Myers Squibb, ImmmPACT Bio, and Gilead Sciences; has rights to royalties for patents licensed to Juno Therapeutics—a Bristol Myers Squibb company; serves as an advisory board member for Bristol Myers Squibb, Caribou Biosciences, Celgene, Genentech, Incyte, Janssen, Juno Therapeutics—a Bristol Myers Squibb company, Mustang Bio, Morphosys, Kite, Lilly, Novartis, and Umoja; and has stocks or stock options in A2 Biotherapeutics and Navan Technologies. SRR has research funding from the National Institutes of Health, Leukemia and Lymphoma Society, Juno Therapeutics—a Bristol Myers Squibb company, Lyelle Immunopharma, and Outpace Biosciences; has rights to royalties from Juno Therapeutics—a Bristol Myers Squibb company, Lyell Immunopharma, Deverra Therapeutics; is a consultant from Lyell Immunopharma and Adaptive Biotechnologies; has patents from Juno Therapeutics—a Bristol Myers Squibb company and Lyell Immunopharma; serves on a board of directors for Ozette Technologies; and has stocks or stock options from Lyell Immunopharma and Adaptive Biotechnologies. DJG held the sponsor-investigator investigational new drug application from the US Food and Drug Administration for this study; has obtained grants or contracts through Fred Hutchinson Cancer Center with Juno Therapeutics—a Bristol Myers Squibb company, Seattle Genetics, Janssen Biotech, SpringWorks Therapeutics, Cellectar Biosciences, The Allen Institute for Immunology, The Leukemia and Lymphoma Society, and the National Institutes of Health; is in consulting agreements with Ensoma; has served on an advisory board for GSK, Janssen Biotech, Legend Biotech, and Celgene; and has two US provisional patent applications (62/582,270 and 62/582,308) through Fred Hutchinson Cancer Center and Juno Therapeutics—a Bristol Myers Squibb company. BDS, DGC, TG, JV, VQW, AGC, and FM declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA-CARTx) is an emerging treatment for relapsed or refractory multiple myeloma (R/R MM). Here we characterize the epidemiology of infections, risk factors for infection, and pathogen-specific humoral immunity in patients receiving BCMA-CARTx for R/R MM. We performed a retrospective cohort study in 32 adults with R/R MM enrolled in 2 single-institution phase 1 clinical trials of BCMA-CARTx administered after lymphodepleting chemotherapy alone (n = 22) or with a gamma secretase inhibitor (GSI). We tested serum before and up to approximately 180 days after BCMA-CARTx for measles-specific IgG and for any viral-specific IgG using a systematic viral epitope scanning assay to describe the kinetics of total and pathogen-specific IgG levels pre- and post-BCMA-CARTx. We identified microbiologically documented infections to determine infection incidence and used Poisson regression to explore risk factors for infections within 180 days after BCMA-CARTx. Most individuals developed severe neutropenia, lymphopenia, and hypogammaglobulinemia after BCMA-CARTx. Grade ≥3 cytokine release syndrome (CRS; Lee criteria) occurred in 16% of the participants; 50% of the participants received corticosteroids and/or tocilizumab. Before BCMA-CARTx, 28 of 32 participants (88%) had an IgG <400 mg/dL, and only 5 of 27 (19%) had seropositive measles antibody titers. After BCMA-CARTx, all participants had an IgG <400 mg/dL and declining measles antibody titers; of the 5 individuals with baseline seropositive levels, 2 remained above the seroprotective threshold post-treatment. Participants with IgG MM (n = 13) had significantly fewer antibodies to a panel of viral antigens compared with participants with non-IgG MM (n = 6), both before and after BCMA-CARTx. In the first 180 days after BCMA-CARTx, 17 participants (53%) developed a total of 23 infections, of which 13 (57%) were mild-to-moderate viral infections. Serious infections were more frequent in the first 28 days post-treatment. Infections appeared to be more common in individuals with higher-grade CRS. Individuals with R/R MM have substantial deficits in humoral immunity. These data demonstrate the importance of plasma cells in maintaining long-lived pathogen-specific antibodies and suggest that BCMA-CARTx recipients need ongoing surveillance for late-onset infections. Most infections were mild-moderate severity viral infections. The incidence of early infection appears to be lower than has been reported after CD19-directed CARTx for B cell neoplasms, possibly due to differences in patient and disease characteristics and regimen-related toxicities., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Importance: Multiple myeloma is a hematologic malignancy characterized by presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year., Observations: Among patients with multiple myeloma, approximately 73% have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at the time of presentation. Evaluation of patients with possible multiple myeloma includes measurement of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels; serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis; and full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging. The Revised International Staging System combines data from the serum biomarkers β2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization-t(4;14), del(17p), and t(14;16)-to assess estimated progression-free survival and overall survival. At diagnosis, 28% of patients are classified as having Revised International Staging stage I multiple myeloma, and these patients have a median 5-year survival of 82%. Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy. This induction therapy combined with autologous hematopoietic stem cell transplantation followed by maintenance lenalidomide is standard of care for eligible patients., Conclusions and Relevance: Approximately 34 920 people in the US and 155 688 people worldwide are diagnosed with multiple myeloma each year. Induction therapy with an injectable proteasome inhibitor, an oral immunomodulatory agent and dexamethasone followed by treatment with autologous hematopoietic stem cell transplantation, and maintenance therapy with lenalidomide are among the treatments considered standard care for eligible patients.

