Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study.

The objective of our study was to report real-world data on the safety and efficacy of standard-of-care teclistamab in patients with relapsed/refractory multiple myeloma (MM). This is a multi-institutional retrospective cohort study and included all consecutive patients that received at least one dose of teclistamab up until August 2023. One hundred and ten patients were included, of whom, 86% had triple-class refractory disease, 76% penta-refractory disease, and 35% had prior exposure to B-cell maturation antigen (BCMA)-targeting therapies. The overall response rate (ORR) in our cohort was 62%, with a ≥ very good partial remission (VGPR) rate of 51%. The ORR in patients with and without prior BCMA-targeted therapies was 54% vs 67%, respectively (p = 0.23). At a median follow-up of 3.5 months (range, 0.39-10.92), the estimated 3 month and 6 month progression free survival (PFS) was 57% (95% CI, 48%, 68%) and 52% (95% CI, 42%, 64%) respectively. The incidence of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) was 56% and 11% respectively, with grade ≥3 CRS and ICANS noted in 3.5% and 4.6% of patients respectively. 78 unique infections were diagnosed in 44 patients, with the incidence of all-grade and grade ≥3 infections being 40% vs 26% respectively. Primary prophylaxis with intravenous immunoglobulin (IVIG) was associated with a significantly lower infection risk on multivariate analysis (Hazard ratio [HR] 0.33; 95% CI 0.17, 0.64; p = 0.001).

Enhancing prognostic power in multiple myeloma using a plasma cell signature derived from single-cell RNA sequencing.

Multiple myeloma (MM) is a heterogenous plasma cell malignancy, for which the established prognostic models exhibit limitations in capturing the full spectrum of outcome variability. Leveraging single-cell RNA-sequencing data, we developed a novel plasma cell gene signature. We evaluated and validated the associations of the resulting plasma cell malignancy (PBM) score with disease state, progression and clinical outcomes using data from five independent myeloma studies consisting of 2115 samples (1978 MM, 65 monoclonal gammopathy of undetermined significance, 35 smoldering MM, and 37 healthy controls). Overall, a higher PBM score was significantly associated with a more advanced stage within the spectrum of plasma cell dyscrasias (all p < 0.05) and a shorter overall survival in MM (hazard ratio, HR = 1.72; p < 0.001). Notably, the prognostic effect of the PBM score was independent of the International Staging System (ISS) and Revised ISS (R-ISS). The downstream analysis further linked higher PBM scores with the presence of cytogenetic abnormalities, TP53 mutations, and compositional changes in the myeloma tumor immune microenvironment. Our integrated analyses suggest the PBM score may provide an opportunity for refining risk stratification and guide decisions on therapeutic approaches to MM.

Symptom clusters and their impact on quality of life in multiple myeloma survivors: Secondary analysis of BMT CTN 0702 trial.

Autologous haematopoietic cell transplantation (autoHCT) and continuous post-transplant maintenance therapy are the standard of care in transplant-eligible multiple myeloma (MM) patients. We sought to describe symptom burden and identify symptom clusters occurring in MM patients after autoHCT using data from the BMT CTN 0702 randomized controlled trial comparing the outcomes of three treatment interventions after an autoHCT in 758 MM patients. We analysed individual transplant-related symptoms assessed via the FACT-BMT questionnaire at enrolment and annually for 4-year post-autoHCT. We also described the effect the individual symptoms and symptom clusters have on quality of life (QoL). We identified three stable symptom clusters: malaise symptom cluster (lack of energy, feeling ill, having pain, experiencing nausea, loss of appetite), physical symptom cluster (having skin problems, tremors, worsening eyesight, change in taste, shortness of breath, frequent colds) and emotional symptom cluster (feeling sad, being nervous, experiencing sleep problems). Malaise and emotional symptom clusters have a greater impact on QoL than the physical symptoms cluster. Identifying these symptoms warrant additional support in terms of psychosocial support, in addition to treatment of the physical symptoms themselves.

Autologous stem cell boost improves persistent immune effector cell associated hematotoxicity following BCMA directed chimeric antigen receptor T (CAR T) cell therapy in multiple myeloma.

