Distress and symptom burden in patients with monoclonal gammopathy of undetermined significance and smoldering myeloma

TO THE EDITOR:

Multiple myeloma (MM) is an incurable plasma cell malignancy that is preceded by the asymptomatic precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). MGUS has a low risk of progression to overt MM of 1% per year, and SMM is generally thought to be 10% per year for the first 5 years; however, high-risk patients with SMM can have a 2-year progression risk that is as high as 44%.^1-3 

These conditions have historically been considered indolent, and thus, the standard clinical paradigm has been watchful waiting until progression to symptomatic MM, a paradigm that is anecdotally reported as a source of distress. Despite well-documented evidence that patients with MM experience substantial emotional distress and symptom burden,⁴ less is known in the setting of MGUS/SMM.

We conducted a cross-sectional analysis of psychological distress and symptom burden in patients with MGUS and SMM participating in a nationwide longitudinal study of plasma cell precursor disease (www.clinicaltrials.gov identifier NCT02269592). Between February and August 2024, patients with MGUS and SMM were offered the opportunity to complete validated questionnaires to assess symptoms of anxiety (Hospital Anxiety and Depression Scale [HADS]),^5,6 depression (HADS),^5,6 post-traumatic stress disorder (PTSD; PTSD Checklist Civilian Version),⁷ symptom burden (Edmonton Symptom Assessment System Revised),^8,9 and fatigue (Functional Assessment of Chronic Illness Therapy: Fatigue).^10,11 Additional details of this cohort and assessments can be found in the supplemental methods.

Participants were adults (aged ≥18 years) with a diagnosis of MGUS or SMM and were English literate. Exclusion criteria included patients who had MM or another known hematological cancer or precursor condition. Eligible individuals were offered the opportunity to participate by solicitation via email or at the time of clinic encounters. This study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board, and written informed consent was obtained.

Descriptive statistics were used to characterize participant socio-demographics and perceptions of psychological distress, symptom burden, and fatigue. We dichotomized the HADS: Anxiety,¹² HADS: Depression,¹² PTSD Checklist Civilian Version,^13,14 Edmonton Symptom Assessment System Revised,^15,16 and Functional Assessment of Chronic Illness Therapy: Fatigue^17,18 scores with clinically validated cut points. Histograms and quantile-quantile (Q-Q) plots were used to check for normality. The Mann-Whitney U test was used to detect unadjusted associations between sociodemographic factors and each subscale. Spearman correlation coefficients were also used. Quantile regression was used in adjusted models to estimate the median scores for each subscale, conditional on age, sex, education, and income. Main effects at the P < .05 level were considered statistically significant in adjusted analyses. Analyses were completed using R Language for Statistical Computing (version 4.2.2).

A total of 3311 individuals in the longitudinal cohort were emailed, and 467 adults with MGUS (n = 284) and SMM (n = 183) completed the study questionnaires (14.1% response rate; Table 1). The mean age was 65.5 years (range, 32.7-88.9); ∼39% were male, and >90% were White, non-Hispanic. Over half of the sample had at least some graduate school education and reported an annual household income of at least $75 000. The average time from diagnosis to survey completion was 3.7 years (standard deviation, 5.2) and was not correlated with any subscale.

Mean scores in patient-reported outcomes were not significantly different between participants with MGUS and SMM (Table 2). The prevalence of clinically significant anxiety, depression, and PTSD symptoms were 27% (125/467), 14% (64/467), and 24% (111/467), respectively. Overall, 31% (143/467) and 21% (98/467) of patients reported moderate-to-severe symptom burden and fatigue, respectively. The most common moderate or severe symptoms reported (scored a ≥4 on the Likert scale) were tiredness (41%), poor well-being (34%), drowsiness (29%), and pain (25%). It is not known whether the physical symptoms described here are attributable to MGUS/SMM. MGUS and SMM are defined as being asymptomatic, and there is not a known mechanism by which these conditions would account for the symptoms described; it is possible that their presence led to the discovery of the plasma cell precursor because of the evaluation for these symptoms.

Overall, there were statistically significant differences between sociodemographic factors and the perceptions of psychological distress, symptom burden, and fatigue (supplemental Table 1). In adjusted models, those with lower income generally had higher levels of depression, PTSD, symptom burden, and fatigue (P < .05). Female patients had higher anxiety than male patients (P < .01). Older age was associated with lower anxiety, lower PTSD, lower symptom burden, and higher fatigue (P < .01). Those with higher education generally had lower fatigue (P <.01). Race and ethnicity were not associated with any subscale in adjusted models.