Since the introduction of lenalidomide into induction therapy for multiple myeloma (MM), there have been conflicting reports about its impact on autologous peripheral blood stem cell (PBSC) mobilization. We evaluated the impact of previous lenalidomide exposure in a large cohort of patients with MM undergoing mobilization and collection at a tertiary stem cell transplantation center. We hypothesized that collection of PBSCs is feasible even with a prolonged duration of previous lenalidomide therapy. We examined patients with MM who attempted stem cell mobilization and collection, seen at our center between January 2012 and July 2015. The patients were categorized into 3 groups for analysis: (1) patients with previous receipt of >6 cycles lenalidomide, (2) patients with previous receipt of ≤6 cycles of lenalidomide, and (3) patients without previous lenalidomide exposure. We compared collection yields and days of apheresis among the 3 groups using linear regression analysis. We identified 297 patients with MM who underwent mobilization of PBSCs. Of these, 35 had received >6 cycles of lenalidomide (median, 8 cycles; range, 7 to 25 cycles), 156 had received ≤6 cycles of lenalidomide (median, 4 cycles; range, 1 to 6 cycles), and 106 had received no lenalidomide. Prior lenalidomide exposure did not have a statistically significant impact on the absolute number of CD34 + cells collected or on the duration of collection based on a multivariate linear regression analysis for association between receipt of >6 cycles of lenalidomide. In this retrospective analysis of MM patients undergoing autologous PBSC transplantation, we show that the duration of previous lenalidomide exposure does not impact the total number of PBSCs collected or the number of days of apheresis. These data suggest that longer courses of induction therapy with lenalidomide-containing regimens to achieve a maximum response can be safe without impairing the ability to collect PBSCs, and that limiting lenalidomide use before mobilization does not appear warranted in all cases., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Multiple myeloma (MM) is a genetically heterogeneous malignancy characterized by variable treatment responses. Although numerous drugs have been approved in recent years, the ability to predict treatment response and tailor individual therapy is limited by the absence of robust predictive biomarkers. The goal of this clinical trial was to use ex vivo, high-throughput screening (HTS) of 170 compounds to predict response among patients with relapsed or refractory MM and inform the next treatment decisions. Additionally, we integrated HTS with multi-omic analysis to uncover novel associations between in vitro drug sensitivity and gene expression and mutation profiles., Materials and Methods: Twenty-five patients with relapsed or refractory MM underwent a screening bone marrow or soft tissue biopsy. Sixteen patients were found to have sufficient plasma cells for HTS. Targeted next-generation sequencing was performed on plasma cell-free DNA from all patients who underwent HTS. RNA and whole-exome sequencing of bone marrow plasma cells were performed on eight and seven patients, respectively., Results: Results of HTS testing were made available to treating physicians within a median of 5 days from the biopsy. An actionable treatment result was identified in all 16 patients examined. Among the 13 patients who received assay-guided therapy, 92% achieved stable disease or better. The expression of 105 genes and mutations in 12 genes correlated with in vitro cytotoxicity., Conclusion: In patients with relapsed or refractory MM, we demonstrate the feasibility of ex vivo drug sensitivity testing on isolated plasma cells from patient bone marrow biopsies or extramedullary plasmacytomas to inform the next line of therapy., Competing Interests: Pamela S. Becker Consulting or Advisory Role: CVS Caremark, Pfizer Research Funding: AbbVie, Amgen, Bristol Myers Squibb, JW Pharmaceutical, Novartis, Pfizer, Glycomimetics, Trovagene, Invivoscribe, Secura Bio, Cardiff Oncology Patents, Royalties, Other Intellectual Property: Provisional patent filed: Application 62/694,874 filed July 6, 2018 entitled: “High Throughput Drug Screening of Cancer Stem Cells” No other potential conflicts of interest were reported.Pamela S. Becker Consulting or Advisory Role: CVS Caremark, Pfizer Research Funding: AbbVie, Amgen, Bristol Myers Squibb, JW Pharmaceutical, Novartis, Pfizer, Glycomimetics, Trovagene, Invivoscribe, Secura Bio, Cardiff Oncology Patents, Royalties, Other Intellectual Property: Provisional patent filed: Application 62/694,874 filed July 6, 2018 entitled: “High Throughput Drug Screening of Cancer Stem Cells” No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Abstract: Despite improvements in effective therapy, multiple myeloma remains incurable, and virtually all patients will face relapsed disease at some point after diagnosis. The prognosis for relapsed myeloma after developing resistance to anti-CD38 monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, and autologous stem cell transplantation has been poor; however, the development of immune effector cell therapy with chimeric antigen receptor (CAR) T cells may dramatically improve the outlook for patients, although none of these therapies are approved for MM to date. Herein, we review the development and history of CAR T-cell therapy for multiple myeloma, mechanisms of resistance, and strategies to improve outcomes with CAR T therapy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

