Impact of clinical surveillance on myeloma-related complications in patients with precursor plasma cell disorders.

Dear Editor,

Multiple myeloma (MM) is consistently preceded by asymptomatic precursor states [ 1 ], including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). With the prevalence of MGUS recently found to be as high as 5% in those above the age of 50 [ 2 – 4 ], defining the clinical value of early detection and logitudinal follow-up of MGUS and SMM is becoming increasingly important.

Previous observational studies in the US, Sweden, and Korea have shown an association with improved overall survival in MM patients with versus without a known preceding MGUS history [ 5 – 8 ]. Less clearly described, however, are differences in myeloma-related morbidity beyond survival, particularly patient-centered outcomes that are poorly captured in population-level datasets, such as symptom duration and healthcare utilization.

Therefore, we conducted a retrospective chart analysis to evaluate whether outcomes, patient symptoms, and healthcare utilization differed in MM patients with or without a prior history of PCD (MGUS, SMM, or a solitary plasmacytoma).

Electronic medical records were used to identify all consecutive patients diagnosed with MM between January 2019 and July 2024 at the Ottawa Hospital, in Ontario, Canada. Patients diagnosed simultaneously with systemic AL amyloidosis or treated with plasma-cell directed therapy for non-MM indications were excluded. Patients with high-risk SMM as per the IMWG 2/20/20 criteria [ 9 ] were also excluded given recent data highlighting the value of early therapeutic intervention in this subgroup [ 10 ]. MM patients with a preceding MGUS or low/intermediate risk SMM diagnosis at least 3 months prior to MM progression were classified as having a prior PCD (pPCD), and were compared to those with no known prior PCD (nPCD). As the only tertiary hospital in the region, all patients treated for MM during the study time period would be included in this analysis. Laboratory monoclonal protein data ordered between January 2010 and July 2024 were reviewed to identify MGUS/SMM diagnoses prior to 2019. This study was approved and performed in accordance with the regulations of the Ottawa Hospital Research Ethics Board, including a waiver of informed consent given the retrospective nature of the study and broad study time period.

Manual chart review was undertaken to identify baseline patient demographics, survival outcomes, and myeloma-defining events at MM diagnosis [ 11 ]. Data included the presence of CRAB/SLIM features, and whether these abnormalities resulted in clinically significant endpoints including anemia that required transfusions, hypercalcemia requiring treatment, bone disease requiring palliative care consultation or radiation, and renal insufficiency requiring dialysis. Time to symptoms was calculated as the time between date of symptom onset (approximated from clinical documentation) and date of MM diagnosis. Details of frontline therapy and statistical analysis are provided in the Supplementary Appendix . A two-sided p < 0.05 was considered statistically significant.

We identified 415 patients diagnosed with MM during the study period, including 95 pPCD and 320 nPCD patients (Table 1 ). Within the pPCD group, 71 had MGUS, 16 had SMM, and 8 had a solitary plasmacytoma. At MGUS diagnosis, risk stratification identified 1 low risk, 43 intermediate risk, and 16 high risk patients, while 11 lacked sufficient baseline monoclonal protein or FLC data and were not evaluable for risk stratification. At SMM diagnosis, 9 patients were low-intermediate risk, and 7 were not evaluable for risk stratification due to missing FLC data. Most SMM patients (12/16) had cross-sectional imaging (MRI axial skeleton, PET/CT, or whole body CT scan); earlier in the study period, routine access to cross-sectional imaging was limited and skeletal surveys were used to assess for lytic lesions. Six of eight solitary plasmacytoma patients had clonal plasma cells on bone marrow biopsy.

Among the 95 pPCD patients, the median time from precursor PCD diagnosis to MM diagnosis was 6.3 (IQR 3.4–14.7) years in MGUS patients, 3.0 (IQR 1.8–9.5) years in SMM patients, and 2.1 (IQR 1.0–2.8) years in solitary plasmacytoma patients. The median time interval between last clinical hematology visit and MM diagnosis in these subgroups was 9 (IQR 3.5–47.3), 4.1 (IQR 2.2–6.2), and 3.6 (IQR 1.85–4.65) months, respectively. The median time from symptom onset to MM diagnosis was significantly shorter in pPCD versus nPCD patients (4.5 [IQR 2–8.5] versus 7.6 [IQR 3.8–14.2] months, respectively, p < 0.001).

Overall, pPCD patients had lower rates of hypercalcemia (6% vs 13%), renal insufficiency (11% vs 23%), anemia (35% vs 65%), and osteolytic lesions (45% vs 59%), compared to nPCD patients at MM diagnosis (Table 1 ). pPCD patients also reported less bone pain (41% vs 58%), had fewer pathologic fractures (26% vs 42%), fewer cord compression events (6% vs 13%), lower rates of dialysis (2% vs 8%), and lower rates of red blood cell transfusions (16% vs 39%), compared to nPCD patients. Additionally, pPCD patients presented less frequently to the emergency department (37% vs 64%) and were hospitalized less frequently (35% vs 57%) prior to their MM diagnosis (Fig. 1 ).