Persistent Immune Effector Cell Associated Hematotoxicity (ICAHT) is a significant side effect of BCMA CAR T-Cell therapy in patients with relapsed multiple myeloma (MM). The use of stem cell boosts in ICAHT has been described, however studies have been limited by small patient numbers and short follow up. Herein, we report on our multi-institutional experience of ICAHT, defined by an absolute neutrophil count (ANC) of ≤ 1000, thrombocytopenia with a platelet count ≤ 50,000 or/and anemia as hemoglobin (hgb) ≤9 g/dL, in patients who received BCMA CAR T therapy, and the effects of subsequent stem cell boost on hematopoietic reconstitution and clinical outcome. In this study, ICAHT was observed in 60% (n = 61/101) of patients at D + 21, and risk factors for its development included history of a prior ASCT, higher number of prior lines of therapy, a decreased platelet count prior to lymphodepletion and history of ICANS. 28% of patients with ICAHT received a stem cell boost at a median of 116 days due to profound and prolonged cytopenias often requiring ongoing transfusion support. Stem cell boost significantly improved cytopenias at 3 and 6 months follow up without any adverse effects on PFS and OS, underscoring the safety of this procedure.

Development and initial validation of the AL-PROfile patient-reported outcome measure in light chain (AL) amyloidosis.

OBJECTIVE: To evaluate the psychometric properties of the AL-PROfile, a patient-reported outcome measure combining the Patient-Reported Outcomes Measurement Information System (PROMIS)-29, two items from PROMIS Cognitive Function, and select Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) items. METHODS: Content validity was assessed through cognitive debriefing interviews of 20 patients who completed the AL-PROfile (Study 1). Study 2 involved 297 participants who completed the AL-PROfile and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Reliability (internal consistency and test-retest reliability) and validity (convergent and discriminant validity, known groups validity by stage/organ involvement) were calculated. RESULTS: Study 1 participants found the AL-PROfile straightforward confirming the relevance of the included content. Some felt that certain questions were not related to their amyloidosis experience. Study 2 demonstrated acceptable internal consistency for all domains/items except PROMIS Cognitive Function and acceptable test-retest reliability for all except PROMIS Cognitive Function and PRO-CTCAE nausea. Large correlations were seen for the same domain across measures while correlations for divergent domains within a measure and different domains across different measures were small. The PRO-CTCAE items showed small to medium correlations with each other and with PROMIS and SF-36 domains. Stage was associated with physical function, fatigue, social roles, swelling, and shortness of breath scores. CONCLUSION: The AL-PROfile has acceptable reliability and validity for use in systemic light chain amyloidosis patients.

Incorporating patient-reported outcome data into a predictive calculator for allogeneic hematopoietic cell transplantation recipients.

BACKGROUND: The Center for International Blood and Marrow Transplant Research (CIBMTR) provides a 1-year overall survival calculator to estimate outcomes for individual patients before they undergo allogeneic hematopoietic cell transplantation (HCT) to inform risk. The calculator considers pre-HCT clinical and demographic characteristics, but not patient-reported outcomes (PROs). Because pre-HCT PRO scores have been associated with post-HCT outcomes, the authors hypothesized that adding PRO scores to the calculator would enhance its predictive power. METHODS: Clinical data were obtained from the CIBMTR and the Blood and Marrow Transplant Clinical Trials Network. The PRO measures used were the 36-Item Short Form Survey (SF-36) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation. One thousand thirty-three adult patients were included. RESULTS: When adjusted for clinical characteristics, the SF-36 physical component score was significantly predictive of 1-year survival (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.81-0.95; p = .0015), whereas the mental component score was not (HR, 1.02; 95% CI, 0.95-1.10; p = 0.6396). The baseline single general health question on the SF-36 was also significantly associated with mortality (HR, 1.91 for those reporting fair/poor health vs. good, very good, or excellent health; 95% CI, 1.33-2.76; p = .0005). The addition of PRO scores to the calculator did not result in a significant change in the model's predictive ability. Self-reported pre-HCT scores were strongly predictive of self-reported health status (odds ratio, 3.35; 95% CI, 1.66-6.75; p = .0007) and quality of life (odds ratio, 3.24; 95% CI, 1.93-5.41; p < .0001) after HCT. CONCLUSIONS: The authors confirmed the significant, independent association of pre-HCT PRO scores with overall survival, although adding PRO scores to the survival calculator did not improve its performance. They also demonstrated that a single general health question was as accurate as the full measure for predicting survival, an important finding that may reduce respondent burden and promote its inclusion in routine clinical practice. Validation of these findings should be performed.

Severity and organ distribution of chronic graft-versus-host disease with posttransplant cyclophosphamide-based versus methotrexate/calcineurin inhibitor-based allogeneic hematopoietic cell transplantation.

