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).

A Risk Stratification System in Myeloma Patients with Autologous Stem Cell Transplantation.

Autologous stem cell transplantation (ASCT) has been a mainstay in myeloma treatment for over three decades, but patient prognosis post-ASCT varies significantly. In a retrospective study of 5259 patients with multiple myeloma (MM) at the University of Arkansas for Medical Sciences undergoing ASCT with a median 57-month follow-up, we divided the dataset into training (70%) and validation (30%) subsets. Employing univariable and multivariable Cox analyses, we systematically assessed 29 clinical variables, identifying crucial adverse prognostic factors, such as extended duration between MM diagnosis and ASCT, elevated serum ferritin, and reduced transferrin levels. These factors could enhance existing prognostic models. Additionally, we pinpointed significant poor prognosis markers like high serum calcium and low platelet counts, though they are applicable to a smaller patient population. Utilizing seven easily accessible high-risk variables, we devised a four-stage system (ATM4S) with primary stage borders determined through K-adaptive partitioning. This staging system underwent validation in both the training dataset and an independent cohort of 514 ASCT-treated MM patients from the University of Iowa. We also explored cytogenetic risk factors within this staging system, emphasizing its potential clinical utility for refining prognostic assessments and guiding personalized treatment approaches.

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.

Amyloid Light-Chain (AL) Amyloidosis of the Trachea Associated With an Indolent B-cell Neoplasm.

We report the case of a 66-year-old woman who was diagnosed with localized tracheal amyloid light-chain (AL) amyloidosis caused by an underlying B-cell neoplasm. The diagnosis was confirmed through subsequent bronchoscopy and biopsies; however, she experienced a challenging episode of hypoxic respiratory failure that required intervention. Repeat bronchoscopies showed persistent subglottic stenosis and tracheobronchomalacia, which led to tracheal debulking surgery and additional interventions. The patient's treatment began with rituximab, zanubrutinib, and dexamethasone with outpatient follow-up. The rarity of tracheobronchial amyloidosis and its connection to B-cell malignancies are highlighted, emphasizing the challenges in diagnosis and the importance of tailored treatment strategies. The patient's clinical course, characterized by atypical respiratory symptoms, delayed diagnosis, and an evolving treatment approach, underscores the complexities of managing such a rare and intricate case.

Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth.

Anti-multiple myeloma B cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies represent a promising treatment strategy with high response rates in myeloma. However, durable cures following anti-BCMA CAR-T cell treatment of myeloma are rare. One potential reason is that a small subset of minimal residual myeloma cells seeds relapse. Residual myeloma cells following BCMA-CAR-T-mediated treatment show less-differentiated features and express stem-like genes, including CD24. CD24-positive myeloma cells represent a large fraction of residual myeloma cells after BCMA-CAR-T therapy. In this work, we develop CD24-CAR-T cells and test their ability to eliminate myeloma cells. We find that CD24-CAR-T cells block the CD24-Siglec-10 pathway, thereby enhancing macrophage phagocytic clearance of myeloma cells. Additionally, CD24-CAR-T cells polarize macrophages to a M1-like phenotype. A dual-targeted BCMA-CD24-CAR-T exhibits improved efficacy compared to monospecific BCMA-CAR-T-cell therapy. This work presents an immunotherapeutic approach that targets myeloma cells and promotes tumor cell clearance by macrophages.

Three years of maintenance with VRD in multiple myeloma: results of total therapy IIIB with a 15-year follow-up.

ABSTRACT: The total therapy (TT) IIIB phase 2 study incorporated bortezomib into tandem melphalan-based hematopoietic stem cell transplantation with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide for induction/consolidation and bortezomib, lenalidomide, and dexamethasone (VRD) for maintenance in patients with newly diagnosed multiple myeloma (MM). This updated analysis presents a 15.4-year median follow-up. Of 177 patients, 21% patients had gene expression profile (GEP)-defined high-risk MM. 15-year progression free survival (PFS) was 27.9%. Median PFS was better in GEP-defined low-risk patients at 7.8 years and in International Staging System stage 1 patients at 8.7 years. Overall, median OS was 9.1 years, and 15-year overall survival (OS) was 35.9%. GEP-defined low-risk patients' median OS was 11.2 years, and that of GEP-defined high-risk patients was 2.8 years. There was no difference in OS between TT IIIB and TT IIIA. This study includes the longest follow-up of patients treated with maintenance VRD reported to date. In patients with GEP-defined low-risk, nearly half and one-third of patients without ongoing treatment showed no signs of progression at 10 and 15 years, respectively. One-third of patients survived more than 15 years, but 3 years of VRD maintenance did not improve outcomes for patients with GEP-defined high-risk MM. The study was registered on www.clinicaltrials.gov as #NCT00572169.

