Scrutiny of chimeric antigen receptor activation by the extracellular domain: experience with single domain antibodies targeting multiple myeloma cells highlights the need for case-by-case optimization.

Introduction: Multiple myeloma (MM) remains incurable, despite the advent of chimeric antigen receptor (CAR)-T cell therapy. This unfulfilled potential can be attributed to two untackled issues: the lack of suitable CAR targets and formats. In relation to the former, the target should be highly expressed and reluctant to shedding; two characteristics that are attributed to the CS1-antigen. Furthermore, conventional CARs rely on scFvs for antigen recognition, yet this withholds disadvantages, mainly caused by the intrinsic instability of this format. VHHs have been proposed as valid scFv alternatives. We therefore intended to develop VHH-based CAR-T cells, targeting CS1, and to identify VHHs that induce optimal CAR-T cell activation together with the VHH parameters required to achieve this. Methods: CS1-specific VHHs were generated, identified and fully characterized, in vitro and in vivo. Next, they were incorporated into second-generation CARs that only differ in their antigen-binding moiety. Reporter T-cell lines were lentivirally transduced with the different VHH-CARs and CAR-T cell activation kinetics were evaluated side-by-side. Affinity, cell-binding capacity, epitope location, in vivo behavior, binding distance, and orientation of the CAR-T:MM cell interaction pair were investigated as predictive parameters for CAR-T cell activation. Results: Our data show that the VHHs affinity for its target antigen is relatively predictive for its in vivo tumor-tracing capacity, as tumor uptake generally decreased with decreasing affinity in an in vivo model of MM. This does not hold true for their CAR-T cell activation potential, as some intermediate affinity-binding VHHs proved surprisingly potent, while some higher affinity VHHs failed to induce equal levels of T-cell activation. This could not be attributed to cell-binding capacity, in vivo VHH behavior, epitope location, cell-to-cell distance or binding orientation. Hence, none of the investigated parameters proved to have significant predictive value for the extent of CAR-T cell activation. Conclusions: We gained insight into the predictive parameters of VHHs in the CAR-context using a VHH library against CS1, a highly relevant MM antigen. As none of the studied VHH parameters had predictive value, defining VHHs for optimal CAR-T cell activation remains bound to serendipity. These findings highlight the importance of screening multiple candidates.

An Assessment of the Effectiveness and Safety of Chimeric Antigen Receptor T-Cell Therapy in Multiple Myeloma Patients with Relapsed or Refractory Disease: A Systematic Review and Meta-Analysis.

Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy's efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy.

Multiple Myeloma.

Multiple myeloma (MM) is a cancer that arises from plasma cells in bone marrow. Approximately 35,730 Americans received a new diagnosis and MM will claim the lives of an estimated 12,590 people in 2023. Complications of the disease process include anemia, leukopenia, thrombocytopenia, renal failure, severe pain, bone loss, and hypercalcemia. Patients with MM have a high risk for pathological fractures. For most forms of MM there are effective treatments that may result in long-term remission using multi-drug regimens. Although the medications approved in the United States to treat MM generally produce good outcomes, they have serious, and potentially life-threatening adverse effects. In addition, patients with specific genetic variations are at high risk for relapse. Communication with the oncology team and early intervention in the event of adverse effects of medications, complications of the disease process, or evidence of relapse are important to obtain the best possible outcome. Patients are easily overwhelmed with a three- to four-drug treatment regimen with some drugs given intravenously and/or subcutaneously at the clinic, and others taken orally at home on specific days of each 28-day cycle. Home care nursing is needed to assess for tolerance, adverse effects, and to address patient concerns. Medication management and teaching are very important in guiding patients to safely manage a schedule that changes daily. In addition, the high risk of pathological fractures and serious injury if the patient should fall supports the need for physical and occupational therapy fall prevention and safety education and exercise programs to help avert decline in functional status and combat cancer-related fatigue.

International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma.

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies.

Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy.

Introduction: Cancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies. Methods: Using a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies. Results: Therapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. Discussion: Mathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.

"They don't care to study it": Trust, race, and health care experiences among patient-caregiver dyads with multiple myeloma.