To improve disease control without increasing the toxicity of a reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM), a phase I trial was performed using an antibody-radionuclide conjugate targeting CD45 ( 90 Y-DOTA-BC8) as conditioning. 90 Y-DOTA-BC8 was combined with fludarabine and low-dose TBI followed by allogeneic HCT in patients with MM and ≥1 adverse risk characteristic at diagnosis, relapse after autologous transplant, or plasma cell leukemia (PCL). The primary objective was to estimate the maximum tolerated radiation absorbed dose. Fourteen patients were treated (one with PCL, nine failed prior autologous HCT, and nine with ≥1 adverse cytogenetics). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Non-hematologic toxicities were manageable and included primarily gastrointestinal (43%) and metabolic/electrolyte disturbances (36%). Treatment-related mortality at 100 days was 0%. At a median follow-up of 5 years, the overall survival was 71% (median not reached) and the progression-free survival was 41% (median 40.9 months). The incorporation of CD45-targeted radioimmunotherapy (RIT) into a reduced-intensity allogeneic HCT is well-tolerated and may induce long-term remissions among patients with poor-risk MM, supporting further development of RIT-augmented conditioning regimens for HCT.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup has organized an annual workshop focused on minimal residual disease (MRD) testing and immune profiling (IP) in multiple myeloma since 2016. In 2019, the workshop took place as an American Society of Hematology (ASH) Friday Scientific Workshop titled "Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma." This workshop focused on 4 main topics: the molecular and immunologic evolution of plasma cell disorders, development of new laboratory- and imaging-based MRD assessment approaches, chimeric antigen receptor T cell therapy research, and statistical and regulatory issues associated with novel clinical endpoints. In this report, we provide a summary of the workshop and discuss future directions., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. All rights reserved.)

