Prognosis and patterns of progression in smoldering multiple myeloma

TO THE EDITOR:

In a 2007 seminal publication, Kyle et al reported the clinical course and prognosis of 276 patients with smoldering multiple myeloma (SMM), finding an overall risk of progression of 10% per year for the first 5 years, 3% per year for the next 5 years, and ∼1% per year thereafter.¹ Since then, the diagnostic landscape of SMM has evolved significantly. In 2014, the International Myeloma Working Group (IMWG) incorporated three biomarkers (collectively referred to as SLiM) as myeloma-defining events, alongside CRAB criteria (hypercalcemia, renal dysfunction, anemia, and bone lesions).² Furthermore, advanced imaging has improved detection of occult bone lesions and is now routinely used in the diagnostic workup of SMM. These updates have led to reclassification of many patients previously categorized as high-risk SMM to multiple myeloma (MM) requiring therapy.

We read with interest the recent study by Kastritis et al who analyzed the clinical course, prognosis, and progression patterns in 427 patients with SMM diagnosed between 2014 and 2023 according to 2014 IMWG criteria and with systematic use of advanced imaging.³ Their findings suggest that the disease trajectory of SMM in contemporary cohorts is more indolent than previously reported. In particular, patients classified as low risk (representing half of the cohort) had a remarkably low progression risk, comparable to monoclonal gammopathy of undetermined significance (MGUS). Conversely, patients classified as high risk did not reach the typical threshold used to define aggressive disease (ie, median time to progression [TTP] of 24 months and a 2-year progression rate of ∼50%).^4,5 To independently validate these findings, we analyzed the risk of progression in a contemporary cohort from a different health care system.^6,7

We assessed patients with SMM at Memorial Sloan Kettering Cancer Center diagnosed between 2002 and 2019 with follow-up through 2023. SMM diagnosis and progression to MM or amyloid light chain (AL) amyloidosis was defined per the IMWG 2014 criteria.² To align the study cohort with contemporary patients, we only included patients who were evaluated with advanced imaging (defined as positron emission tomography–computed tomography [CT], whole-body CT, whole-body magnetic resonance imaging [MRI], or total spine MRI) confirming the absence of osteolytic lesions before progression to MM. Risk stratification was performed using the 2/20/20 model.⁵ TTP was calculated from the date of SMM diagnosis to the date of MM or AL amyloidosis, with log-rank tests for comparisons between groups. Patients were censored at last clinic visit or death (if no evidence of progression) or at treatment initiation for those enrolled in clinical trials. TTP was estimated using the Kaplan-Meier method, and cumulative incidence of progression at each time point was calculated as 1 minus the Kaplan-Meier survival probability. The institutional review board approved the study.

We included 308 patients with SMM (median age of 63 years, 55% male, and 12% Black; Table 1). The median bone marrow plasma cell infiltration was 17%, the median M-spike level was 1.29 g/dL, and the median free light chain ratio was 7.6. Fifteen patients (4.9%) had an M-spike of ≥3 g/dL. Based on the 2/20/20 score, 49% were low risk, 30.5% were intermediate risk, and 20.5% high risk. Although all patients were evaluated with an advanced imaging modality, 78.2% were evaluated with positron emission tomography–CT scan and/or whole-body MRI at baseline. Fourteen patients (4.5%) enrolled in clinical trials during follow-up. The 2/20/20 risk distribution among these trial participants was similar to the overall cohort. Unfortunately, cytogenetic data were not available for our cohort, limiting our ability to assess the impact of high-risk chromosomal abnormalities on progression risk. Over a median follow-up time of 79 months, 108 patients progressed to MM or AL amyloidosis. At progression, 41% of patients developed bone lesions (n = 44), 27% anemia (n = 29), 7.4% renal insufficiency (n = 8), and 1 patient had hypercalcemia. Twenty-seven percent of patients progressed via free light chain ratio and/or bone marrow plasma cell ≥60% as the only myeloma-defining events. Four patients (3.7%) developed AL amyloidosis.

Table 1.

Baseline characteristics

Characteristic	N = 308
Demographics
Age, median (IQR), y	63 (55-71)
Sex, male, n (%)	169 (55)
Black race, n (%)	37 (12)
Disease characteristics
BMPC, median (IQR), %	17 (13-25)
M-protein, median (IQR), g/dL	1.29 (0.7-1.89)
FLCr (involved to uninvolved)	7.6 (2.95-20.9)
M-protein ≥3 g/dL, n (%)	15 (4.9)
2/20/20 risk group, n (%)
Low (0 risk factors)	151 (49)
Intermediate (1 risk factor)	94 (30.5)
High (2-3 risk factors)	63 (20.5)
Imaging modality at baseline, n (%)
PET-CT and/or WB-MRI	241 (78.2)
Other advanced imaging∗	67 (21.8)

BMPC, bone marrow plasma cells; FLCr, free light chain ratio; IQR, interquartile range; PET, positron emission tomography; WB-MRI, whole-body MRI.