The reduced risk of chronic graft-versus-host-disease (GVHD) with posttransplant cyclophosphamide (ptCy) in the setting of haploidentical related donor and more recently, with HLA-matched related and matched and mismatched unrelated donor allogeneic transplantation has been established. There is, however, paucity of data to show if ptCy impacts chronic GVHD pathogenesis, its phenotype and evolution after HCT regardless of the donor status. We examined the differences in chronic GVHD incidence and presentation in 314 consecutive patients after receiving their first allogeneic transplantation (HCT) using ptCy-based GVHD prophylaxis (ptCy-HCT; n = 120; including 95 with haploidentical related donor) versus conventional calcineurin inhibitor-based prophylaxis (CNI-MUD; n = 194) between 2012 and 2019. The 1-year cumulative incidence of all-grade chronic GVHD and moderate/severe chronic GVHD was 24% and 12%, respectively, after ptCy-HCT and 40% and 23% in the CNI-MUD recipients (p = 0.0003 and 0.007). Multivariable analysis confirmed that use of CNI-based GVHD prophylaxis and peripheral blood stem cell graft as the risk factors for chronic GVHD. The cumulative incidence of visceral (involving ≥1 of the following organs: liver, lungs, gastrointestinal tract, serous membranes) chronic GVHD was significantly higher with CNI-MUD vs. ptCy-HCT (27% vs. 15% at 1 year, p = 0.009). The incidence of moderate/severe visceral chronic GVHD was 20% in CNI-MUD group vs. 7.7% in the ptCy-HCT group at 1 year (p = 0.002). In addition, significantly fewer ptCy-HCT recipients developed severe chronic GVHD in ≥3 organs (0.8%) vs. 8.8% in the CNI-MUD group at 1-year posttransplant (p = 0.004). There was no significant different in relapse, non-relapse mortality, and relapse-free and overall survival between the two groups. Further investigation is needed to confirm that reduced risk and severity of chronic GVHD, less visceral organ distribution with ptCy-HCT leads to improved quality of life.

Timing and co-occurrence of symptoms prior to a diagnosis of light chain (AL) amyloidosis.

It is well-established that light chain (AL) amyloidosis patients have multi-organ involvement and are often diagnosed after a lag period of increasing symptoms. We leverage electronic health record (EHR) data from the TriNetX research network to describe the incidence, timing, and co-occurrence of precursor conditions of interests in a cohort of AL amyloidosis patients identified between October 2015-December 2020. Nineteen precursor diagnoses of interest representing features of AL amyloidosis were identified using ICD codes up to 36 months prior to AL amyloidosis diagnosis. Among 1,401 patients with at least 36 months of EHR data prior to AL amyloidosis diagnosis, 46% were females, 16% were non-Hispanic Black, and 6% were Hispanic. The median age was 71 (range, 21-91) years. The median number of precursor diagnoses was 5 with dyspnea and fatigue being the most prevalent. The time from the first occurrence of a precursor to AL diagnosis ranged from 3.2 to 21.4 months. Analyses of pairwise co-occurrence of specific diagnoses indicated a high association (Cole's coefficient > 0.6) among the examined precursor diagnoses. These findings provide novel information about the timing and co-occurrence of key precursor conditions and could be used to develop algorithms for early identification of AL amyloidosis.

The changing spectrum of infection with BCMA and GPRC5D targeting bispecific antibody (bsAb) therapy in patients with relapsed refractory multiple myeloma.

There is a paucity of granular data on infection risk with B-cell maturation antigen (BMCA) and GPRC5D bispecific antibodies (bsAb) in relapsed/refractory multiple myeloma (RRMM). The aim of our multi-institutional study was to characterize the incidence, etiologies, and risk factors of infections from the start of therapy to the last follow-up or 90 days after study exit. A total of 66 patients received BCMA bsAb monotherapy, 15 GPRC5D bsAb monotherapy, and 15 GPRC5D bsAb combination therapy with daratumumab and/or pomalidomide. While the infection rate per 100 days was 0.57 for BCMA bsAb, it was 0.62 for GPRC5D bsAb combination and 0.13 for GPRC5D bsAb monotherapy; P=0.05. The proportion of infections that were grade ≥3 was higher in the BCMA bsAb group compared to the GPRC5D groups (58% vs. 36%; P=0.04). Grade 5 events were observed in 8% (n=8) of the patients, all treated with BCMA bsAb. The 9 month cumulative incidence of any grade of infection was similar in the BCMA and GPRC5D-combination groups (57% and 62%) and significantly higher than in the GPRC5D-mono group (16%); P=0.012. The cumulative incidence of grade ≥3 infections was highest in the BCMA group reaching 54% at 18 months; P=0.06. Multivariate analysis showed that BCMA bsAb therapy or GPRC5D combination therapy, history of previous infections, baseline lymphopenia, and baseline hypogammaglobulinemia were significantly associated with a higher risk of grade ≥3 infections. Our results indicate that BCMA bsAb and GPRC5D-combination therapies in RRMM are associated with higher cumulative incidence of infection and grade ≥3 infection compared to GPRC5D bsAb mono.