BACKGROUND: Medical mistrust, rooted in unethical research, is a barrier to cancer-related health care for Black/African American (AA) persons. Understanding trust, mistrust, and health care experiences is crucial, especially in multiple myeloma (MM), which disproportionately burdens Black/AA persons in incidence and survival. STUDY PURPOSE: This study qualitatively examines the experiences of Black/AA and White dyads (patient with MM and adult caregiver) to gain insights into these phenomena. METHODS: From November 2021 to April 2022, we recruited 21 dyads from the UNC Lineberger Comprehensive Cancer Center. Participants completed a sociodemographic survey and a 60-90 min semi-structured interview. We used ATLAS.ti v9 for project management and to facilitate data analysis using the Sort and Sift, Think and Shift approach (ResearchTalk Inc). RESULTS: We interviewed 21 racially concordant dyads (11 Black/AA, 10 White) with mean patient ages of 70 (Black/AA) and 72 (White) at enrollment. Both Black/AA and White caregivers had a mean enrollment age of 68. The mean duration from MM diagnosis to enrollment for all patients was 5.5 years. Four key themes emerged: (1) knowledge and trust, (2) heightened emotions and discomfort, (3) differing mental constructs of health care experiences, and (4) mitigating mistrust, which varied by self-identified race. Black/AA participants had greater knowledge of historical events like the U.S. Public Health Service Untreated Syphilis Study at Tuskegee and carried the emotional burden longer. They also emphasized self-learning and self-guided research about MM for informed medical decision-making. Both Black/AA and White dyads emphasized the pivotal role of patient-provider relationships and effective communication in fostering trust and addressing concerns. CONCLUSION: Our study offers contextual insights into the enduring challenges of medical mistrust, particularly within the Black/AA community, and its implications for patients and caregivers accessing and receiving MM-related care. Future studies should leverage these insights to guide the development of multilevel interventions addressing medical mistrust within the Black/AA community.

Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies.

Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.

Multiple myeloma patients with a long remission after autologous hematopoietic stem cell transplantation.

Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after autoHCT, a small proportion achieve a durable response. In this retrospective study we included 1576 patients, 244 (15%) of whom were long-term responders (LTR), defined as having a progression-free survival (PFS) of ≥8 years after transplant. Patients in the LTR group were younger than the non-LTR group (median age 58.4 vs. 59.5 years; p = 0.012), less likely to have high-risk cytogenetics (4% vs. 14%; p < 0.001), more often had <50% bone marrow plasma cells (67% vs. 58%; p = 0.018) and R-ISS stage I disease (43% vs. 34%). More patients in the LTR group received post-transplant maintenance (63% vs. 52%; p = 0.002). Patients in the LTR group had higher rates of complete response (CR) at day100 (41% vs. 27%; p < 0.001) and at best post-transplant response (70% vs. 37%; p < 0.001), compared to the non-LTR group. Patients in the LTR groups had a median PFS of 169.3 months and the median overall survival (OS) had not been reached. The leading cause of death in the LTR was disease progression. In conclusion, 15% of patients in the cohort were LTR after upfront autoHCT, with distinct characteristics and a median PFS of more than 14 years.

The establishment of a multiple myeloma clinical registry in the Asia-Pacific region: The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR).

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer worldwide. Along with related diseases including monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukaemia (PCL) and plasmacytoma, MM incidence is rising, yet it remains incurable and represents a significant disease burden. Clinical registries can provide important information on management and outcomes, and are vital platforms for clinical trials and other research. The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR) was developed to monitor and explore variation in epidemiology, treatment regimens and their impact on clinical outcomes across this region. Here we describe the registry's design and development, initial data, progress and future plans. METHODS: The APAC MRDR was established in 2018 as a multicentre collaboration across the Asia-Pacific, collecting prospective data on patients newly diagnosed with MM, MGUS, PCL and plasmacytoma in Korea, Singapore, Malaysia and Taiwan, with China recently joining. Development of the registry required a multidisciplinary team of clinicians, researchers, legal and information technology support, and financial resources, as well as local clinical context from key opinion leaders in the APAC region. Written informed consent is obtained and data are routinely collected throughout treatment by hospital staff. Data are stored securely, meeting all local privacy and ethics requirements. Data were collected from October 2018 to March 2024. RESULTS: Over 1700 patients from 24 hospitals have been enrolled onto the APAC MRDR to date, with the majority (86%) being newly diagnosed with MM. Bortezomib with an immunomodulatory drug was most frequently used in first-line MM therapy, and lenalidomide-based therapy was most common in second-line. Establishment and implementation challenges include regulatory and a range of operational issues. CONCLUSION: The APAC MRDR is providing 'real-world' data to participating sites, clinicians and policy-makers to explore factors influencing outcomes and survival, and to support high quality studies. It is already a valuable resource that will continue to grow and support research and clinical collaboration in MM and related diseases across the APAC region.

