Food for Thought: Addressing a Research Gap for Dietary Trials in Hematologic Malignancies

Summary:

There is growing interest from both patients and clinicians in understanding the role nutrition plays across hematologic malignancies. In this study, we highlight key unanswered questions related to studying dietary interventions in hematologic malignancies, including questions about how to conduct research, trial design considerations, and integrating dietary interventions into hematologic cancer care and policy.

Introduction

The influence of diet on cancer, especially in hematologic malignancies, is historically underappreciated and poorly integrated into clinical care, given limited observational data. Addressing this knowledge gap is important, considering the increasing interest from clinicians and patients, along with the potential of diet to improve clinical outcomes. In this piece, we propose key research directions and outline critical considerations for testing dietary interventions in blood cancers.

Unanswered Questions

Although observational data can be hypothesis-generating, interventional trials are needed to elucidate mechanisms and confirm these effects on cancer outcomes in patients. Key areas for future investigation include defining optimal dietary patterns, understanding biological mediators such as the microbiome and metabolic pathways, and clarifying whether effects differ by disease subtype or treatment modality.

Metabolic disorders such as obesity and diabetes mellitus are associated with hematologic malignancy risk and survival (1). For example, obesity has been shown to increase the risk of progression of the multiple myeloma (MM) precursor state, monoclonal gammopathy of uncertain significance (MGUS), to MM by twofold (2). These metabolic disorders also contribute to chronic conditions such as cardiovascular disease and renal disease. As survival improves with newer therapies, long-term outcomes are increasingly influenced by these chronic comorbidities. In several hematologic malignancies, noncancer conditions represent a leading cause of mortality, highlighting the potential value of dietary and lifestyle interventions in survivorship care (3). Yet the relevance of addressing these metabolic disorders in certain blood cancer subtypes has not been fully elucidated.

Dietary patterns also directly affect microbiome health. Increased microbial diversity, levels of beneficial bacteria such as butyrate producers, and the production of metabolites such as short-chain fatty acids (including butyrate) could potentially have anticancer and anti-inflammatory effects, improve prognosis, and enhance response to immunotherapy. In MM, these features are associated with improved response [sustained minimal residual disease (MRD) negativity] and correlate with dietary flavonoids, as well as plant and seafood protein intake (4).

Designing Interventional Trials

There are several key factors to consider when designing rigorous interventional trials that explore the relationship between diet and hematologic cancers—participant selection, disease setting, type of pharmacologic therapy, clinical outcome endpoints, translational biomarker endpoints, type of dietary intervention, duration of intervention, and funding (Fig. 1). To date, there are limited interventional trials testing the effect of diet on cancer outcomes, with no phase III trials in hematologic cancers.

Figure 1.

Key considerations in designing dietary intervention trials in hematologic malignancies. This figure outlines the major trial design considerations for implementing dietary interventions in hematologic malignancies. Each domain (including participant selection, disease setting, type of therapy, clinical outcome endpoints, translational biomarker endpoints, type of intervention, duration, and funding) is depicted with key elements to consider branching from each category. Together, these considerations provide a framework for designing rigorous and clinically meaningful nutrition studies tailored to the specific challenges and opportunities in hematologic malignancies.

Participant Selection

Participant selection, using broad disease-specific criteria or targeting a specific clinical or socioeconomic subgroup within the disease, is an important consideration for interventional trials. Patients with higher baseline adiposity, insulin resistance, and inflammation may show greater biomarker changes. Microbiome-guided selection of participants may be challenging as real-time testing is not widely available. Cancer outcomes are closely linked to social determinants of health, and dietary quality is largely shaped by food availability and economic factors. Non-Hispanic Black and Hispanic populations bear a disproportionate burden of obesity, diabetes mellitus, and cardiovascular disease (5), driven largely by poor diets and food insecurity (6, 7). Recognizing external factors that may affect outcomes is essential, and studies should include diverse participants so that findings may be generalizable.

Disease Setting

Different phases of disease—prevention, survivorship, and treatment—present distinct opportunities, and tailoring trials to these phases can maximize clinical relevance.

