•Teclistamab is effective in real-world patients with R/RMM, including those with prior anti-BCMA therapy exposure, albeit with slightly poorer progression-free survival.•Peripheral blood regulatory ...T cells associate with teclistamab failure, whereas CD8+ effector T cells associate with teclistamab response.
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Teclistamab, a B-cell maturation antigen (BCMA)- and CD3–targeting bispecific antibody, is an effective novel treatment for relapsed/refractory multiple myeloma (R/RMM), but efficacy in patients exposed to BCMA-directed therapies and mechanisms of resistance have yet to be fully delineated. We conducted a real-world retrospective study of commercial teclistamab, capturing both clinical outcomes and immune correlates of treatment response in a cohort of patients (n = 52) with advanced R/RMM. Teclistamab was highly effective with an overall response rate (ORR) of 64%, including an ORR of 50% for patients with prior anti-BCMA therapy. Pretreatment plasma cell BCMA expression levels had no bearing on response. However, comprehensive pretreatment immune profiling identified that effector CD8+ T-cell populations were associated with response to therapy and a regulatory T-cell population associated with nonresponse, indicating a contribution of immune status in outcomes with potential utility as a biomarker signature to guide patient management.
•Patients with MM receiving BsAbs or CAR T-cell therapies require frequent UHIs.•BsAb patients had more frequent unscheduled health care interactions than CAR T-cell therapy patients, largely due to ...more frequent URIs.
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Outcomes for patients with relapsed/refractory multiple myeloma (R/RMM) have dramatically improved after the development and now growing utilization of B-cell maturation antigen–targeted chimeric antigen receptor (CAR) T-cell therapy and bispecific antibody (BsAb) therapy. However, health care utilization as a quality-of-life metric in these growing populations has not been thoroughly evaluated. We performed a retrospective cohort study evaluating the frequency and cause of unscheduled health care interactions (UHIs) among patients with R/RMM responding to B-cell maturation antigen–targeted BsAb and CAR T-cell therapies (N = 46). This included the analysis of remote UHIs including calls to physicians’ offices and messages sent through an online patient portal. Our results showed that nearly all patients with R/RMM (89%) receiving these therapies required a UHI during the first 125 days of treatment, with a mean of 3.7 UHIs per patient. Patients with R/RMM responding to BsAbs were significantly more likely to remotely contact their physicians’ offices (1.8-fold increase; P = .038) or visit an urgent care center (more than threefold increase; P = .012) than patients with R/RMM responding to CAR T-cell therapies. This was largely due to increased reports of mild upper respiratory tract infections in BsAb patients. Our results underscore the need to develop preemptive management strategies for commonly reported symptoms that patients with R/RMM experience while receiving CAR T-cell or BsAb therapies. This preemptive management may significantly reduce unnecessary health care utilization in this vulnerable patient population.
•There are no prior prospective studies of thrombopoietin receptor agonists to enhance platelet recovery after auto-HCT.•As studied, romiplostim did not shorten the duration and depth of the platelet ...nadir, but it enhanced platelet recovery after day +15.
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There are no standard treatments to prevent or hasten the recovery from severe conditioning-regimen–induced thrombocytopenia occurring after autologous hematopoietic cell transplantation (auto-HCT). We conducted an open-label, single-arm pilot study of romiplostim, a thrombopoietin receptor agonist, to enhance platelet recovery in patients with multiple myeloma or lymphoma undergoing auto-HCT. All patients were treated weekly with romiplostim starting day +1 after auto-HCT until the platelet count was >50 × 109/L without transfusion. Compared with contemporary retrospective data from romiplostim-naïve patients (N = 853), romiplostim-treated patients (N = 59) had a similar median number of days of grade 4 thrombocytopenia or days requiring transfusions, time to platelet engraftment, and number of platelets transfusions during the auto-HCT. However, romiplostim-treated patients had enhanced platelet recovery to normal values beginning at approximately day +15. In matched cohort multivariable analyses, romiplostim treatment was associated with higher platelet counts by an average of 40 × 109/L (95% confidence interval (CI) (14, 67), P = .003) and 118 × 109/L (95% CI 84, 152, P<.001) at days +21 and +30, respectively, compared with those of no romiplostim. Only 1 adverse event was deemed possibly attributable to romiplostim: a low-risk pulmonary embolism in a patient with multiple myeloma. In conclusion, romiplostim showed promising activity and safety after auto-HCT, but the improvement in platelet counts occurred later than the goal of shortening the duration and depth of the platelet nadir. This trial was registered at www.clinicaltrials.gov (#NCT04478123).