[Investigation of the immune profile of multiple myeloma patients achieving long-term survival after autologous stem cell transplantation].

Objective: To identify the characteristics of the bone marrow immune microenvironment associated with long-term survival in multiple myeloma (MM) patients. Methods: In the follow-up cohort of patients with newly diagnosed MM and who received "novel agent induction therapy and subsequent autologous stem cell transplantation and immunomodulator maintenance therapy" in the First Affiliated Hospital of Sun Yat-sen University, a cross-sectional study was carried out between August 2019 and May 2020. Using NanoString technology, the RNA expression of 770 bone marrow immune-related markers was compared between 16 patients who had progression-free survival ≥5 years and 5 patients with progressive disease. Among the 16 patients who achieved long-term survival, 9 achieved persistent minimal residual disease (MRD) negative while the other 7 had persistent positive MRD. The functional scores of each kind of immune cells were calculated based on the expression level of characteristic genes, so as to indirectly obtained the proportion of each immune cell subset. The Mann-Whitney U test and the Kruskal Wallis test were used for statistical analysis. Results: The proportion of neutrophils was significantly higher in long-surviving MM patients than in patients with progressive disease [functional scores, 13.61 (13.33, 14.25) vs. 12.93 (12.58, 13.38); Z=2.31, P=0.021]. Among long-surviving patients, those who were MRD-positive had a significantly greater number of mast cells compared with those who were MRD-negative [functional scores, 7.09 (6.49, 8.57) vs. 6.03 (5.18, 6.69); H=2.18, P=0.029]. Compared with patients with progressive disease, four genes (CTSG, IFIT2, S100B, and CHIT1) were significantly downregulated and six (C4B, TNFRSF17, CD70, IRF4, C2, and GAGE1) were upregulated in long-surviving patients. Among long-surviving patients, only gene CMA1 was significantly upgraded, 10 genes (ISG15, OAS3, MX1, IFIT2, DDX58, SIGLEC1, CXCL10, IL1RN, SERPING and TNFSF10) were significantly downregulated in the MRD-positive group compared with that in the MRD-negative group, the first 5 of which are related to the interferon response pathway. Conclusions: The increased neutrophil and mast cell numbers may be related to long-term survival in MM. Interferon signaling activation may be a key bone marrow immune profiling feature for MRD-negative, long-surviving patients with MM.

[Guideline for the diagnosis and management of multiple myeloma-related renal impairment (2024 version)].

Renal impairment is a common complication of multiple myeloma (MM). All patients with MM should be assessed for the presence and severity of renal impairment. The clinicopathological manifestations of MM-related renal impairment are diverse and complex; accordingly, except for light-chain nephropathy, which can often be diagnosed without biopsy based solely on clinical criteria, a renal biopsy is needed for an accurate diagnosis. Supportive care, such as adequate hydration, is required for all patients with MM-related renal impairment. The guideline provide the principles for dose adjustment of the drugs used for MM with renal impairment, including proteasome inhibitors, immunomodulators, monoclonal antibodies, small molecule inhibitors, and alkylating agents, as well as those used for myeloma bone disease. Autologous stem cell transplantation (ASCT) and chimeric antigen receptor T-cell immunotherapy (CAR-T) are effective in patients with moderate renal impairment and are tolerated by the patients. The Chinese Hematology Association; the Chinese Geriatrics Association, Society of Hematology; and the Chinese Research Hospital Association, Society of Nephrology asked experts to collate information on current progress in clinical research relating to MM with renal impairment. This guideline was developed based on the gathered data combined with the latest international consensus and clinical practice guidelines.