^∗Other advanced imaging includes whole-body CT and total spine MRI.

The cumulative risk of progression to MM or AL amyloidosis at 1, 2, and 3 years was 6.3%, 13.2%, and 21.6%, respectively (Figure 1). The median TTP was 142 months (95% confidence interval [CI], 109 to nonevaluable [NE]). The 5- and 10-year progression rates were 29.8% and 43.6%, respectively. The annual risk of progression, estimated under an exponential model, was ∼6.8% per year for the first 5 years, followed by 2.9% per year for the next 5 years. The risk of progression to MM defined by CRAB criteria was lower, with an annual progression rate of 4.8% for the first 5 years (supplemental Figure 1), and 5- and 10-year progression rates of 22% and 36%, respectively.

Figure 1.

TTP to MM or AL amyloidosis in a contemporary cohort of 308 patients with SMM. (A) TTP from SMM to MM or AL amyloidosis by SLiM-CRAB criteria. (B) TTP stratified by the 2/20/20 model. (C) Summary of progression rates and median TTP by risk group with 95% CIs.

For patients classified as low risk (0 points) by the 2/20/20 risk score, the 1-, 2-, 5-, and 10-year progression rates were 1.3%, 4.8%, 12.2%, and 28.9%, respectively; median TTP was 213 months (95% CI, NE). For intermediate-risk patients (1 point), the 1-, 2-, 5-, and 10-year progression rates were 7.6%, 12.1%, 34.1%, and 40.4%, respectively, with a median TTP of 128 months (95% CI, 70 to NE). High-risk patients (2-3 points) had 1-, 2-, 5-, and 10-year progression rates of 16%, 34.8%, 66.7%, and 83.2%, respectively, and a median TTP of 34 months (95% CI, 27-55).

A total of 75 patients (24%) died during follow-up. The median overall survival (OS) was not reached (95% CI, 168 to NE) during a median follow-up time of 106 months for OS. The 5- and 10-year OS rates were 89.9% (95% CI, 86.5-93.5) and 71.8% (95% CI, 65.9-78.3), respectively. There was no significant OS difference between the 2/20/20 groups (P = .17; supplemental Figure 2).

Overall, we found a lower risk of progression to MM than historically reported, with an annual progression rate of ∼6.8% during the first 5 years. Notably, patients classified as high risk by the 2/20/20 model did not exhibit the high progression rates typically associated with this category (ie, 2- and 5-year risks of ∼50% and ∼80%). Instead, we observed more moderate progression 2- and 5-year progression risks of 35% and 67%, respectively. Although progression rates in our cohort were higher than those reported by Kastritis et al, our findings align in suggesting that contemporary SMM populations have lower overall progression risk.

Although the 2/20/20 model was developed using the IMWG 2014 criteria, the original testing and validation cohorts included patients diagnosed as early as 2003, often without advanced imaging, potentially inflating risk estimates by including cases of undetected early MM. In contrast, both our study and that of Kastritis et al, which either required advanced imaging or included only patients diagnosed after 2014, showed longer median TTP and higher proportions of low-risk SMM (49%-52% vs 34%-38% in earlier studies^4,5). Findings from the iStopMM population-based screening study further highlight how the extent of diagnostic evaluation can influence diagnostic and risk classification. Among patients with SMM from arm 3, in which all patients with MGUS were offered advanced imaging and bone marrow biopsy, 68% were classified as low risk by the 2/20/20 model.⁸ These findings suggest that many individuals classified as MGUS may be upstaged to low-risk SMM if routinely biopsied, and that the degree of workup may contribute to variability in risk across cohorts.

In summary, these findings indicate that SMM overall may be more indolent than previously appreciated. As early-intervention strategies continue to expand for patients with high-risk SMM,9, 10, 11 there is a pressing need for more refined tools that reliably identify those most likely to benefit from treatment. Current risk models do not incorporate disease biology including the presence of genomically transformed clones, and may not accurately identify high-risk SMM in contemporary cohorts. Nevertheless, the integration of dynamic biomarkers and genomic profiling, alongside the 2/20/20 model, may better capture true high-risk biology and improve patient selection for early therapeutic intervention.

Conflict-of-interest disclosure: K.H.M. reports grant support from the American Society of Hematology, Multiple Myeloma Research Foundation, and the International Myeloma Society. S.Z.U. reports grants and personal fees from AbbVie, Amgen, Bristol Myers Squibb (BMS), Celgene, GSK, Janssen, Merck, Mundipharma, Oncopeptides, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDx, and Takeda. M.H. reports research funding from AbbVie, BeOne, BMS, Cosette Pharmaceuticals, Daiichi Sankyo, GSK, Johnson & Johnson (J&J), and Binding Site; consulting fees from Curio Science LLC and Intellisphere LLC; has participated in scientific advisory boards for BMS, J&J, Pfizer, and GSK; and has participated in an independent review committee for BMS. The remaining authors declare no competing financial interests.