Michael L. Grossbard, MD, and Rabi Upadhyay, MD, Instructor, Department of Medicine at NYU Grossman School of Medicine, discuss the qualities that make someone a great mentor for an oncology fellow.

Grossbard is professor in the Department of Medicine at NYU Grossman School of Medicine, chief, Hematology and Medical Oncology Inpatient Service, Tisch Hospital, and section chief of hematology, at NYU Langone Health's Perlmutter Cancer Center.

Upadhyay is an instructor in the Department of Medicine at NYU Langone Health's Perlmutter Cancer Center.

In this segment, Grossbard discusses how someone can be an exceptional mentor for an oncology fellow throughout their training.

"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).

"The most pressing question we have right now is the use of CAR T-cell therapy for patients at their first relapse. I don’t believe there is uniformity in opinion in terms of what to do because some [clinicians] still want to see more data and to better understand the risk of certain toxicities, particularly the long-term toxicities."

Rafael Fonseca, MD, director for Innovation and Transformational Relationships, at Mayo Clinic, discussed factors that he considers when selecting a treatment for patients with relapsed/refractory multiple myeloma.

In prior years, understanding the entire possible sequence of therapy was a focus with respect to treatment selection, but now the priority has become selecting the best treatment possible, Fonseca began. This is partially due to the benefit of treatment and duration of response decreasing with each subsequent line of therapy, he continued.

Additionally, with each line of therapy that is given, there is a portion of patients who do not go on to receive more treatment, Fonseca noted. This is frequently due to disease progression, death, or treatment toxicity, he said. Therefore, although reserving certain therapies for later seems logical, this rate of attrition must be factored into treatment selection decisions, he said.

Fonseca noted that a major question that remains is the role of CAR T-cell therapies for patients at their first relapse. In April 2024, the FDA expanded the approval of ciltacabtagene autoleucel (cilta-cel; Carvykti) to include patients with relapsed/refractory multiple myeloma who received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide (Revlimid). The regulatory decision made the agent the first BCMA-targeted therapy approved for the treatment of patients with multiple myeloma as early as first relapse. Data from the phase 3 CARTITUDE-4 study (NCT04181827), which supported the approval, demonstrated that patients who received cilta-cel experienced a 59% reduction in the risk of disease progression or death compared with standard-of-care treatments.

Some investigators are still waiting for additional data and want to better understand the potential toxicities of CAR T-cell agents in the first-relapse setting, Fonseca said. However, the benefit of these therapies in this setting, particularly in terms of progression-free survival and patient quality of life, are notable, he concluded.

"What often occurs is that patients do well [as they receive] venetoclax for the designated 1- to 2-year treatment period, but [they] experience disease progression after completing therapy. The challenge is how to define treatment failure in this context. With venetoclax, it can be a bit challenging to define failure, and as a CLL community, I don't think we have standard definitions for failure yet in that setting.”

Nitin Jain, MD, a professor of medicine in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the current challenges in defining venetoclax (Venclexta) failure in chronic lymphocytic leukemia (CLL) and highlighted the need for consensus within the CLL community to guide clinical practice and research.

Unlike BTK inhibitors, which are administered continuously, venetoclax is typically given as part of a time-limited regimen, often in combination with agents such as obinutuzumab (Gazyva) or rituximab (Rituxan) for a fixed duration of 1 to 2 years, Jain explained. He noted that disease progression with BTK inhibitors is generally easier to identify, as disease progression during active therapy—evidenced by rising lymphocyte counts or lymphadenopathy—can serve as a clear reflection of treatment resistance. However, ambiguity can arise when patients discontinue BTK therapy due to intolerance and later experience disease progression. In these cases, it is important to distinguish true resistance from progression following intolerance, Jain explained.

In contrast, defining failure on venetoclax-based regimens remains more complex, he continued. Since venetoclax is administered as a fixed-duration therapy, patients often complete and remain off treatment until disease progression.

Jain highlighted the clinical uncertainty surrounding whether relapse occurring after treatment completion constitutes true venetoclax failure. Some clinicians propose that a relapse within 1 to 2 years of discontinuation should be considered venetoclax failure, although Jain cautions that this remains an informal framework without standardized criteria.

