Showing papers by "Thomas Martin published in 2023"

Systemic Light Chain Amyloidosis, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Abstract: Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study

Abstract: Longer-term outcomes with the anti-CD38 antibody isatuximab in combination with carfilzomib-dexamethasone (Isa-Kd) were evaluated in the randomized Phase 3 trial IKEMA (NCT03275285), in a prespecified, follow-up analysis of progression-free survival (PFS, primary study endpoint), final complete response (CR) using Hydrashift Isa immunofixation assay, minimal residual disease (MRD) negativity, and safety. Enrolled patients had relapsed/refractory multiple myeloma (1-3 prior treatment lines). Isa 10 mg/kg was administered intravenously weekly in cycle 1 then biweekly. Efficacy analyses were performed in the intent-to-treat population (Isa-Kd: n = 179, Kd: n = 123) and safety evaluated in treated patients (Isa-Kd: n = 177, Kd: n = 122). Consistent with the primary interim analysis, the addition of Isa to Kd prolonged PFS (HR 0.58, 95.4% CI: 0.42-0.79; median PFS 35.7 [95% CI: 25.8-44.0] vs 19.2 [95% CI: 15.8-25.0] months). PFS benefit was observed with Isa-Kd across subgroups, including patients with poor prognosis. The stringent CR/CR rate was 44.1% vs 28.5% (odds-ratio: 2.09, 95% CI: 1.26-3.48), the MRD negativity rate 33.5% vs 15.4% (odds-ratio: 2.78, 95% CI: 1.55-4.99) and the MRD negativity CR rate 26.3% vs 12.2%, with Isa-Kd vs Kd. The safety profile of Isa-Kd was similar to that reported in the prior interim analysis. These findings further support Isa-Kd as a standard-of-care treatment for relapsed multiple myeloma patients.Clinical trial information: ClinicalTrials.gov, NCT03275285.

Plain language summary of the MajesTEC-1 study of teclistamab for the treatment of people with relapsed or refractory multiple myeloma.

Abstract: WHAT IS THIS SUMMARY ABOUT? This is a summary of a phase 1-2 clinical trial called MajesTEC-1. This trial tested the cancer drug teclistamab in people with relapsed or refractory multiple myeloma, a cancer that forms in a certain type of white blood cells known as plasma cells. Most participants who took part in the study had at least 3 prior treatments for multiple myeloma before their cancer came back. HOW WAS THE STUDY IN THIS SUMMARY CONDUCTED? A total of 165 participants from 9 countries were included in this study. All participants were given teclistamab once per week and monitored for side effects. Once participants started taking teclistamab, they were checked regularly to monitor if their cancer had no change, improved (responded to treatment), or worsened or spread (known as disease progression). WHAT WERE THE RESULTS OF THE STUDY? After approximately 14.1 months of follow-up (from 2020 to 2021), 63% of participants who were given teclistamab had a decrease in myeloma burden, meaning that they responded to treatment with teclistamab. Participants who responded to teclistamab lived without their myeloma coming back for approximately 18.4 months. The most common side effects were infections, cytokine release syndrome, abnormally low white and red blood cell counts (neutropenia, lymphopenia, and anemia), and low platelet cell counts (thrombocytopenia). Approximately 65% of participants experienced serious side effects. WHAT DO THE RESULTS OF THIS STUDY MEAN? Overall, more than half of the participants (63%) in the MajesTEC-1 study responded to treatment with teclistamab despite previous myeloma treatment failures. Clinical Trial Registration: NCT03145181, NCT04557098 (ClinicalTrials.gov).

Human Bone Marrow Plasma Cell Atlas: Maturation and Survival Pathways Unraveled by Single Cell Analyses

Abstract: Human bone marrow (BM) plasma cells are heterogeneous, ranging from newly arrived antibody-secreting cells (ASC) to long-lived plasma cells (LLPC). We provide single cell transcriptional resolution of 17,347 BM ASC from 5 healthy adults. Fifteen clusters were identified ranging from newly minted ASC (cluster 1) expressing MKI67 and high MHC Class II that progressed to late clusters 5-8 through intermediate clusters 2-4. Additional clusters included early and late IgM-predominant ASC of likely extra-follicular origin; IFN-responsive; and high mitochondrial activity ASC. Late ASCs were distinguished by differences in G2M checkpoints, MTOR signaling, distinct metabolic pathways, CD38 expression, and utilization of TNF-receptor superfamily members. They mature through two distinct paths differentiated by the degree of TNF signaling through NFKB. This study provides the first single cell resolution atlas and molecular roadmap of LLPC maturation, thereby providing insight into differentiation trajectories and molecular regulation of these essential processes in the human BM microniche. This information enables investigation of the origin of protective and pathogenic antibodies in multiple diseases and development of new strategies targeted to the enhancement or depletion of the corresponding ASC. One Sentence Summary: The single cell transcriptomic atlas of human bone marrow plasma cell heterogeneity shows maturation of class-switched early and late subsets, specific IgM and Interferon-driven clusters, and unique heterogeneity of the late subsets which encompass the long-lived plasma cells.