Individuals with precursor conditions (i.e., MGUS, clonal hematopoiesis of indeterminate potential) offer the chance to study whether nutritional strategies can delay disease progression. For example, the NUTRIVENTION trial (NCT04920084) in 20 participants with MGUS and smoldering MM and an elevated body mass index (BMI) ≥25 kg/m² showed that a high-fiber, plant-based dietary (HFPBD) intervention reduced BMI, fasting insulin, and inflammation and increased the adiponectin–leptin ratio, microbiome α-diversity, and butyrate producers. Two participants had a slowing of the disease progression trajectory based on the rate of change of paraprotein before and after the intervention (8). This trial focused on a specific hematologic patient population with a metabolomic BMI cutoff with a primary feasibility endpoint of adherence and BMI reduction. It included multiple translational biomarker endpoints. The findings suggest that precursor conditions offer opportunities for interventions, moving beyond the traditional watchful waiting approach. A larger randomized trial, NUTRIVENTION3 (NCT05640843; n = 150), is ongoing in patients with MGUS and smoldering MM with all BMI categories being randomized to an HFPBD, curcumin and algae omega-3 supplements, or placebo supplements with a microbiome biomarker endpoint at 12 weeks.

Dietary interventions during active anticancer treatment can be more challenging but may help improve quality of life, decrease treatment-related toxicities, support cardiometabolic health, or enhance response to treatment. The IDEAL trial in adolescents and young adults (n = 40) demonstrated that a healthy, calorie-restricted diet following United States Department of Agriculture MyPlate guidelines and a moderate-intensity, home-based aerobic and resistance exercise intervention during induction chemotherapy in high-risk acute lymphoblastic leukemia (ALL) improved the primary endpoint of percentage change in fat mass (9).

Patients in survivorship settings may be more open to dietary changes due to a renewed focus on health after treatment. Beyond the direct impact on cancer-related mortality, there may be indirect benefits on noncancer mortality, particularly about cardiometabolic conditions and quality-of-life indicators such as fatigue, cognitive function, and mental health. In patients with MM, a dietary substudy of a maintenance therapy quality-of-life trial (NUTRIVENTION-4; NCT04497961) is evaluating the effect of an HFPBD on the microbiome while on maintenance daratumumab or lenalidomide therapy.

Type of Pharmacologic Therapy

When designing trials, it is important to consider the type and mechanism of treatment, as differing mechanisms may affect the potential of each therapy to synergize with diet, such as immunotherapies (checkpoint inhibitors, bispecific antibodies, monoclonal antibodies, or chimeric antigen receptor T cells), targeted therapies, chemotherapies, or transplantation. For example, in melanoma, higher dietary fiber intake was associated with longer progression-free survival among patients receiving immune checkpoint inhibitors, possibly mediated through favorable microbiome profiles (10). Building on this, the DIET study (NCT04645680) and a series of trials (PreFED) are currently underway to evaluate the impact of dietary fiber on immunotherapy outcomes in melanoma (NCT04778449, NCT06466434, NCT06548789). As checkpoint inhibitors and other immunotherapies are used to treat hematologic malignancies, these studies may serve as a model for future fiber-based dietary interventions in this patient population. There are insufficient data on the interaction between dietary patterns and commonly used chemotherapy regimens in hematologic malignancies, and this is an area that needs more research.

Clinical Outcome Endpoints

Clinical outcome endpoints in dietary intervention trials should be tailored to the disease setting and intervention timing. These may include incidence, time to progression, treatment response, relative dose intensity, treatment toxicity, progression-free and overall survival, and quality of life. Earlier-phase trials may prioritize feasibility, whereas later-phase studies should incorporate clinically meaningful endpoints. For example, MRD negativity has emerged as a valuable surrogate endpoint in hematologic malignancies such as MM and ALL. The IDEAL trial in ALL showed improved rates of MRD negativity compared with historical controls in a secondary analysis (9). Based on these results, a randomized phase II multicenter trial, IDEAL2 (NCT05082519; n = 240), is evaluating this same intervention for a primary endpoint of MRD-negativity rate and reduction in fat mass. In solid tumors, early results from the randomized DIET study evaluating a high-fiber diet in melanoma on checkpoint inhibitors suggest benefits in response and survival (11). These results raise the question of whether similar dietary strategies could enhance response in hematologic cancers.