Background: Bortezomib has been incorporated into thalidomide and dexamethasone provided with cisplatin, doxorubicin, cyclophosphamide, and etoposide (PACE) as an intensive regimen before autologous stem-cell transplantation for multiple myeloma (MM). We examined MM patients at our center who received chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (KRD-PACE)., Patients and Methods: This was a retrospective study of 27 MM patients who received KRD-PACE for chemomobilization. Our analysis included patients who had circulating plasma cells (CPCs) by flow cytometry, ≥ 10% bone marrow plasma cells (BMPC), a monoclonal protein ≥ 1 g/dL, or an involved serum free light chain ≥ 10 mg/dL., Results: The most common indication for KRD-PACE was BMPC ≥ 10% in 16 patients (60%), followed by CPCs in 11 (41%). The median (range) age was 61 (35-69) years, and the median (range) BMPC before treatment was 10% (5%-47%). The overall response rate was 43%, and a median (range) of 20.24 (8.08-69.88) × 10 6 CD34 + cells/kg were collected. CPC clearance rate was 50%, and the median reduction in BMPC was 75%. Two patients had sinus bradycardia and 5 (19%) had neutropenic fever., Conclusion: KRD-PACE is an effective therapy to mobilize peripheral blood stem cells in MM patients with residual disease burden. This regimen was successful at clearing CPCs and reducing BMPC burden, with an overall response rate of 43%. Despite theoretical concern regarding the combination of 3 cardiotoxic agents, we observed a low frequency of cardiac issues., (Published by Elsevier Inc.)

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.)

Background: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT., Patients and Methods: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles., Results: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression., Conclusions: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed., (© 2019 S. Karger AG, Basel.)

B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/γc-/- mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA+ tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577., (© 2019 by The American Society of Hematology.)

Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients., (© 2019 by The American Society of Hematology.)

We previously reported initial results in 102 multiple myeloma (MM) patients treated with sequential high-dose melphalan and autologous hematopoietic cell transplantation followed by 200 cGy total body irradiation with or without fludarabine 90 mg/m 2 and allogeneic hematopoietic cell transplantation. Here we present long-term clinical outcomes among the 102 initial patients and among 142 additional patients, with a median follow up of 8.3 (range 1.0-18.1) years. Donors included human leukocyte antigen identical siblings (n=179) and HLA-matched unrelated donors (n=65). A total of 209 patients (86%) received tandem autologous-allogeneic upfront, while thirty-five patients (14%) had failed a previous autologous hematopoietic cell transplantation before the planned autologous-allogeneic transplantation. Thirty-one patients received maintenance treatment at a median of 86 days (range, 61-150) after allogeneic transplantation. Five-year rates of overall survival (OS) and progression-free survival (PFS) were 54% and 31%, respectively. Ten-year OS and PFS were 41% and 19%, respectively. Overall non-relapse mortality was 2% at 100 days and 14% at five years. Patients with induction-refractory disease and those with high-risk biological features experienced shorter OS and PFS. A total of 152 patients experienced disease relapse and 117 of those received salvage treatment. Eighty-three of the 117 patients achieved a clinical response, and for those, the median duration of survival after relapse was 7.8 years. Moreover, a subset of patients who became negative for minimal residual disease (MRD) by flow cytometry experienced a significantly lower relapse rate as compared with MRD-positive patients ( P =0.03). Our study showed that the graft- versus -myeloma effect after non-myeloablative allografting allowed long-term disease control in standard and high-risk patient subsets. Ultra-high-risk patients did not appear to benefit from tandem autologous/allogeneic hematopoietic cell transplantation because of early disease relapse. Incorporation of newer anti-MM agents into the initial induction treatments before tandem hematopoietic cell transplantation and during maintenance might improve outcomes of ultra-high-risk patients. Clinical trials included in this study are registered at: clinicaltrials.gov identifiers: 00075478, 00005799, 01251575, 00078858, 00105001, 00027820, 00089011, 00003196, 00006251, 00793572, 00054353, 00014235, 00003954., (Copyright © 2019 Ferrata Storti Foundation.)