Allogeneic CAR T Cells: Complex Cellular Therapy Designs Test the Limits of Our Preclinical Models.

All chimeric antigen receptor (CAR) T-cell products currently approved by the FDA are autologous, which poses several challenges for widespread use. In this issue, Degagné and colleagues present their preclinical research on creating off-the-shelf CAR T cells for multiple myeloma. They utilized the CRISPR/Cas12a genome editing platform and gene knock-in techniques to eliminate alloreactivity and decrease susceptibility to natural killer (NK)-cell elimination. This work has led to an ongoing phase I trial of off-the-shelf CAR T cells for multiple myeloma treatment. See related article by Degagné et al., p. 462 (2).

Expanding Myeloma Training and Care in Western Kenya Through the ECHO Model: The Pilot Phase.

PURPOSE: Multiple myeloma (MM) in rural western Kenya is characterized by under and late diagnosis with poor long-term outcomes. Inadequate skilled rural health care teams are partly to blame. The Extension for Community Healthcare Outcomes (ECHO) model attempts to bridge this skills gap by linking rural primary/secondary health care teams (spokes) to myeloma experts in a tertiary care center (hub) in a longitudinal training program. METHODS: A hub team comprising myeloma experts and administrators from Moi Teaching and Referral Hospital/Academic Model Providing Access to Healthcare was assembled and spoke sites were recruited from rural health care facilities across western Kenya. A curriculum was developed by incorporating input from spokes on their perceived skills gaps in myeloma. Participants joined sessions remotely through virtual meeting technology. ECHO sessions consisted of a spoke-led case presentation with guided discussion followed by an expert-led lecture. An end-of-program survey was used to evaluate participant satisfaction, knowledge, and practice patterns. RESULTS: A total of eight sessions were conducted between April and November 2021 with a median of 40 attendees per session drawn from diverse health care disciplines. Twenty-four spoke sites were identified from 15 counties across western Kenya. The majority of attendees reported satisfaction with the ECHO program (25 of 29) and improvement in their myeloma knowledge (24 of 29). There were 74 new myeloma diagnoses made at the hub site in 2021, representing a 35% increase from the previous 3-year average despite the COVID-19 pandemic that suppressed health care access globally. RECOMMENDATIONS: The pilot ECHO model was successfully implemented in myeloma training for rural-based health care teams. Key attributes included collaborative curriculum development, interactive case-based bidirectional learning, and multidisciplinary engagement.

[Application of the Second Revision of the International Staging System (R2-ISS) in the prognostic assessment of newly diagnosed multiple myeloma].

Objective: To investigate the prognostic value of the Second Revision of the International Staging System (R2-ISS) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The retrospective study was performed in 326 NDMM patients with immunomodulatory drugs and/or proteasome inhibitors as the first-line treatment attending the Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, from December 2012 to March 2022. The Kaplan-Meier method was used for the survival analysis, with the Log-rank test comparing the between-group differences and Cox proportional risk regression modeling A multifactorial analysis was performed. Results: ①326 patients were included in the study, 190 of whom were males. The median age was 63 years, and the median followup time was 37 months. R2-ISS can effectively predict prognosis, particularly for R-ISS Ⅱ patients. The median progression-free survival (PFS) time of R2-ISS Ⅰ, R2-ISS Ⅱ, R2-ISS Ⅲ, and R2-ISS Ⅳ was 52, 29, 20, and 15 months (P<0.001), while the median overall survival (OS) time was 91, 60, 44, and 36 months (P<0.001). Multifactor analysis revealed that ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, LDH increased, and age >65 years old were independent negative prognostic factors for OS. ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, and LDH were independent negative prognostic factors for PFS. ②The C-index score of R2-ISS was 0.724, higher than that of R-ISS (0.678), indicating high prediction efficiency. ③The median PFS for 1q+-related double-hit in R2-ISS Ⅲ and Ⅳ were 20, 15 months (P=0.084) and the median OS were 35, 36 months (P=0.786), respectively. In R2-ISS Ⅲ, there were twenty-seven cases of 1q+-related double-hit, sixty-one cases of 1q+ single abnormality, and sixty-eight cases with no 1q+. The median PFS for the three groups were 20, 18, and 21 months (P=0.974), while the median OS was 35, 47, and 56 months (P=0.042), respectively. Adjusting the assignment of 1q+ to 1, the median PFS and OS of different R2-ISS stages differed significantly after regrouping (P<0.001) . Conclusions: The prognostic stratification value of R2-ISS is higher than R-ISS, particularly in the highly heterogeneous R-ISS Ⅱ population. Adjusting the assignment of the 1q+-related double-hit can improve R2-ISS, which should be validated in future studies with multi-center and expanded cases.