Translational Biomarker Endpoints

Translational biomarker endpoints can serve as early indicators of dietary benefit. Dietary interventions may directly or indirectly lead to changes in metabolic markers (such as weight, body composition, insulin resistance, and lipid metabolism) and microbiome markers (such as gut microbiome diversity, function, and composition). These metabolic and microbiome changes could lead to changes in inflammatory/immune markers (such as C-reactive protein, cytokines, immune subsets, and neutrophil-to-lymphocyte ratio), affecting cancer therapy response and outcomes (8, 12). Therefore, biomarker endpoints are especially valuable as intermediate endpoints, providing mechanistic insights in which long-term clinical outcomes are impractical to assess due to small sample sizes, low event rates, or long latency periods.

Type of Dietary Intervention

The choice of intervention could be a dietary pattern (such as HFPBD, Mediterranean, vegetarian, ketogenic, low carbohydrate), a dietary food or supplement (such as dietary fiber, fermented foods, protein, or fruit and vegetable intake), or a reduction in calorie intake through calorie restriction, intermittent fasting, or fasting-mimicking diets. Although Mediterranean diets are a type of HFPBD, the focus on a dietary pattern from a specific region in the world may not be as inclusive to all races and communities. Ketogenic diets may be challenging for long-term adherence, cardiovascular side effects, and fat-free mass loss, which could be an issue for patients with cachexia (12). Intermittent fasting allows participants to eat within a narrow time window without changing their dietary pattern and, therefore, may have a less robust effect on translational biomarkers. The fasting mimicking diet is a very low-calorie, plant-based diet for 5 days with each cycle of chemotherapy, allowing patients to maintain their usual dietary pattern for the rest of the cycle. Changing a certain food group, such as increasing dietary fiber with resistant potato starch or inulin, can be easier for patients but may not have all the benefits of the vitamins, minerals, and flavonoids seen with improving dietary quality.

Another consideration is the way the intervention will be administered, whether by providing meals, food coupons, behavioral coaching through a dietitian, an app, or all of the above. It is very challenging to conduct a randomized dietary study with all meals provided to both arms, although the DIET study in melanoma was able to do this (11). In the NUTRIVENTION trials, most meals are provided to allow for some flexibility and the ability to begin changing behavior by cooking some meals. The usual care or control arm does not receive meals.

As with any dietary intervention, it is important to consider participants’ baseline diet quality and the feasibility of the implementation strategy. Trials that supply meals or dietary foods can improve adherence and control variability but may reduce generalizability and raise costs. However, it may be the best method to achieve scientific rigor and the desired effect quickly. In contrast, education-based approaches may be more scalable but often require greater support to achieve behavior change.

Conducting large dietary intervention trials presents several challenges. Isolating single food components often fails to reflect how people eat in real life, in which dietary elements are consumed in combinations and influenced by cultural, economic, and habitual patterns. This complexity can introduce heterogeneity to the data, making it difficult to find statistically significant observed effects of the intervention.

Adherence is another challenge, especially in cancer, in which treatment-induced gastrointestinal side effects may make adherence difficult. However, facing a grave diagnosis such as cancer may enhance motivation compared with the general population. Without intensive behavioral support, it can be difficult to sustain dietary changes over time, especially in large, multicenter trials with long-term clinical endpoints. In many studies, participants in the placebo arm may independently adopt elements of the intervention diet (a phenomenon known as “drop-in”), whereas participants in the intervention arm may fail to fully adhere, both of which can diminish the contrast between groups. These challenges, combined with the smaller effect sizes typically associated with nutrition interventions compared with pharmacologic therapies, necessitate much larger patient group sizes to detect meaningful clinical outcomes.