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.

BCMA- and CST6-specific CAR T cells lyse multiple myeloma cells and suppress murine osteolytic lesions.

We have previously demonstrated that cystatin E/M (CST6), which is elevated in a subset of patients with multiple myeloma (MM) lacking osteolytic lesions (OLs), suppresses MM bone disease by blocking osteoclast differentiation and function. CST6 is a secreted type 2 cystatin, a cysteine protease inhibitor that regulates lysosomal cysteine proteases and the asparaginyl endopeptidase legumain. Here, we developed B cell maturation antigen (BCMA) CST6 chimeric antigen receptor T cells (CAR-T cells), which lysed MM cells and released CST6 proteins. Our in vitro studies show that these CAR-T cells suppressed the differentiation and formation of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Using xenografted MM mice, bioluminescence images showed that both BCMA-CAR-T and BCMA-CST6-CAR-T cells inhibited MM growth to a similar extent. Reconstructed micro-computed tomography images revealed that BCMA-CST6-CAR-T cells, but not BCMA-CAR-T cells, prevented MM-induced bone damage and decreased osteoclast numbers. Our results provide a CAR-T strategy that targets tumor cells directly and delivers an inhibitor of bone resorption.

High NEK2 expression in myeloid progenitors suppresses T cell immunity in multiple myeloma.

Multiple myeloma (MM) growth is supported by an immune-tolerant bone marrow microenvironment. Here, we find that loss of Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) in tumor microenvironmental cells is associated with MM growth suppression. The absence of NEK2 leads to both fewer tumor-associated macrophages (TAMs) and inhibitory T cells. NEK2 expression in myeloid progenitor cells promotes the generation of functional TAMs when stimulated with MM conditional medium. Clinically, high NEK2 expression in MM cells is associated with increased CD8+ T effector memory cells, while low NEK2 is associated with an IFN-γ gene signature and activated T cell response. Inhibition of NEK2 upregulates PD-L1 expression in MM cells and myeloid cells. In a mouse model, the combination of NEK2 inhibitor INH154 with PD-L1 blockade effectively eliminates MM cells and prolongs survival. Our results provide strong evidence that NEK2 inhibition may overcome tumor immune escape and support its further clinical development.

EDNRA-Expressing Mesenchymal Cells Are Expanded in Myeloma Interstitial Bone Marrow and Associated with Disease Progression.

Multiple myeloma (MM) induces dysfunctional bone marrow (BM) mesenchymal cells and neoangiogenesis. Pericytes and smooth muscle cells (SMCs) could detach from vessels and become cancer-associated fibroblasts. We found that the pericyte and SMC marker endothelin receptor type A (EDNRA) is overexpressed in whole MM bone biopsies; we sought to characterize its expression. EDNRA expression gradually increased with disease progression. High-risk MM patients had higher EDNRA expression than low-risk MM patients and EDNRA expression was highest in focal lesions. High EDNRA expression was associated with high expression of pericyte markers (e.g., RGS5, POSTN, and CD146) and the angiogenic marker FLT1. A single-cell analysis of unexpanded BM mesenchymal cells detected EDNRA expression in a subset of cells that coexpressed mesenchymal cell markers and had higher expression of proliferation genes. Immunohistochemistry revealed that the number of EDNRA+ cells in the interstitial BM increased as MM progressed; EDNRA+ cells were prevalent in areas near the MM focal growth. EDNRA+ cells were detached from CD34+ angiogenic cells and coexpressed RGS5 and periostin. Therefore, they likely originated from pericytes or SMCs. These findings identify a novel microenvironmental biomarker in MM and suggest that the presence of detached EDNRA+ cells indicates disrupted vasculature and increased angiogenesis.

Necrotizing Enterocolitis in a Patient With Newly Diagnosed Multiple Myeloma and Hyperviscosity Syndrome: A Case Report.

Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterized by the abnormal increase of monoclonal paraprotein and can lead to specific end-organ damage. Necrotizing enterocolitis or bowel necrosis is a surgical emergency defined by cellular death because of reduced blood flow to the gastrointestinal tract. We report a case of a 75-year-old female who was diagnosed with hyperviscosity syndrome (HVS) and was sent to ED. Further workup showed that she had a new diagnosis of IgG kappa MM for which she was started on chemotherapy. Later, she developed respiratory distress and abdomen distention with less frequent bowel movements, and general surgery was consulted. CT scan of the abdomen and pelvis with contrast showed findings consistent with bowel ischemia vs infarction. The patient was immediately taken to the operating room, and exploratory laparotomy showed nonsurvivable bowel necrosis. She was transitioned to comfort care and passed away later. We aim to increase awareness among physicians to include HVS as one of the possible complications of MM and to detect it early to prevent morbidity and mortality.