Previous work from our group reported significantly elevated emotional distress in patients and caregivers throughout the continuum of treatment for MM.⁴ For example, in patients with MM, the overall rates of depression (24%), anxiety (24%), and PTSD (24%) were similar to those with MGUS/SMM in this study. Symptom burden (mean score, 21.5 vs 18.5) and fatigue (mean score, 35.3 vs 38.3) for MM vs MGUS/SMM were also similar.⁴ The high prevalence of clinically significant psychological distress, symptoms, and fatigue before MM diagnosis calls in to question the commonplace assertions that these conditions are benign and asymptomatic.

Interestingly, psychological distress, symptom burden, and fatigue were not measurably different for individuals with MGUS compared with those with SMM, despite the potential for these patients to have markedly different risks of transformation to MM. This finding is consistent with a recent study by Patel et al, which used qualitative interviews to evaluate dimensions of psychological, emotional, social, and familial well-being in 115 individuals with MGUS and 131 individuals with SMM and found the prevalence of disease-related anxiety was similar in those with MGUS and SMM.¹⁹ Furthermore, a cross-sectional study evaluating the associations between resilience, depressive symptoms, and health-related quality of life in patients with MGUS/SMM (n = 99), newly diagnosed MM (n = 98), and patients with MM undergoing treatment (n = 106) found no differences in psychological health across the disease continuum, despite the striking differences in their disease states and treatment history.²⁰ Together, these data are in line with a growing body of literature highlighting the impact of illness perception, a construct that is distinct from a clinical disease state, on psychological heath and symptom burden and underscore the significant physical and psychological burden of illness in these populations, even before classic symptoms of overt MM.

There is a diverse array of therapeutic and nontherapeutic interventions that are being tested in clinical trials to prevent the risk of disease progression and improve survival in patients with MGUS and SMM. Although the impact of these novel interventions on the psychological well-being of patients and physical quality of life remains to be elucidated, data from this study highlight that these are important key outcomes for all interventional studies in plasma cell disorder precursor disease and underscores the importance of describing these end points alongside other conventional metrics of study outcomes, such as treatment response.

Strengths of this study include a moderate sample size, a clinical population that had a verified diagnosis, and the use of validated questionnaires. Limitations include the results of this study are based on participant self-report of psychological distress, symptom burden, and fatigue, potentially being affected by recall error, social desirability bias, and reporting bias. Specifically, it is unclear whether patients have higher psychological stress due to other factors related to socioeconomic status or from the worry of progression to MM. Respondent bias may have also skewed the results due to higher digital literacy or higher likelihood of psychological or symptom burden. This analytic sample was recruited throughout the United States via an academic medical center with a primarily White, non-Hispanic population. Additionally, many of the questionnaires specifically asked about the past week, which may not accurately represent a patient’s typical experience because symptoms may vary across the disease course.

In summary, patients with MGUS and SMM experience substantial psychological distress before developing MM. Certain sociodemographic subgroups of patients had higher rates of psychological distress, symptom burden, and fatigue for reasons that remain to be elucidated. It is essential that we develop a more comprehensive understanding of the supportive care needs of patients to improve their quality of life and care throughout their illness course.

Acknowledgment: This study was funded in part by the National Institutes of Health under award numbers R21 CA256644 and K22 CA251648 (Marinac).

Contribution: E.K.O., O.N., A.E.-J., I.M.G., and C.R.M. conceptualized the study, and edited and reviewed the manuscript; E.K.O. supervised the study; J.E.C. performed formal analysis and wrote the original draft; J.P. and V.P. performed investigation; and J.P. curated the data. K.P. and B.H. faciliated patient recruitment and data entry.

Conflict-of-interest disclosure: E.K.O. reports advisory board fees/honoraria from Janssen, Bristol Myers Squibb, Sanofi, Pfizer, Exact Sciences, and Grail; has served as a consultant for Takeda; and is on the steering committee for Natera and Legend Pharmaceuticals. A.E.-J. has served as a consultant for Novartis, Incyte, GlaxoSmithKline, and Tuesday Health. I.M.G. has served as a consultant/advisor for AbbVie, Adaptive, Amgen, Aptitude Health, Bristol Myers Squibb, Novartis, GlaxoSmithKline, Huron Consulting, Janssen, Menarini Silicon Biosystems, Oncopeptides, Pfizer, Sanofi, Sognef, Takeda, Regeneron, Binding Site (a part of ThermoFisher Scientific), CurioScience, Window Therapeutics, and 10× Genomics; receives speaker fees from Vor Biopharma, Veeva Systems, Standard BioTools, Bristol Myers Squibb, Janssen, Menarini Silicon Biosystems, Takeda, Pfizer, Amgen, Regeneron, and Curio Science; is a cofounder and holds private equity in Predicta Bioscience; and her spouse is the Chief Medical Officer and holds private equity in Disc Medicine. The remaining authors declare no competing financial interests.

Correspondence: Elizabeth K. O’Donnell, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215; email: elizabeth_odonnell@dfci.harvard.edu.