Past trials have also struggled due to their focus on individual food groups rather than broader dietary patterns and the use of long-term survival endpoints that may take years to mature. These limitations may partially explain the mixed findings of some prior dietary trials. Overcoming these challenges calls for strategic investment from institutions and funders to design trials that are appropriately powered, feasible to implement, and reflective of real-world behavior.

Duration of Intervention

Study duration should be established based on the disease setting and anticipated time to clinical outcomes. Disease settings that have low event rates for conversion to cancer from precancer, such as MGUS or clonal hematopoiesis of indeterminate potential, can make the sample size needed unfeasible. For example, if only 1% of MGUS patients progress to MM annually, trials assessing disease progression as an endpoint would require very long follow-up periods to detect meaningful changes. Survivorship settings for diseases with high cure rates and overall survival rates, such as Hodgkin lymphoma, will have similar challenges in designing studies with clinical endpoints. Longer-term endpoints such as survival require sustained dietary changes, whereas endpoints such as response, quality of life, and biomarker changes can be observed in a limited duration. Leveraging surrogate markers and intermediate outcomes may enhance trial feasibility in these settings.

Funding

Funding considerations also significantly determine study design. Conducting large-scale, well-controlled dietary intervention trials presents financial challenges. Beyond dietitian and staff costs for adherence and education, some trials also provide meals, which can add to the costs.

Dietary interventions may be less attractive to industry partners, such as pharmaceutical companies, as they do not offer the same potential for product development or financial return as pharmacologic therapies. One cost-effective strategy is to embed nutrition-related questions and endpoints into existing pharmaceutical trials, allowing researchers to gather valuable data without the need for standalone nutrition trials. Collecting dietary data or adding dietary intervention subgroups to pharmaceutical study protocols could be a method of evaluating the role of dietary practices in enhancing the efficacy of anticancer treatments (e.g., NUTRIVENTION4, which is a dietary interventional substudy to a pharmaceutical investigator–initiated clinical trial assessing quality of life with two pharmacologic maintenance therapies).

Food industry funding is possible, although small businesses often lack research budgets and may not meet trial regulations. Additionally, strict oversight and transparency are necessary to avoid conflicts of interest and ensure an unbiased study design and analysis that is not influenced by the funder.

Given these limitations in funding, public institutions, internal hospital grants, government agencies, and patient foundations/philanthropies can play a critical role in the progress of dietary intervention trials. Dietary interventions have the potential to improve public health, reduce healthcare costs, and address racial and socioeconomic disparities—goals that are directly aligned with the mission of many public health organizations, including the 2020 to 2030 Strategic Plan for NIH Nutrition Research. As such, strategic investment is justified and urgently needed.

Planning Considerations

Early stages of planning a dietary trial often involve identifying collaborators with expertise in nutrition, biostatistics, clinical trial methodology, and developing a good understanding of the disease biology and outcomes. Reviewing existing protocols on ClinicalTrials.gov or collaborating with investigators with dietary trial experience may make the intervention more feasible and help refine the research question. Utilizing institutional trial infrastructure built for interventional drug trials can help run the trial successfully. Low-resource observational studies, such as embedding dietary surveys, biospecimen collections, or substudies into active pharmaceutical trials, may be a small first step in this field. Freely available resources—such as American Institute of Cancer Research guidelines and American College of Lifestyle Medicine toolkits—may further support protocol development and patient education.

Integrating Diet into Hematologic Clinical Care

Research efforts should be accompanied by clinical integration, which presents its own barriers. A significant hurdle to this is a lack of formal nutrition training for physicians. Most US medical schools fail to provide significant nutrition education to students, leaving physicians underprepared to offer dietary guidance in clinical settings (13). More recently, a 2022 bipartisan resolution passed by the US House of Representatives called for meaningful nutrition education for health professionals, as there is growing recognition of nutrition’s role in reducing the current chronic disease burden (14).