•Patients with multiple myeloma previously treated with T-cell redirection therapy have a significantly lower risk of developing CRS with Tec.•Patients with high-risk cytogenetic features were at a ...low risk of developing CRS with Tec.
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Teclistamab (Tec) is a first-in-class BCMA × CD3 bispecific T-cell engager antibody approved for treating multiple myeloma progressing after at least 4 lines of therapy. The objective of this study was to evaluate the rate of cytokine release syndrome (CRS) in patients who were treated with commercial Tec and had prior exposure to other T-cell redirection therapies. A retrospective chart review was performed to identify patients who completed the Tec step-up dosing phase between November 2022 and November 2023. Patients were divided into 2 cohorts based on prior exposure to T-cell redirection therapy (cohort 1: T-cell redirection therapy experienced; cohort 2: T-cell redirection therapy naïve). The primary objective was to compare the differences in the rates of CRS between the 2 cohorts. Univariate and multivariate logistic regression analyses were performed to assess the association between CRS rates with Tec and prior treatment with T-cell redirection therapy. A total of 72 patients were included in the analysis (27 in cohort 1 and 45 in cohort 2). The CRS rates were significantly lower in cohort 1 (37%, n = 10) compared with cohort 2 (80%, n = 36; P = .0004). Based on multivariate logistic regression analysis, patients without prior exposure to T-cell redirection therapy (cohort 2) had about a fourfold increase in the incidence of CRS (95% confidence interval, 1.40-14.90; P = .0002) with Tec. In our study, prior exposure to T-cell redirection therapy reduced the risk of CRS with Tec during the step-up dosing phase. This observation will allow for the optimization of CRS prophylactic strategies for Tec.
•It is safe and feasible to deliver autologous hematopoietic cell transplantation care in a homebound setting.•Less than one-half of patients required inpatient admission.•Patients and caregivers ...report high satisfaction with care.
For eligible patients with multiple myeloma (MM) and amyloid light chain (AL) amyloidosis, high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) is a standard and widely used consolidation therapy. Autologous HCT requires specialized care at a transplantation center and investment from patients and caregivers. We studied the safety and feasibility of delivering transplantation care in a homebound setting to decrease the burden of therapy and increase access to autologous HCT. Patients with MM and AL amyloidosis undergoing autologous HCT were eligible if they resided in designated ZIP codes and had a full-time caregiver, Wi-Fi connection, HCT Comorbidity Index ≤3, and Karnofsky Performance Status score ≥80. High-dose melphalan (on day -2) and hematopoietic cell reinfusion (day 0) were administered in the outpatient clinic. Protocol-specific home care was provided from day +1 through engraftment. Patients were assessed and blood was drawn daily by advanced practice providers. Interventions were delivered by registered nurses. Attending physicians communicated daily through telemedicine. Quality of life, patient and caregiver satisfaction, and fecal microbiota profiling data were collected. Fifteen patients were enrolled and received transplantation care at home starting on day +1 following hematopoietic cell infusion. Patients remained in the program for an average of 12 days and required an average of 2 outpatient visits while receiving home care. Seven of 15 patients were admitted for a median of 4 days (range, 3 to 10 days); admission occurred on day +7 in 5 patients, on day +8 in 1 patient, and on day +12 in 1 patient for neutropenic fever in 2 patients, fever attributed to engraftment syndrome in 2 patients, diarrhea in 2 patients, and dehydration in 1 patient. Only 1 patient had a documented infection (Clostridioides difficile). One patient admitted with neutropenic fever required intensive care unit admission for a gastrointestinal bleed. Forty-seven percent of the patients experienced a grade ≥3 nonhematologic toxicity. There were no deaths on the study. Patients and caregivers reported high satisfaction with care. Microbiota diversity patterns were similar to those of autologous HCT recipients who did not receive post-HCT care at home, although a subset of the cohort maintained microbiota diversity throughout. Homebound HCT in an urban setting is safe and feasible, with less than one-half of patients requiring inpatient admission. Despite increased patient and caregiver responsibility in the homebound setting compared with an inpatient setting, patient and caregiver satisfaction was high. These results support expansion of homebound transplantation care programs.