Sixth Nerve Palsy From Multiple Myeloma in Central Nervous System: Case Series and Review of Current Literature.

We reported two cases of the central nervous system (CNS) multiple myeloma (MM) with unusual presentation of sixth nerve palsy. The first patient developed in the setting of newly diagnosed MM and the second patient in the relapsed refractory setting. One underwent surgery, and the other received radiation. Both patients received systemic chemotherapy and noted improvement. We also performed a comprehensive literature review of previously published cases of sixth nerve palsy from MM. This review highlights the importance of recognizing this presentation of CNS multiple myeloma to avoid delays in diagnosis and to get appropriate management in time.

Growth and dormancy control of myeloma cells by mesenchymal stem cells.

Bone marrow mesenchymal stem cells (MSCs) may have contrasting impacts on the progression of multiple myeloma (MM). Priming normal MSCs, by culturing them with MM cells, mimics the MSC-induced MM growth. We studied the contrasting effects of conditioned medium (CM) from unprimed or primed MSCs on growth of MM cells from newly diagnosed cases. We elucidated potential molecular pathways using global gene expression profiling and focused on the role of the mTOR2 component, RICTOR, as a novel mediator of dormancy in MM. Primed MSCs CM consistently increased proportions of proliferating cells and supported MM growth in 3-day (n = 20) and 10-day (n = 12) cultures, effects that were partially mediated through the IGF1 axis. In contrast, unprimed MSCs CM inhibited growth of MM cells in cases mainly from stages I/II MM. The genes most overexpressed in MM cells treated with primed MSCs CM were associated with cell cycle, DNA-damage repair, and proliferation; genes most overexpressed in MM cells treated with unprimed MSCs CM were associated with dormancy pathways including RICTOR (mTOR2 pathway), CXCR4, and BCL2. RICTOR protein level was induced by unprimed MSCs CM and was lower in KI67+ proliferating MM cells treated with primed MSCs CM. RICTOR was underexpressed in clinical relapse samples compared with baseline samples of the same patients. Inhibiting RICTOR expression in primary MM cells promoted their growth, and enforced expression of RICTOR in MM cell lines inhibited their growth. Our findings suggest that, after prolonged interactions with MM cells, bone marrow MSCs shift from MM-repressive to MM-permissive. AVAILABILITY OF DATA AND MATERIALS: Our institutional GEP data of MM cells from newly diagnosed patients used to show RICTOR expression have been deposited at Gene Expression Omnibus (GEO: GSE2658, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE2658).

Under-representation of black patients with multiple myeloma in studies supporting International Myeloma Working Group guidelines.

INTRODUCTION: Multiple myeloma (MM) is more common in Black persons when compared to non-Hispanic White persons. The International Myeloma Working Group (IMWG) provides consensus for diagnosis and treatment of MM. Our study aimed to assess the racial composition of supporting studies used by IMWG to publish their guidelines METHODS: We performed a cross sectional study that included all IMWG publications up to July 2022. References cited in each publication were reviewed. Review articles, comments, editorials, case reports, and animal-based studies were excluded. RESULTS: A total of 59 IMWG publications with 3956 references were reviewed. Final analysis included 2047 references of which 39 % (n = 804) were clinical trials, 35 % (n = 712) were observational studies, 20 % (n = 401) were diagnostic and or genetic testing-based studies, 3 % (n = 65) were population-based analysis and 3 % (n = 65) classified as others. Only 10.4 % of included references (n = 213/2047) reported race/ethnicity of studied patients. The total number of patients in all referenced studies were 5,747,920, only 2.6 % (n = 150,790) black patients. Of the trials referenced and done exclusively in the US, 41 out of 282 (14.5 %) reported race/ethnicity with a total number of patients of 38,050 of which 2493 (6.5 %) were black patients. CONCLUSION: IMWG guidelines were based mainly on studies that did not include enough Black patients. Guidelines should consider inclusion of observational, diagnostic and population-based studies with more black patients to allow for better reflection of disease prevalence, clinical characteristics and/or outcomes.

Concomitant deletion of the short arm (del(1p13.3)) and amplification or gain (1q21) of chromosome 1 by fluorescence in situ hybridization are associated with a poor clinical outcome in multiple myeloma.