Beyond training, physicians also face significant time constraints in their patient encounters to effectively implement dietary counseling. Within these time constraints, oncologists can acknowledge the importance of lifestyle changes and direct patients to existing nutrition resources from credible organizations, including cancer charities and registered dietitians. Oncologists may be the first to introduce the idea to patients that nutrition plays a role in the course of their disease state and overall health. This can empower patients and provide a sense of control, especially in cancer care, in which the internal locus of control is often greatly limited. There is also significant patient interest in such information to guide their management. A survey of 421 individuals with plasma cell disorders indicated that 82% of participants had questions about nutrition and only 23% felt their oncologist addressed it appropriately (15). Even in the absence of large phase III trials, oncologists can play a vital role by moving beyond vague messages such as “eat a balanced diet.” Instead, they can offer concrete, evidence-informed recommendations based on United States Department of Agriculture and American Institute of Cancer Research guidelines, such as aiming for at least 25 to 30 g/day of dietary fiber, consuming at least two servings of fruit and three servings of vegetables, and minimizing intake of sugar-sweetened beverages. Timely dietitian referrals also have the potential to support patient change.

Translating Evidence into Policy

Dietary interventions must be formally integrated into standard hematologic cancer care. Currently, nutrition is rarely included in treatment protocols. As the body of evidence grows, major medical societies, including the American Society of Hematology and the European Hematology Association, could establish consensus guidelines to legitimize the role of nutrition in hematology and promote adoption in clinical practice.

Translating nutrition research into policy requires collaboration between healthcare institutions, government agencies, and medical organizations. Although research continues to uncover the role of diet in disease risk and progression, the implementation of nutrition-focused policies remains inadequate, leaving providers and patients without access to evidence-based dietary support. Addressing this gap will require strategic efforts in funding allocation, insurance coverage, and healthcare policy to facilitate the connection between scientific discovery and clinical application.

In this respect, Oklahoma’s Food is Medicine Act (Senate Bill 806) is the first of its kind, incentivizing Medicaid providers to offer medically tailored meals and produce prescriptions for individuals managing chronic conditions. Nationally, the proposed Medical Nutrition Therapy Act aims to expand Medicare coverage for nutrition services to include conditions like cancer, which would improve access and strengthen clinical implementation. Routine nutrition screening in hematology clinics can help identify high-risk individuals early. Additionally, strengthening federal and community-based food assistance programs, such as the Supplemental Nutrition Assistance Program and the Special Supplemental Nutrition Program for Women, Infants, and Children, could improve access to healthy, nutritious diets for people with cancer facing food insecurity and address disparities. Hospital-led nutrition initiatives, including subsidized meal programs, could further support patients with food insecurity by ensuring that cost does not remain a barrier to following dietary recommendations.

Conclusion

Although historically overlooked in hematologic malignancies, nutrition is gaining increased attention as evidence suggests it may influence disease risk, progression, treatment response, and survivorship. Although observational data have laid the foundation, there is a need for well-designed interventional trials that assess clinically meaningful outcomes and explore mechanisms such as metabolic health and the microbiome. Embedding dietary endpoints into existing trials and pursuing innovative, collaborative trials can help expand the evidence base in a cost-effective manner. Oncologists and the broader care team should provide clear, actionable nutrition guidance and engage dietitians, recognizing the growing impact of diet-related comorbidities. It is also essential to address disparities in access to nutritious foods, which contribute to unequal outcomes. Advancing nutrition as a pillar of care requires coordinated research, practice, and policy efforts.

Authors’ Disclosures

U.A. Shah reports grants from the Leukemia Lymphoma Society, NIH/NCI Cancer Center Support Grant (P30CA008748), American Society of Hematology, Gabrielle’s Angel Foundation, Paula and Rodger Riney Foundation, Willow Foundation, and HealthTree Foundation during the conduct of the study as well as grants and personal fees from Bristol Myers Squibb and Janssen, personal fees from Sanofi and i3 Health, and nonfinancial support from Sabinsa and M&M Labs outside the submitted work. No disclosures were reported by the other authors.