Circulating plasma cells (CPCs) have been detected in patients with multiple myeloma (MM) at various stages of disease and associated with worse outcomes. Little data exist regarding the impact of CPCs at the time of autologous peripheral blood stem cell (PBSC) collection on outcomes, and the impact of maintenance therapy after autologous stem cell transplantation (ASCT) on prognosis in patients with CPC-containing collections. All patients with MM who underwent first ASCT at Fred Hutchinson Cancer Research Center from 2012 to 2015 and had evaluation for CPCs at the time of PBSC collection were included in our analysis. Seven-color flow cytometry was used to detect the presence of CPCs. Kaplan-Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS) rates from the time of ASCT. A multivariate analysis, including receipt of maintenance therapy post-ASCT, high-risk cytogenetics, and international staging system (ISS) stage, was included in a Cox proportional hazards regression model for associations with OS and PFS. We identified 227 patients with MM who underwent ASCT; of these, 144 (63.4%) patients had routine assessment of CPCs at the time of PBSC collection. One hundred seventeen (81.3%) patients did not have CPCs and 27 (18.8%) did have CPCs. The presence of CPCs was highly associated with poorer PFS (P = .031 by log-rank analysis), but did not affect OS. The median PFS for those patients without CPCs was 39.4 months (95% confidence interval [CI], 31.1 to not reached), while the median PFS for those patients with CPCs was 16.5 months (95% CI, 13.7 to not reached). A subgroup analysis of patients achieving very good partial response (VGPR) or better at time of collection, showed the median PFS for patients without CPCs was 38.3 months (95% CI, 29 to not reached), as compared with those patients with CPCs, where it was only 16.5 months (95% CI, 12 months to not reached; P = .02). There was no statistically significant difference in PFS or OS among those patients achieving partial response at the time of collection. In a Cox proportional hazards model, adjusting for post-ASCT maintenance therapy, high-risk cytogenetics, and ISS stage at time of initial diagnosis, there was a 43% higher risk of progression or death among the patients with CPCs (P = .04). The presence of CPCs at the time of autologous PBSC collection is a negative prognostic factor for risk of early relapse or death despite the advent of novel agents and maintenance strategies. The impact of CPCs was most significant among patients achieving a VGPR or better at time of collection. The presence of CPCs denotes a unique group of high-risk MM patients for whom alternative treatment strategies are needed to overcome resistance to current standard therapies., (Copyright © 2018. Published by Elsevier Inc.)

Pretargeted radioimmunotherapy (PRIT) has demonstrated remarkable efficacy targeting tumor antigens, but immunogenicity and endogenous biotin blocking may limit clinical translation. We describe a new PRIT approach for the treatment of multiple myeloma (MM) and other B-cell malignancies, for which we developed an anti-CD38-bispecific fusion protein that eliminates endogenous biotin interference and immunogenic elements. In murine xenograft models of MM and non-Hodgkin lymphoma (NHL), the CD38-bispecific construct demonstrated excellent blood clearance and tumor targeting. Dosimetry calculations showed a tumor-absorbed dose of 43.8 Gy per millicurie injected dose of 90 Y, with tumor-to-normal organ dose ratios of 7:1 for liver and 15:1 for lung and kidney. In therapy studies, CD38-bispecific PRIT resulted in 100% complete remissions by day 12 in MM and NHL xenograft models, ultimately curing 80% of mice at optimal doses. In direct comparisons, efficacy of the CD38 bispecific proved equal or superior to streptavidin (SA)-biotin-based CD38-SA PRIT. Each approach cured at least 75% of mice at the highest radiation dose tested (1200 µCi), whereas at 600- and 1000-µCi doses, the bispecific outperformed the SA approach, curing 35% more mice overall ( P < .004). The high efficacy of bispecific PRIT, combined with its reduced risk of immunogenicity and endogenous biotin interference, make the CD38 bispecific an attractive candidate for clinical translation. Critically, CD38 PRIT may benefit patients with unresponsive, high-risk disease because refractory disease typically retains radiation sensitivity. We posit that PRIT might not only prolong survival, but possibly cure MM and treatment-refractory NHL patients., (© 2018 by The American Society of Hematology.)

Allogeneic hematopoietic cell transplant (allo-HCT) represents the earliest form of immunotherapy used to treat multiple myeloma (MM). Since the first successful myeloablative allografts were performed in the early 1980s, highly effective new agents to treat this disease have been identified at an unprecedented pace. Currently, sixteen FDA-approved therapies are available to treat MM. As a consequence of these advances, the median overall survival for standard risk MM patients has extended to over 7 years. In light of the effective treatment options available, and as a consequence of high rates of toxicity, the role of allo-HCT to treat MM has been called into question. Patients with high-risk disease however continue to face early relapse and death, underscoring the need for approaches that more effectively treat this group. Moreover, allo-HCT remains the only mechanism through which MM patients are reliably cured and for the high-risk population represent an important treatment option that provides them access to an otherwise elusive survival plateau.