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Introduction
Dysproteinemia refers to a spectrum of gammopathies in which an aberrant clone(s) of late stage B lymphoid cells or plasma cells produces monoclonal immunoglobulins and/or fragments. The ...spectrum includes incidentally noted benign conditions like monoclonal gammopathy of undetermined significance (MGUS) to life threatening diseases such as multiple myeloma (MM) and systemic light chain (AL) amyloidosis. Exploitation of normal plasma cell biology forms the basis of treatments used in both MM and AL amyloidosis. In recent years, immunotherapeutic strategies targeting plasma cells have redefined the treatment landscape of MM and could be particularly useful in AL amyloidosis which is distinguished by a low burden of less proliferative disease and a paucity of high risk genetics. We sought to characterize the expression of potentially clinically relevant and/or immunotherapeutic targets in amyloidogenic plasma cells.
Methods
All patients diagnosed with systemic AL amyloidosis at Memorial Sloan Kettering Cancer Center, NY between January 1, 2012, and December 31, 2018, who had unstained bone marrow samples were identified. Decalcified formalin fixed paraffin embedded bone marrow biopsy sections were stained for G protein-coupled receptor, class C group 5 member D (GPRC5D), Cyclin D1 (CCND1), B-cell lymphoma 2 (BCL2), and B-cell maturation antigen (BCMA) expression using standard laboratory developed Immunohistochemistry (IHC) assays in a CLIA compliant setting. We scored the biopsies for percentage expression, and intensity of staining. We also obtained the demographic details, staging, and cytogenetic information for the patients from whom these samples were obtained.
Results
During the queried period, 32 unstained samples were available for testing from 27 unique patients. There were 27 diagnostic and 5 patients had additional samples from the time of relapse. The median age was 63 years (range 41-73). 64% of patients were male and 75% had lambda restricted plasma cells. Cytogenetic abnormalities using fluorescence in situ hybridization (FISH) were reviewed, t(11;14) was seen in 38% samples. The median clonal PC burden in BM at diagnosis was 10% (range 2-80%) and 36% had >10% plasma cells. In clonal PCs, the median BCL2 expression was 100% (range 80-100%) with a staining intensity of 2 (range 1-3). 84% (27) samples had BCL2 expression meeting threshold used in the Bellini study. CCND1 expression could be tested in 16 samples median expression 100% (range 20-100%) and median staining intensity 2 (range 1-3). Patients with CCND1 expression also had 100% BCL2 staining. GPRC5D expression was available in 18 samples and all samples tested expressed GPRC5D with median 80% (range 30-100%) with median intensity 1 (range 1-3). BCMA expression was available for 25 samples, with median expression 80% (range 50-100%) with a median staining intensity 2 (range 1-3). Among the five patients with samples from diagnosis and relapse, samples retained their expression of BCL2, BCMA, and GPRC5D. Among samples with t(11;14) by FISH, 92% expressed BCL2 (per Bellini study) and 58% expressed CCND1.
Conclusion
Cell surface expression of novel targets has enabled the development of several efficacious therapeutic strategies in MM. Amyloidogenic plasma cells express GPRC5D, BCMA and BCL2. Our data provides the rationale for careful investigation and development of targeted agents (BCL2 inhibitors, e.g.venetoclax) and immunotherapeutic strategies directed at GPRC5D and BCMA in AL amyloidosis.
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Dogan: Roche: Consultancy, Research Funding; Peer View: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; EUSA Pharma: Consultancy. Hassoun: Celgene, Takeda, Janssen: Research Funding. Mailankody: Fate Therapeutics: Research Funding; Allogene Therapeutics: Research Funding; Bristol Myers Squibb/Juno: Research Funding; Plexus Communications: Honoraria; Legend Biotech: Consultancy; Evicore: Consultancy; Jansen Oncology: Research Funding; Physician Education Resource: Honoraria; Takeda Oncology: Research Funding. Giralt: SANOFI: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Landau: Takeda: Research Funding; Genzyme: Honoraria; Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees.
•Autologous transplantation allows clonal hematopoiesis to escape mutagenic chemotherapy and be reinfused to expand to neoplasm.•Distinct chemotherapies can promote the selection and acquisition of ...genomic drivers in therapy-related myeloid neoplasms.
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Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Preleukemic clones (ie, clonal hematopoiesis CH) are detectable years before the development of these aggressive malignancies, although the genomic events leading to transformation and expansion are not well defined. Here, by leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of prechemotherapy samples, we reconstructed the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy was revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan were hypermutated and enriched for complex structural variants (ie, chromothripsis), whereas neoplasms with nonmutagenic chemotherapy exposures were genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to discrete clinical exposure in each patient’s life, we estimated that several complex events and genomic drivers were acquired after chemotherapy was administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected after reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA damage. Overall, we revealed a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select preexisting CH but also promote the acquisition of recurrent genomic drivers.
