Elisabet E. Manasanch, MD, associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses outcomes seen with elranatamab (PF-06863135) in patients with relapsed or refractory multiple myeloma.

Results from the phase 2 MagnetisMM-3 trial (NCT04649359) showed that among the 4 patients enrolled to the study who had received prior treatment with a BCMA-directed therapy, 3 of them still achieved a response with elranatamab, according to Manasanch. This provides further evidence that patients can receive previous treatment with a BCMA-targeted agent, such as belantamab mafodotin-blmf (Blenrep), and still respond to a subsequent BCMA-directed approach, Manasanch says.

Previously, it was not known whether utilizing a BCMA-directed approach after prior BCMA-directed therapy would lead to positive outcomes; however, it is becoming evident that these agents can be effectively sequenced, Manasanch concludes.

"We performed comprehensive testing of NAPRT at the gene expression level, the methylation level, and the protein level, and found that approximately 30% to 40% of patients also have loss of NAPRT expression. [Based on this, we think that NAPRT expression] could be a viable biomarker for [the efficacy of NAMPT inhibitors] going forward."

Juan Vasquez, MD, an assistant professor of Pediatrics (Hematology/ Oncology) and the associate program director of the Pediatrics Hematology/Oncology Fellowship at Yale School of Medicine, discussed research elucidating the potential predictive utility of NAPRT expression due to tumor-specific promoter CpG island methylation for successful responses to NAMPT inhibition in a subset of patients with pediatric rhabdomyosarcoma.

In a preclinical study, Vasquez and colleagues evaluated the role of NAPRT expression as a potential biomarker of sensitivity to NAMPT inhibitors. Approximately 50% of rhabdomyosarcoma models demonstrated loss of NAPRT expression, which conferred marked sensitivity to NAMPT inhibition, Vasquez began. In vitro, NAPRT-deficient cells exhibited profound cell death upon treatment with NAMPT inhibitors at nanomolar concentrations, whereas NAPRT-expressing cells were resistant, he detailed. Notably, the cytotoxic effect of NAMPT inhibitors in NAPRT-expressing models was reversed with the addition of nicotinic acid, suggesting the salvage pathway mediated by NAPRT functionally protects against NAD+ depletion, Vasquez explained.

This mechanistic relationship was validated in vivo using rhabdomyosarcoma mouse models, Vasquez continued. NAPRT-deficient tumors responded robustly to NAMPT inhibition, whereas co-administration of dietary nicotinic acid reversed this therapeutic effect in NAPRT-expressing models, he reported. These findings supported the hypothesis that NAPRT loss renders rhabdomyosarcoma cells dependent on the NAMPT-mediated salvage pathway for NAD+ synthesis, creating a selective vulnerability to NAMPT inhibition, he said.

To assess the clinical relevance of this biomarker, Vasquez and colleagues partnered with the Children’s Oncology Group to access tumor specimens from 109 pediatric patients with rhabdomyosarcoma previously enrolled on cooperative group trials. Comprehensive profiling of these samples—including gene expression, promoter methylation, and protein analysis—revealed that approximately 30% to 40% of tumors lacked NAPRT expression, Vasquez shared. These data suggest that NAPRT loss may be a clinically relevant biomarker to identify patients who are most likely to benefit from NAMPT-targeted therapies and inform the design of future biomarker-driven clinical trials in pediatric rhabdomyosarcoma, he concluded.

“This is a study we’ve been conducting for 7 years. It’s the only study of its kind. We have gone to [approximately] 150 sites in the United States, and we’ve [suggested to hematologists]: If you’re seeing a patient who has cytopenias and in whom you suspect a diagnosis of MDS, enroll them to this study. We received, through the generosity of patients, samples of their bone marrow, clinical data, and quality-of-life data.”

Mikkael A. Sekeres, MD, a professor of medicine and chief of the Division of Hematology in the Leukemia Section at the University of Miami Health System and Sylvester Comprehensive Cancer Center, discussed the design of a study investigating the association between smoking intensity, genetic mutations, and disease progression in patients with myelodysplastic syndrome (MDS). 

Sekeres explained that he and coinvestigators carried out a unique prospective cohort study to assess the relationship between smoking intensity/duration and the quantity/types of genetic mutations detected in patients diagnosed with MDS starting in June 2016. This study was led by Sangeetha Venugopal, MD, MS, of Sylvester Comprehensive Cancer Center. The investigators used prospective data from patients across approximately 150 sites in the United States who were enrolled in the National Heart, Lung, and Blood Institute MDS Natural History Study, Sekeres described. Hematologists were asked to consider enrollment to this study for patients with cytopenias and suspected MDS, he explained. Bone marrow samples, clinical data, and quality-of-life data were collected from 1898 enrolled patients, who were also followed over time, according to Sekeres.

Univariate analyses revealed that the total number of mutations was comparable between smokers and nonsmokers, including within specific disease categories, such as idiopathic cytopenia of undetermined significance, clonal cytopenia of undetermined significance, MDS, MDS/myeloproliferative neoplasm overlap syndrome, and acute myeloid leukemia. Nonetheless, the overall prevalence of mutations was higher in smokers than in nonsmokers, particularly for mutations in gene pathways for chromatin modification (smokers, 15% vs nonsmokers, 11%; P < .01) and RNA splicing (26% vs 19%; P < .001), as well as mutation in individual genes like ASXL1 (12% vs 8%; P < .01), SF3B1 (9% vs 6%; P < .05), U2AF1 (6% vs 3%; P < .05), and ZRSR2 (2% vs 1%; P < .05). Furthermore, multivariable regression models showed that after adjusting for sex, age, and disease group, the average number of mutations was significantly higher among smokers (2.0) vs nonsmokers (1.4; P = .04).