BACKGROUND: Chromosome 1 abnormalities in multiple myeloma (MM) are increasingly recognized as high risk-defining features. The authors report the prognostic value of del(1p13.3) by fluorescence in situ hybridization (FISH) at enrollment in subjects treated on total therapy clinical trials 2-6. METHODS: FISH probes were generated from specific BAC DNA clones for the AHCYL1 gene locus (1p13.3) and the CKS1B locus (1q21). RESULTS: A total of 1133 patients were included in this analysis. Although del(1p13.3) was detected in 220 (19.4%) patients, 1q21gain or 1q21amp were observed in 300 (26.5%) and 150 (13.2%) patients, respectively. Concomitant del(1p13.3) with 1q21 gain or amp was observed in 65 (5.7%) and 29 (2.5%) patients, respectively. There was enrichment of high-risk features such as International Staging System (ISS) stage 3 disease and gene expression profiling (GEP)70 high risk (HR) in the group with del(1p13.3). Presence of del(1p13.3) confers inferior progression-free survival (PFS) and overall survival (OS). On multivariate analysis, the presence of ISS stage 3 disease, GEP70 HR, 1q21gain, and 1q21amp were independent predictors of PFS or OS. CONCLUSIONS: The PFS and OS of patients with combined abnormalities of del (1p13.3)/1q21gain or amp was significantly worse compared to del(1p13.3) alone and 1q21gain or 1q21 amp alone, which identifies a subset of patients with poor clinical outcomes.

A gene signature can predict risk of MGUS progressing to multiple myeloma.

Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS). Serum markers are currently used to stratify MGUS patients into clinical risk groups. A molecular signature predicting MGUS progression has not been produced. We have explored the use of gene expression profiling to risk-stratify MGUS and developed an optimized signature based on large samples with long-term follow-up. Microarrays of plasma cell mRNA from 334 MGUS with stable disease and 40 MGUS that progressed to MM within 10 years, was used to define a molecular signature of MGUS risk. After a three-fold cross-validation analysis, the top thirty-six genes that appeared in each validation and maximized the concordance between risk score and MGUS progression were included in the gene signature (GS36). The GS36 accurately predicted MGUS progression (C-statistic is 0.928). An optimal cut-point for risk of progression by the GS36 score was found to be 0.7, which identified a subset of 61 patients with a 10-year progression probability of 54.1%. The remainder of the 313 patients had a probability of progression of only 2.2%. The sensitivity and specificity were 82.5% and 91.6%. Furthermore, combination of GS36, free light chain ratio and immunoparesis identified a subset of MGUS patients with 82.4% risk of progression to MM within 10 years. A gene expression signature combined with serum markers created a highly robust model for predicting risk of MGUS progression. These findings strongly support the inclusion of genomic analysis in the management of MGUS to identify patients who may benefit from more frequent monitoring.

Variability of definition of high-risk multiple myeloma across phase III clinical trials.

The definition of high-risk multiple myeloma (HRMM) is evolving. Use of a clear definition of HRMM in clinical trials was not previously studied. We explored the definition of HRMM in completed phase III clinical trials. There is extreme variability in the definition and cutoffs used to define HRMM, with a significant number of studies lacking a clear definition. Our study provides a quantification of the variability in defining HRMM and suggests a need to better define HRMM in future clinical trials to enable more consistent treatment recommendations.

Risk of infections associated with the use of bispecific antibodies in multiple myeloma: a pooled analysis.

The use of bispecific antibodies (BsAbs) in the treatment of relapsed/refractory multiple myeloma (MM) is showing early promising overall response rates in heavily pretreated patients. Infectious complications related to the use of BsAbs are not well described. We conducted a pooled analysis that included all single-agent BsAbs used in MM with no prior use of different BsAbs. A total of 1185 patients with MM were treated with a BsAb in the studied period (71.6% of the patients treated with an agent targeting B-cell maturation antigen (BCMA). Pooled median follow-up was short at 6.1 months (7.5 vs 5.2 months for BCMA vs non-BCMA BsAbs, respectively). Adverse events of interest included all grade neutropenia in 38.6%, all grade infections in 50% (n = 542/1083), all grade cytokine release syndrome in 59.6% (n = 706/1185), grade III/IV neutropenia in 34.8% (n = 372/1068), grade III/IV infections in 24.5% (n = 272/1110), grade III/IV pneumonia in 10% (n = 52.4/506), and grade III/IV coronavirus disease 2019 in 11.4% (n = 45.4/395) of the patients. Non-BCMA-targeted BsAbs were associated with lower grade III/IV neutropenia (25.3% vs 39.2%) and lower grade III/IV infections (11.9% vs 30%) when compared with BCMA-targeted BsAbs. Hypogammaglobulinemia was reported in 4 studies, with a prevalence of 75.3% (n = 256/340) of the patients, with IV immunoglobulin used in 48% (n = 123/256) of them. Death was reported in 110 patients, of which 28 (25.5%) were reported to be secondary to infections. Certain precautions should be used when using BsAbs to mitigate the risk and/or identify and treat infections promptly.