Using a multivariable logistic regression model, a prior PCD diagnosis was associated a 71% reduction in the odds of presenting with a composite outcome of clinically significant myeloma-defining events at MM diagnosis (dialysis, pathologic fracture, hospital admission, spinal cord compression, hypercalcemia requiring treatment, or packed red blood cell [PRBC] transfusion) (OR 0.29 95% 0.18–0.47, p < 0.001), after adjusting for age at MM diagnosis and sex. Excluding patients treated for hypercalcemia or those that received PRBC transfusions yielded similar findings (OR 0.37 95% CI 0.23–0.59, p < 0.001). When further restricting to pPCD patients with documented hematology clinical follow-up within 1 year prior to MM diagnosis ( N = 34), the association persisted (OR 0.35 95% CI 0.20–0.61, p < 0.001).

At MM diagnosis, patients with a pPCD were more likely to be diagnosed with earlier stage (ISS Stage I/II) disease compared to nPCD patients, supporting the possibility that structured clinical follow-up may facilitate earlier detection of MM. Patients with pPCD also had a significantly lower incidence of hypercalcemia, renal insufficiency, anemia, and osteolytic bone lesions. This finding is consistent with other studies, which have shown a lower incidence of anemia, bone disease, and vertebral fractures in patients with MM previously followed for a plasma cell disorder [ 6 , 12 ]. These observations likely reflect the impact of multiple complementary mechanisms, including earlier biochemical detection, faster clinical assessment for new symptoms among patients already engaged in hematologic care, and prevention of irreversible end-organ injury through timely initiation of therapy. We also showed that a composite of symptomatic patient outcomes was 71% less likely to occur in pPCD patients, and that pPCD patients were symptomatic for significantly shorter periods of time before diagnosis of MM compared to nPCD patients. Importantly, the ability to estimate symptom duration, a metric rarely available in population-level datasets, allowed us to capture a more patient-centered view of morbidity at diagnosis.

PRBC transfusion and the spinal cord compression were notably more common in nPCD compared to pPCD patients. While transfusion thresholds may vary, the baseline hemoglobin values at MM diagnosis were correspondingly lower in nPCD patients. Our observed rate of spinal cord compression and lytic lesions, while high, was likely driven by the inclusion of both symptomatic and asymptomatic spinal cord/bone lesions as a combined statistic, and the recent adoption of more sensitive imaging techniques to evaluate for bony disease defined by SLiM criteria [ 12 , 13 ]. We did not observe any significant differences in PFS or OS. This is in contrast to prior analyses which had estimated an OS benefit of approximately 13–14% [ 5 – 8 , 12 ]. However, measurable survival advantage may require larger cohorts, longer follow-up, or uniform access to contemporary myeloma therapies.

Although limited by a relatively small sample size, the strength of our study lies in the granular symptom- and outcome-level details obtained through comprehensive clinical chart review, offering a degree of clinical nuance that distinguishes it from population-based studies. Our study has several limitations. Firstly, our study was a single-center, retrospective analysis, examining patients over a limited time period. As the sole tertiary hospital able to administer MM therapy within the region, our population may be enriched for individuals diagnosed with precursor PCDs during evaluations for other medical issues, potentially increasing detection of earlier-stage MM. We also considered the potential that pPCD patients may inherently represent a lower-risk group; however, similar rates of high-risk cytogenetics between pPCD and nPCD patients argue against substantial biological differences in the MM phenotypes. Finally, the results may not be generalizable in settings where MGUS/SMM patients are followed at non-tertiary centers as all patients in our analysis were followed by hematologists.

In conclusion, our retrospective analysis demonstrates that the benefit of structured follow-up of patients with precursor disease extends beyond survival, to include reductions in symptomatic complications and healthcare utilization at MM diagnosis. These reductions in emergency department presentations, hospitalizations, and dialysis requirements also suggest meaningful potential benefits for health-system resource use. Taken together, these findings support the broader concept that routine follow-up of precursor plasma cell disorders—independent of early therapeutic intervention—may reduce the morbidity associated with myeloma presentation. These findings highlight the value of upcoming prospective studies such as iSTOP-MM [ 2 ], which will be critical in determining the broader impact standardized screening and of longitudinal follow-up in precursor PCDs.

Supplementary information

Supplementary Appendix

Author contributions

AV and EK designed the study. SA, BP, MH, YR, and EK collected the data. All authors (EK, SA, BP, MH, YR, CM, VJ, IS, MC, HM, AV) analyzed and interpreted the study data, and participated in drafting the manuscript.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

Janssen Inc. provided financial support for this work. The funder had no role in the design and conduct of the study; collection, analysis, or interpretation of the data; preparation, approval of the manuscript, or the decision to submit the manuscript for publication. The authors have no other relevant conflicts of interests to disclose.

Footnotes

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Supplementary information

The online version contains supplementary material available at 10.1038/s41408-026-01463-5.

References

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Associated Data

Supplementary Materials

Supplementary Appendix

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.