Multiple myeloma (MM) is the second most common hematologic malignancy in the United States and is preceded by well-defined precursor conditions called monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) [1,2]. MGUS and SMM are asymptomatic conditions that have an annual progression rate to overt MM of 1% and 10%, respectively, but can be as high as 58% in 20 years in certain risk groups [3,4]. Despite the increasingly strong interest in intervening at the precursor stage for the early interception and prevention of MM, safe and cost-effective interventions are lacking. Although clinical trials have shown that earlier initiation of anti-MM therapies at the precursor stage (eg, lenalidomide-based regimen for high-risk SMM [5]) may alter the natural disease course and improve survival [5,6], early treatment remains highly controversial due to high costs and toxicity risks to patients, limiting its use to only a subset of patients at the highest risk strata [7-10].

Lifestyle interventions targeting excess adiposity and metabolic health in precursor patients may have an important role in MM prevention. Obesity is a well-established, potentially modifiable risk factor of MM [11], and there is accumulating evidence that obesity may also increase the risk of MGUS and its progression to overt MM [12-14]. Although current dietary and weight control guidelines for cancer prevention focus largely on calorie restriction and optimizing intake of specific food groups [15], challenges related to their integration into individuals’ daily lives for a sustained period of time remain a consideration [16-19]. Time-restricted feeding, a form of intermittent fasting whereby ad libitum energy consumption is constrained to a window of time (typically between 4 and 12 hours daily), may be a simple, feasible alternative for weight loss and cancer risk reduction [16,20]. When food intake timing occurs during the wake phase of the 24-hour day, time-restricted feeding may benefit metabolic health and cancer risk by synchronizing feeding-fasting regimens with daily circadian rhythms, which, in turn, improve oscillations in the circadian clock expression of numerous genes important for glucose metabolism and overall cellular homeostasis (eg, autophagy and DNA damage repair) [16,21,22].

The PROlonged nightly FASTing (PROFAST) study is a randomized controlled pilot trial investigating the clinical benefit of a 4-month prolonged nightly fasting regimen in individuals with overweight or obesity with MGUS, those with SMM, and those with smoldering Waldenström macroglobulinemia (SWM). The intervention is supported by evidence that prolonged nighttime fasting is not only a simple and sustainable behavior change [16,23] but also improves metabolism and body weight regulation [24-29]. Here, we describe the study design, rationale, and framework for assessing the potential clinical significance of a low-risk, cost-effective lifestyle intervention in patients with MM precursor conditions.

The PROFAST Study was funded in June 2022. Participant recruitment commenced in April 2023, after developing and testing the text messaging system. As of July 2023, a total of 6 participants consented to the study. The study is expected to be completed by April 2024, and data analysis and results are expected to be published in the first quarter of 2025.

The PROFAST study provides important preliminary data regarding the impact of prolonged nightly fasting on body composition, bone marrow adipose tissue, and biomarkers of tumor burden (SPEP/IFX and SFLCs) in patients with MM precursor conditions, thereby generating hypotheses on how targeting obesity-related mechanisms of carcinogenesis may help prevent MM development.

Obesity is a well-established, potentially modifiable risk factor of MM [11], and there is accumulating evidence that obesity may also increase the risk of MGUS and its progression to overt MM [12-14]. A study of 3 large prospective cohorts of US-based adults followed over 5 million person-years observed a 17% increase in MM risk per 5 kg/m² increase in BMI [36]. In another study of 7818 patients with MGUS in the US Veterans Health Administration database, being overweight and obese were associated with an increased risk of transformation to MM (hazard ratio [HR] for overweight 1.55, 95% CI 1.16-2.06; HR for obesity 1.98, 95% CI 1.47-2.68) [12]. Concordant with these findings, a more recent analysis of patients with MGUS identified through a population-based screening study in Olmstead County, Minnesota, between 1995 and 2003 observed that having a BMI ≥25 was also associated with increased progression to MM or other plasma cell or lymphoid disorders in univariate analysis (HR 2.14, 95% CI 1.05-4.36) and in a multivariable model accounting for clinical factors [13].

These epidemiological studies are supported by mechanistic evidence that obesity may lead to chronic low-grade inflammation and dysregulation of endogenous growth factors linked to myelomagenesis [76,77], together suggesting that weight control may be an effective MM prevention strategy. Indeed, according to a compelling 2016 consensus statement, an expert panel convened by the International Agency for Research on Cancer concluded that there is sufficient mechanistic evidence that a preventative relationship has been established between the “absence of body fatness” and MM [76]. In obesity, adipose tissue, including adipocytes in the bone marrow, is altered in ways that may promote carcinogenesis, including by creating an unfavorable tumor microenvironment in which MM can engraft and grow [44,78]. Notably, the adipose tissue of obese individuals leads to excess free fatty acids as well as altered levels of proinflammatory cytokines (eg, tumor necrosis factor α and interleukin 6), adipokines (eg, adiponectin and leptin), and metabolic peptide hormones (eg, insulin and insulin-like growth factor 1) [44,78,79]. Dysregulated levels of these biological compounds may fuel tumor initiation and influence the genetic characteristics of MM cells in ways that increase cell proliferation [80], reduce apoptosis [81], and contribute to immune cell evasion [82,83]. The implication of these factors is that weight loss may curb the contribution that excess adiposity-associated chronic inflammation and metabolic dysregulation have on MM development.