[Minimal residual disease assessment and progress in multiple myeloma].

With the rapid iteration of multiple myeloma therapeutics over the last two decades, as well as increasing remission rates and depth of remission in patients, traditional methods for monitoring disease response are insufficient to meet the clinical needs of new drugs. Minimal residual disease (MRD) is a more sensitive test for determining the depth of response, and data from multiple clinical trials and meta-analyses show that a negative MRD correlates with a better prognosis than a traditional complete response. MM is at the forefront of MRD evaluation and treatment. MRD detection methods have been continuously updated. The current MRD assessment has three dimensions: bone marrow-based MRD testing, MRD testing based on images of residual metabolic of focal lesions, and peripheral blood-based MRD testing. The various MRD assessment methods complement one another. The goal of this article is to discuss the currently used MRD assays, the progress, and challenges of MRD in MM, and to provide a reference for clinicians to better use the techniques.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion.

BACKGROUND: Despite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach. METHODS: In this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1KD BCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients. RESULTS: Compared with parental BCMA CAR-T cells, PD-1KD BCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1KD BCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4/7, 57.1%) with at least one extramedullary site and four patients (4/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity. CONCLUSIONS: Our study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.

Real-world advantage and challenge of post-autologous stem cell transplantation MRD negativity in high-risk patients with double-hit multiple myeloma.

BACKGROUND: Autologous stem-cell transplantation (ASCT) remains a beneficial approach for patients with newly diagnosed multiple myeloma (NDMM) in the age of novel therapeutic agents. Nevertheless, limited real-world data is available to establish criteria for identifying high-risk ASCT patients. METHODS: We analyzed outcomes for 168 NDMM patients who underwent ASCT at our center from December 2015 to December 2022. We investigated the impact of the number of high-risk cytogenetics (HRCA), defined as t(4;14), t(14;16), 1q21 gain/amplification, and del(17p), as well as the post-ASCT minimal residual disease (MRD) status as prognostic indicators. We assessed progression-free survival (PFS) and overall survival (OS), and focused on identifying risk factors. RESULTS: The cohort included 42% of patients (n = 71) with 0 HRCA, 42% (n = 71) with 1 HRCA, and 16% (n = 26) with ≥ 2 HRCA. After a median follow-up of 31 months, the median PFS was 53 months (95% CI, 37-69), and OS was not reached for the entire cohort. Despite similar rates of MRD-negativity post-ASCT, patients with ≥ 2 HRCA, termed "double hit" (DH), had a significantly higher risk of progression/mortality than those with 0 or 1 HRCA. Multivariate analysis highlighted DH (HR 4.103, 95% CI, 2.046-8.231) and MRD positivity post-ASCT (HR 6.557, 95% CI, 3.217-13.366) as adverse prognostic factors for PFS, with DH also linked to inferior OS. As anticipated, DH patients with post-ASCT MRD positivity displayed the poorest prognosis, with a median PFS of 7 months post-ASCT. Meanwhile, DH patients with MRD negativity post-ASCT showed improved prognosis, akin to MRD-negative non-DH patients. It is noteworthy to exercise caution, as DH patients who initially achieved MRD negativity experienced a 41% cumulative loss of that status within one year. CONCLUSIONS: This study strongly advocates integrating DH genetic assessments for eligible ASCT patients and emphasizes the importance of ongoing MRD monitoring, as well as considering MRD-based treatment adaptation for those patients in real-world settings.