Patients receiving cytotoxic chemotherapy and autologous transplantation may develop therapy-related myeloid neoplasms (tMN). Diamond and colleagues analyzed the genomic evolution of tMN to distinguish between chemotherapy-induced mutations and evolution from previous clonal hematopoiesis. tMN arising after mutagenic chemotherapy shows a complexity of new mutations, while tMN arising after nonmutagenic chemotherapy resembles de novo acute leukemia. The trajectory of tMN may arise from the acquisition of new mutations, selection of previously mutated clones, or the expansion of mutant clones transferred from the apheresis product.
Background
While survival of patients with multiple myeloma (MM) continues to improve, disparities in care are widely prevalent. While sex-based differences in cancer outcomes are apparent in several ...malignancies, these have not been studied as extensively in MM and consequently, the biology underlying these differences are unknown.
Methods
We utilized the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA11) to evaluate the outcomes of MM by sex. The CoMMpass database includes over 1000 newly-diagnosed MM patients with enriched tumor samples analyzed using RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) were predicted from RNA-seq data using the limma-voom method after TMM normalization, then gene set enrichment analyses using GSEA and WebGestalt and ClueGo were performed to assess for highly enriched pathways. We then performed multiple linear regression analysis using sex as the dependent variable. Other known high-risk prognostic markers were used as independent categorical or numeric variables. Categorical variables included age (</>65 years), beta2 microglobulin (>5.5 mg/L), elevated LDH (>ULN), presence of del 17p, t(4;14), t(14;16), gain chr 1q, del 1p and hyperdiploid status. Numeric variables included genes from the EMC-92 gene signature. Overall survival (OS) was estimated by Kaplan Meier method and log-rank test.
Results
Among patients with available data, females accounted for 44% (N=384) and males 56% (N=487) patients. Male sex is associated with inferior overall survival, with median survival (men 55 months vs women NR) (p=0.00024).
GSEA detected 310 out of 668 gene sets to be up-regulated in the female cohort of which 69 gene sets were significantly up-regulated (FDR q <25%). While in males, 358 out of the 668 gene sets queried were up-regulated and no gene set was significantly upregulated at FDR q<25%. Compared to males, significantly enriched gene sets in females were those involved oxidative metabolism (oxidative phosphorylation, respiratory electron transfer, and TCA cycle) which have been shown to be a function of B cell differentiation to support increased antibody production and may suggest a more differentiated plasma cell phenotype in women.
We then performed WebGestalt over-representation analysis (ORA) using up and down DEGs which showed that cell-cell junction, ECM proteoglycans, IFN gamma signaling, L1CAM interactions and axon guidance pathways were affected when comparing by sex.
Using the limma-voom method to predict DEGs (after TMM normalization), the up-regulated genes in women included those involved in protective processes such as inhibition of JAK/STAT mediated signaling (SOCS3), increased glutathione S transferase to detoxify products of oxidative stress (GSTM1), promotion of autophagy (DEPP1) as well as development of long term T cell immunity (TNFRSF4). Downregulated genes in women include those associated with increased proliferative potential such as cell-cell adhesion and signaling (LPHN2, EPHB1, LSAMP, NCAM1, CADM1, CD44, ANK3, CD99), cell cycle regulation (ZNF256, TEAD1, PDGFD), cytoskeletal proteins (MAP9, HYDIN, TMSB4X, TIAM1) and angiogenesis (PDE3B, VASH2).
Multiple linear regression analysis with sex as dependent variable showed no differences in the independent categorical variables tested between the male and female groups. 14 genes of the EMC-92 gene signature were also noted to significantly differ between the female and male groups (EHBP1L1, FGFR3, C1S, GRB14, HMGB3, ITM2B, LBR, MRPL41, RAB2A, RPS28, RPS4X, SPATS2L, TOP2A, TMEM97) along with genes expressed in multiple high-risk gene expression profiling signatures (TMEM97, ITM2B). These genes have been associated with cell survival, proliferation, differentiation and angiogenesis which may explain the differences in survival outcomes.
Conclusion
Female sex was associated with improved overall survival in the MMRF CoMMpass database. Over expression of several protective signatures and under expression of genes associated with increased proliferative signal may explain the differences in disease biology. Validation of these results in an independent cohort will help clarify these interesting and novel findings.
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Girnius:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Landau:Caelum: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Costa:GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau.
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