Beyond weight loss, the PROFAST study tests the hypothesis that “when we eat,” not just “what or how much we eat,” is relevant to cancer prevention [24,25,84,85]. There is evidence suggesting that chronic exposure to circadian rhythm disturbances may lead to metabolic dysregulation, upregulation of proinflammatory cytokines, and abnormal cell proliferation [21,86]. As food intake contributes to the setting of circadian clock rhythms in peripheral organs, such as by inducing changes in body temperature and through the action of hormones such as insulin and nutrient-sensing enzymatic and nuclear receptor signaling systems [21,87], the synchronization of feeding-fasting patterns with circadian rhythms may be important for preventing chronic diseases [24,26,27]. This hypothesis is supported by a large prospective study of patients with early-stage breast cancer, which observed that a short nightly fasting duration (<13 hours per night), compared with a nightly fasting of ≥13 hours, was associated with an increased risk of breast cancer recurrence [25]. In that same study, each 2-hour increase in the nightly fasting duration was associated with lower hemoglobin A_1c levels and a longer duration of nighttime sleep [25]. These findings are consistent with the results of population-based studies [24,26,27], including a large case-control study in Spain that observed that diurnal eating patterns, specifically in maintaining longer time intervals between the last meal of the day and initiation of sleep, were inversely associated with risk of breast and prostate cancer [27]. Similarly, two US-based studies of 2009-2010 National Health and Nutrition Examination Survey data evaluating biomarkers of breast cancer risk observed that a longer duration of nighttime fasting was associated with improved measures of glycemic control and systemic inflammation [24,26], aligning with pathophysiological mechanisms underlying cancer risk [76].

Results from these human observational studies are consistent with rodent studies demonstrating that mice subjected to a time-restricted (16-hour) fasting regimen of a high-fat diet during the sleep phase were protected against weight gain, abnormal glucose metabolism, and inflammation, all of which were associated with cancer outcomes [22,88-91]. Notably, protective effects were observed despite these mice having the same caloric intake as those that had ad libitum access to food and ate frequently throughout day and night [22], suggesting that the beneficial effects of this fasting regimen were partly mediated through mechanisms independent of calorie restriction. Together, these data provide a strong basis of our intervention aimed to curb the inflammatory and metabolic mechanisms shown to contribute to myelomagenesis [44,77].

Finally, and importantly, prolonged nightly fasting represents a lifestyle modification that is safe, practical, and acceptable for patients who otherwise are managed by a “watchful waiting” strategy. Patients with MM precursor conditions are reported to have diminished quality of life, increased comorbidities, and heighted anxiety and a sense of loss of control regarding their MM risk [61,62,92,93]. There is, therefore, a need to identify lifestyle-based interventions that patients can safely and practically adopt into their daily lifestyles and ultimately help curb disease progression. Fasting, as a practice, developed independently among different people groups and religions (eg, Ramadan in Islam) around the world [94], and intermittent fasting has become one of the most common dietary patterns reported in the United States [95]. Prolonged nightly fasting is attractive because of its simplicity and feasibility, as supported by evidence from clinical trials of time-restricted eating strategies [16,23], and, thus, may be a potentially effective disease prevention strategy at the population level [16].

The limitations of this study include the relatively small sample size of the study and the potential lack of sociodemographic and geographic diversity of participants due to recruitment occurring at a single academic institution, thus, possibly impacting generalizability of findings. Also, participants willing to participate in a 4-month prolonged overnight fasting intervention may not be representative of the general population of patients with overweight or obesity with MM precursors, and selection bias for patients who are motivated to participate in PROFAST could increase the study adherence rate. Furthermore, although participants in the intervention group are prescribed solely a prolonged overnight fasting regimen with no other recommendations regarding lifestyle patterns, it is theoretically possible that participants may change their dietary, physical activity, and sleep habits due to paying closer attention to the timing of their eating and evaluations of their body composition before and after the intervention. These changes may also impact outcomes.

In summary, the study described herein serves as an important first step in exploring the premise that prolonged nightly fasting is a practical, effective strategy to control obesity and intercept disease progression in individuals with MM precursor conditions. By evaluating the impact of this lifestyle intervention on relevant biomarkers of excess adiposity and myeloma tumor burden, this pilot study may generate hypotheses and inform further investigations in identifying clinical and public health strategies for MM prevention.