Multiple myeloma is an incurable often devastating disease that is responsible for 1-2% of all cancers. Multiple myeloma is the second most common hematologic malignancy. Over the past two decades, advances in therapy have doubled life expectancy. Unfortunately, all patients ultimately relapse. Novel agents (immunomodulatory drugs and proteasome inhibitors) have changed the outlook for patients, but further breakthroughs are needed. Epigenetic treatments offer potential for advancing therapy by modifying oncogene responses. The acetylation status of various proteins can affect the availability of chromatin for transcription. This response may be modulated epigenetically to advantage using histone deacetylase inhibitors like panobinostat.

Objectives To evaluate the real-world performance and reference intervals of the Binding Site Freelite serum free light chain (SFLC) assay (Thermo Fisher Scientific), a global standard for diagnosis, prognostication, and response assessment for monoclonal gammopathies. Methods An informatics-based approach was used to retrospectively evaluate concordance between SFLC and the orthogonal Sebia HYDRASYS immunofixation assay results in a large clinical data set consecutively reported between 2010 and 2020. Results Among patients with monoclonal-negative results by both SFLC and Sebia HYDRASYS immunofixation assays, 25% (1226/5057) had κ/λ ratios (KLRs) outside the manufacturer-defined and International Myeloma Working Group–cited normal reference interval of 0.26 to 1.65. These results were consistent over the study period and were not affected by sex, age, impaired kidney function, or assay antisera lot variation. Assay drift, in addition to other potential factors, affected the KLR distribution. Using International Statistical Classification of Diseases (ICD) codes, kidney function data, and the central 95% of KLR values generated on the Optilite platform (Thermo Fisher Scientific), we derived a new reference interval of 0.67 to 2.13, reducing the KLR false-positive rate to 8%. However, normal KLR persisted among 16% (14/85) of samples with free λ chains by immunofixation, warranting caution during interpretation. Conclusions Our analysis indicated that revision of Freelite SFLC reference intervals improves assay interpretation and should prompt reconsideration of Freelite reference intervals worldwide. [ABSTRACT FROM AUTHOR]

Circulating plasma cells (CPCs) have been detected in patients with multiple myeloma (MM) at various stages of disease and associated with worse outcomes. Little data exist regarding the impact of CPCs at the time of autologous peripheral blood stem cell (PBSC) collection on outcomes, and the impact of maintenance therapy after autologous stem cell transplantation (ASCT) on prognosis in patients with CPC-containing collections. All patients with MM who underwent first ASCT at Fred Hutchinson Cancer Research Center from 2012 to 2015 and had evaluation for CPCs at the time of PBSC collection were included in our analysis. Seven-color flow cytometry was used to detect the presence of CPCs. Kaplan-Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS) rates from the time of ASCT. A multivariate analysis, including receipt of maintenance therapy post-ASCT, high-risk cytogenetics, and international staging system (ISS) stage, was included in a Cox proportional hazards regression model for associations with OS and PFS. We identified 227 patients with MM who underwent ASCT; of these, 144 (63.4%) patients had routine assessment of CPCs at the time of PBSC collection. One hundred seventeen (81.3%) patients did not have CPCs and 27 (18.8%) did have CPCs. The presence of CPCs was highly associated with poorer PFS ( P  = .031 by log-rank analysis), but did not affect OS. The median PFS for those patients without CPCs was 39.4 months (95% confidence interval [CI], 31.1 to not reached), while the median PFS for those patients with CPCs was 16.5 months (95% CI, 13.7 to not reached). A subgroup analysis of patients achieving very good partial response (VGPR) or better at time of collection, showed the median PFS for patients without CPCs was 38.3 months (95% CI, 29 to not reached), as compared with those patients with CPCs, where it was only 16.5 months (95% CI, 12 months to not reached; P  = .02). There was no statistically significant difference in PFS or OS among those patients achieving partial response at the time of collection. In a Cox proportional hazards model, adjusting for post-ASCT maintenance therapy, high-risk cytogenetics, and ISS stage at time of initial diagnosis, there was a 43% higher risk of progression or death among the patients with CPCs ( P  = .04). The presence of CPCs at the time of autologous PBSC collection is a negative prognostic factor for risk of early relapse or death despite the advent of novel agents and maintenance strategies. The impact of CPCs was most significant among patients achieving a VGPR or better at time of collection. The presence of CPCs denotes a unique group of high-risk MM patients for whom alternative treatment strategies are needed to overcome resistance to current standard therapies. [ABSTRACT FROM AUTHOR]