Efficacy of Multiple SARS-CoV-2 Vaccine Doses in Patients with B Cell Hematologic Malignancies Receiving Chimeric Antigen Receptor T Cell Therapy: A Contemporary Cohort Analysis.

The mortality due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) approaches 40% in recipients of chimeric antigen receptor (CAR) T cell therapy (CAR-T). The efficacy of repeated vaccine doses, including bivalent boosters, remains unknown. We examined the efficacy of repeated vaccine doses among CAR-T recipients who received at least 2 or more vaccine doses after T cell infusion. This single-center retrospective study included adults age >18 years receiving CAR-T for relapsed/refractory (R/R) B cell hematologic malignancies targeting CD19, BCMA, or CD19 and CD20 between September 2018 through March 2022 and were alive beyond 2021 to receive incremental SARS-CoV-2 vaccine doses with available seroconversion data. Multivariable analyses were performed using the design-adjusted Cox regression and logistic regression approaches with stratification. In multivariable analysis, seroconversion rates were significantly greater with a total of 4 or more vaccine doses (odds ratio [OR], 8.22; P = .008). CAR-T recipients with other B cell hematologic malignancies had significantly lower seroconversion rates and diminished Ab titers compared to those with R/R multiple myeloma (OR, .07; P = .003). One patient died due to COVID-19 in this vaccinated study cohort, accounting for a COVID-19-attributable mortality rate of 1.7%. The results provide baseline vaccine response data in a contemporary cohort including patients with diverse group of SARS-COV2 variants and support the latest Centers for Disease Control and Prevention guidelines for repeated vaccinations directed against the prevalent variant of concern.

Chimeric antigen receptor and bispecific T-cell engager therapies in multiple myeloma patients with prior allogeneic transplantation.

Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR-T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo-HCT). Thirty-three MM patients with prior allo-HCT received CAR-T (n = 24) or BsAb (n = 9) therapy. CAR-T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR-T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR-T and 78% of BsAb recipients, while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three CAR-T patients. Infections of grade ≥3 were reported in 50% of CAR-T and 44% of BsAb recipients. No exacerbation of graft-versus-host disease occurred except in one BsAb recipient. CAR-T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo-HCT.

Amyloid consults do not have to be vexing.

Diagnosing amyloidosis can be challenging due to its clinical heterogeneity, need for multiple specialists to make a diagnosis, and lack of a single diagnostic test for the disease. Patients are often diagnosed late, in advanced stage, and after exhibiting multiple symptoms and signs for a long period. It is important to develop a clinical suspicion of amyloidosis, particularly in those with multisystemic symptoms and high-risk patient populations such as those with precursor hematologic conditions. A systematic approach to the workup of suspected amyloidosis is key, including a comprehensive clinical assessment, laboratory tests to assess organ involvement, advanced imaging studies, screening for plasma cell disorder, and tissue biopsy when necessary. After making a diagnosis of amyloidosis, accurate typing of amyloid deposits, differentiating between localized and systemic amyloidosis, and appropriately staging the disease is important. Early diagnosis is crucial for improving patient outcomes and quality of life in light chain amyloidosis.

Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial.