Jain concluded by noting that the lack of a universally accepted definition of venetoclax failure complicates treatment sequencing and clinical trial eligibility. Without clarity on what constitutes venetoclax failure, it becomes difficult to compare outcomes across studies or determine optimal salvage strategies.

"The first question we ask is, ‘Is this patient a transplant candidate?’ We ask that based on a variety of factors,mostly the patient's overall health status, and it often has less to do with molecular characteristics of the disease than other health characteristics of the patient globally."

Jeffrey Zonder, MD, leader of the Multiple Myeloma Sub-Committee at Barbara Ann Karmanos Cancer Institute and professor of medicine in the Department of Hematology and Oncology at Wayne State University School of Medicine, discussed the role of personalized medicine in the treatment of multiple myeloma, emphasizing the importance of individualizing therapy based on patient-specific characteristics.

One of the initial decisions in the treatment algorithm is determining whether a patient is eligible for autologous stem cell transplant (ASCT), Zonder explained. This decision is primarily informed by the patient’s overall health status, functional reserve, and comorbid conditions, rather than the molecular features of the disease. Factors such as age, cardiac function, renal function, and performance status are critical in guiding the intensity of frontline treatment.

In addition to transplant eligibility, treatment selection often incorporates a patient’s comorbidities and medication tolerance, Zonder continued. For example, in patients with preexisting peripheral neuropathy—particularly from diabetes—bortezomib (Velcade) may be avoided or dose-reduced to limit neurotoxicity. Similarly, in patients with a history of fluid retention, dexamethasone doses may be modified to minimize treatment-related complications.

Zonder also addressed how risk stratification influences maintenance strategies. Although not always defined by a single genetic alteration, patients with high-risk cytogenetics or clinical features may benefit from intensified maintenance regimens. In these cases, clinicians may opt for doublet or triplet maintenance approaches, rather than a single-agent therapy, to achieve deeper and more durable remissions.

Personalized medicine in multiple myeloma encompasses more than genomic profiling, Zonder emphasized. It requires a holistic assessment of the patient’s clinical status, comorbidities, treatment preferences, and tolerability. This approach ensures that therapeutic decisions are tailored to each patient's unique clinical context and long-term goals of care.

"In our model of pancreatic cancer, the KRAS(ON) multiselective inhibitor shrank the tumors in an unprecedented way. [Additionally], in animals where we have eliminated the key elements of the immune system—the T cells—the effect [of this approach] is lessened. Finally, we found that by adding immune therapies…to KRAS inhibition, the tumor regressions were deeper."

Robert Herman Vonderheide, MD, DPhil, director of the Abramson Cancer Center and the John H. Glick Abramson Cancer Center Professor at Penn Medicine, discussed preclinical data supporting the role of the adaptive immune system in enhancing the antitumor efficacy of RAS(ON) multi-selective inhibitors in pancreatic ductal adenocarcinoma (PDAC).

RAS(ON) multi-selective inhibitors, including agents such as RMC-6236 and RMC-7977, target the active, GTP-bound state of both mutant and wild-type RAS isoforms and have demonstrated potent antitumor activity in PDAC murine models. In a series of studies using immunocompetent mouse models of PDAC, Vonderheide and colleagues investigated whether the adaptive immune system is required for the full therapeutic effect of these inhibitors.

The findings revealed 3 primary observations, according to Vonderheide. First, treatment with KRAS(ON) multi-selective inhibitors resulted in marked tumor regression, with effects more profound than previously observed in laboratory models. Second, in mice lacking T cells, the antitumor efficacy of KRAS inhibition was significantly diminished, indicating that T cells contribute meaningfully to therapeutic response. Third, the addition of immune-based therapies, including checkpoint blockade, enhanced the depth and durability of tumor regressions. In some cases, mice achieved complete and sustained remissions even after discontinuation of the KRAS inhibitor, suggesting an immunologic memory response.

These preclinical findings suggest that the antitumor activity of RAS(ON) multi-selective inhibitors is, at least in part, immune mediated. Vonderheide noted that these results support the clinical evaluation of RAS(ON) inhibitors in combination with immunotherapy for patients with PDAC. Clinical trials evaluating agents like RMC-6236 are currently underway, including a phase 1/1b study (NCT05379985) of RMC-6236 in patients with KRAS G12-mutant solid tumors.