#6402 impact of daratumumab and belatacept on hla antibodies in kidney transplant candidates with 100% cpra: early results of attain (itn090st)

Abstract: Despite high allocation priority, <10% of kidney transplant candidates with cPRA 100% can find a compatible donor. Current desensitization strategies are ineffective due to antibody rebound. Adding costimulation blockade to plasma cell (PC) depletion prevents antibody rebound in nonhuman primates by countering nodal B cell and Tfh expansion. ATTAIN is a pilot, phase I/II trial of daratumumab, a CD38 mAb used in multiple myeloma, plus belatacept, a high affinity CTLA4-Ig, to desensitize kidney transplant candidates with cPRA ≥99.9%. Enrolled subjects receive daratumumab (6 doses: 8 mg/kg) and belatacept (4 doses: 10 mg/kg) over 10 weeks with bone marrow and blood assessments pre-and post-treatment. The primary efficacy endpoint (PE) is a composite of (1) elimination of ≥1 HLA antibody specificity, (2) ≥50% reduction in the MFI of ≥3 HLA antibody specificities, or (3) kidney transplant from a previously incompatible donor. Target accrual is 15, enrolled in 2 cohorts (5+10). Cohort 1 (n = 5, mean age 44, 60% with previous transplant) has been enrolled and treated, with 5-31 weeks follow-up to date. The treatment was tolerated well in all 5 patients who showed a significant reduction in most HLA antibodies after treatment without manifestation of rebound. 3 of 5 participants reached the PE and 5 of 5 had >50% bone marrow (BM) PC depletion. One patient received a kidney transplant from a previously incompatible deceased donor and is doing well at 7 months post-transplant without rejection or rebound of HLA antibody. Treatment was temporarily paused in 3 subjects due to AEs (acute cholecystitis and COVID, upper GI bleed, fevers); no cases of opportunistic infection or malignancy occurred. A novel HLA desensitization regimen consisting of PC depletion with Daratumumab and costimulatory blockade with Belatacept appears safe and successful in the ongoing ATTAIN clinical trial. In the initial subject, this regimen led to transplant without HLA antibody rebound or acute rejection. Longer follow-up and additional subjects are needed to confirm these promising results. ATTAIN (NCT04827979) is a trial conducted by the Immune Tolerance Network and sponsored by NIAID (award UM1AI109565).

Disease Monitoring In Multiple Myeloma.

Abstract: The outcome for multiple myeloma (MM) patients has significantly improved in the last two decades, mainly due to the use of novel drugs with a singular mechanism of action, including immunotherapy. This has sparked a new debate about the possibility of curing a substantial proportion of MM patients which implicitly entails the need for most sensitive tools for evaluating treatment efficacy and disease monitoring (minimal residual disease –MRD) both at the Bone marrow (BM) level (next generation flow cytometry (NGF) and sequencing) and outside of the BM (magnetic resonance imaging [MRI]/positron emission tomography [PET] computed tomography [CT], mass spectrometry)

Plain language summary of the CARTITUDE-1 study of ciltacabtagene autoleucel for the treatment of people with relapsed or refractory multiple myeloma.

Abstract: WHAT IS THIS SUMMARY ABOUT? This is a summary of a clinical study called CARTITUDE-1. This study tested the anti-cancer chimeric antigen receptor-T cell (CAR-T) therapy ciltacabtagene autoleucel, abbreviated as cilta-cel, in people with multiple myeloma, a cancer that affects a specific type of blood cell called plasma cells. The participants in this study had relapsed or refractory disease, which means that their cancer did not improve or returned after 3 or more previous anti-cancer treatments. HOW WAS THE STUDY IN THIS SUMMARY CONDUCTED? Ninety-seven participants went through the treatment process, which included collecting participants' own T cells (a type of immune cell), genetically modifying those T cells to recognize a certain protein found on myeloma cancer cells, pretreating with chemotherapy to prepare the participant's immune system to accept the modified T cells (cilta-cel), and finally injecting cilta-cel. WHAT WERE THE RESULTS OF THIS STUDY? Ninety-eight percent of participants showed decreases in indicators of cancer after treatment with cilta-cel. Seventy percent of participants were still alive approximately 28 months after treatment, and 55% of participants were still living without their cancer getting worse. The most common side effects were low blood cell levels, infections, cytokine release syndrome (a potentially serious side effect caused by overactivation of the immune system), and side effects that involved the nervous system (called neurotoxicities). Some participants experienced late-onset symptoms of neurotoxicity like the signs and symptoms of parkinsonism, meaning that they affected people's movement. Improvements in recognition of factors that increase the risk of these late-onset neurotoxicities and strategies to help avoid them has reduced their occurrence, although long-term monitoring for side effects is still an important part of treatment. WHAT DO THE RESULTS OF THE STUDY MEAN? Overall, almost all participants treated with cilta-cel had long-term reductions in signs of myeloma, and the majority of participants were alive and had no detectable signs of cancer over 2 years after being injected with cilta-cel. Clinical Trial Registration: NCT03548207 (1b/2 CARTITUDE-1 study) NCT05201781 (Long-term Follow-up Study for Participants Previously Treated With Ciltacabtagene Autoleucel).