BACKGROUND: For patients with newly diagnosed multiple myeloma, reaching minimal residual disease (MRD) negativity after treatment is associated with improved outcomes; however, the use of MRD to modulate therapy remains elusive. We present the final analysis of the MASTER trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) therapy in patients with newly diagnosed multiple myeloma, in which MRD status is used to modulate treatment duration and cessation. METHODS: MASTER was a multicentre, single-arm, phase 2 trial conducted in five academic medical centres in the USA. Eligible participants were 18 years or older with newly diagnosed multiple myeloma (measurable by serum or urine protein electrophoresis or serum free light chains), a life expectancy of at least 12 months, and an Eastern Cooperative Oncology Group performance status of 0-2, and had received no previous treatment for multiple myeloma except up to one cycle of therapy containing bortezomib, cyclophosphamide, and dexamethasone. The study was enriched for participants with high-risk chromosome abnormalities (HRCAs). During the induction phase, participants received four 28-day cycles of Dara-KRd, each comprising daratumumab (16 mg/kg intravenously on days 1, 8, 15, and 22), carfilzomib (56 mg/m2 intravenously on days 1, 8, and 15), lenalidomide (25 mg orally on days 1-21), and dexamethasone (40 mg orally or intravenously on days 1, 8, 15, and 22); induction was followed by autologous haematopoietic stem-cell transplantation and up to two phases of consolidation with Dara-KRd. We assessed MRD by next-generation sequencing after or during each phase. The primary endpoint was reaching MRD negativity (<10-5). Participants who reached MRD negativity after or during two consecutive phases stopped treatment and began observation with MRD surveillance (MRD-SURE); participants who did not reach two consecutive MRD-negative results received maintenance lenalidomide. Secondary endpoints included progression-free survival and cumulative incidence of progression. All analyses were conducted in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03224507, and is complete. FINDINGS: Between Mar 21, 2018, and Oct 23, 2020, 123 participants were recruited to the study, of whom 70 (57%) were men, 53 (43%) were women, 94 (76%) were non-Hispanic White, 25 (20%) were non-Hispanic Black, and four (3%) were of another race or ethnicity. The median age of participants was 61 years (IQR 55-68), and 24 (20%) were aged 70 years or older. The median duration of follow up was 42·2 months (IQR 34·5-46·0). Of the 123 participants, 53 (43%) had no HRCAs, 46 (37%) had one HRCA, and 24 (20%) had two or more HRCAs. For 118 (96%) of 123 participants, MRD was evaluable by next-generation sequencing; the remaining five had an absence of sufficiently unique clonogenic sequences to enable tracking by the assay. Of these 118 participants, 96 (81%, 95% CI 73-88) reached MRD of less than 10-5 (comprising 39 [78%, 64-88] of 50 participants with no HRCAs, 38 [86%, 73-95] of 44 participants with one HRCA, and 19 [79%, 58-93] of 24 participants with two or more HRCAs) and 84 (71%, 62-79) reached MRD-SURE and treatment cessation. 36-month progression-free survival among all 123 participants was 88% (95% CI 78-95) for participants with no HRCAs, 79% (67-88) for those with one HRCA, and 50% (30-70) for those with two or more HRCAs. For the 84 participants reaching MRD-SURE, the 24-month cumulative incidence of progression from cessation of therapy was 9% (95% CI 1-19) for participants with no HRCAs, 9% (1-18) for those with one HRCA, and 47% (23-72) for those with two or more HRCAs. 61 participants (comprising 52% of 118 MRD-evaluable participants and 73% of 84 participants who reached MRD-SURE) remain free of therapy and MRD-negative as of Feb 7, 2023. The most common grade 3-4 adverse events were neutropenia (43 patients, 35%), lymphopenia (28 patients, 23%), and hypertension (13 patients, 11%). Three treatment-emergent deaths were recorded: two sudden deaths and one due to viral infection, none of which were judged to be treatment-related. INTERPRETATION: This approach provided positive outcomes and a pathway for treatment cessation in most patients with newly diagnosed multiple myeloma. Outcomes for patients with ultra-high-risk multiple myeloma, defined as those with two or more HRCAs, remain unsatisfactory, and these patients should be prioritised for trials with early introduction of therapies with novel mechanisms of action. FUNDING: Amgen and Janssen Pharmaceuticals.

Cancer-specific mortality in multiple myeloma: a population-based retrospective cohort study.

Survival has improved in patients diagnosed with multiple myeloma (MM) over the last two decades; however, there remains a paucity of data on the causes of death in MM patients and whether causes of death change during the disease trajectory. We conducted a retrospective population-based study to evaluate the rates of MM-specific versus non-MM cause of death and to identify factors associated with cause-specific death in MM patients, stratified into autologous stem cell transplant (ASCT) and non-ASCT cohorts. A total of 6,677 patients were included, 2,576 in the ASCT group and 4,010 in the non-ASCT group. Eight hundred and seventy-three (34%) ASCT patients and 2,787 (68%) non-ASCT patients died during the follow-up period. MM was the most frequent causes of death, causing 74% of deaths in the ASCT group and 67% in the non-ASCT group. Other cancers were the second leading causes of death, followed by cardiac and infectious diseases. Multivariable analysis demonstrated that a more recent year of diagnosis and novel agent use within 1 year of diagnosis were associated with a decreased risk of MM-specific death, whereas a history of previous non-MM cancer, older age, and the presence of CRAB criteria at diagnosis increased the risk of non-MM death. Our data suggests that despite improvement in MM outcomes in recent years, MM remains the greatest threat to overall survival for patients. Further advances in the development of effective MM therapeutic agents in both ASCT and non-ASCT populations and patient access to them is needed to improve outcomes.