Multiple myeloma (MM) is a malignant proliferation of plasma cells, which accounts for 10%-15% of all hematologic malignancy, making it the second most common hematologic malignancy worldwide. In 2022, age-standardized rate of incidence was 1.8 per 100,000 person-years with 188,000 newly diagnosed cases were estimated globally[1]. MM is a complex disease with high genetic heterogeneity that develops as a multistep process, involving acquisition of genetic alterations in the tumor cells and changes in the bone marrow microenvironment[2]. During this process, MM is almost always preceded by asymptomatic precursor stages, such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM)[3]. MGUS is present in more than 3% of the general population older than 50 years, with an annual risk of progression to MM of approximately 1%[4]. SMM accounts for 8–10% of the MM cases carrying a higher risk of progression to symptomatic MM[5]. Within the first 5 years, around 10% of SMM patients progress to symptomatic MM each year, which may be considered as MM with early detection[6]. Consequently, there have been ongoing efforts to more precisely define “symptomatic disease” and identify patients with a higher risk of progression at an earlier stage[7], enabling timely therapeutic intervention.

In 2014, the International Myeloma Working Group (IMWG) incorporated three biomarkers (SLiM, bone marrow plasma cells [BMPC] ≥ 60 (Sixty)%, serum free Light chain ratio [FLCr] ≥ 100, and > 1 focal lesion [≥ 5 mm] detected by Magnetic resonance imaging [MRI]) into the ‘myeloma-defining events’ in addition to the CRAB criteria (hyperCalcemia, Renal insufficiency, Anemia, Bone lesions), because these biomarkers were significantly associated with early progression to active multiple myeloma[8]. For example, a report from the Mayo Clinic found that patients with BMPC ≥ 60% had a significantly shorter time to progression (TTP) to MM (median 7 months, p < 0.001) compared with those who had less than 60% involvement.[9]. This finding was replicated in a Greek report, which showed that patients with BMPC ≥ 60% had a median TTP to MM of 15 months[10]. Similarly, multiple studies have demonstrated that approximately 15% of patients with SMM harbor more than one focal lesion on whole-body MRI, which is associated with a significantly shorter TTP to MM compared with patients with zero or one focal lesion[11–13].

However, several subsequent reports published after 2014 update of the diagnostic criteria demonstrated that patients who met SLiM biomarkers showed favorable outcomes compared to the previous reports[14, 15]. A recent meta-analysis including 11 studies with 3,482 patients found that studies published after 2014 reported an approximately threefold longer TTP compared with those were published before 2014[16].

Patients with MM diagnosed solely on the basis of SLiM biomarkers (SLiM-only MM) exhibited distinct features compared with those diagnosed according to the CRAB criteria (CRAB-MM). In a subgroup analysis of the CASSIOPEIA trial, which evaluated bortezomib, thalidomide, and dexamethasone with or without daratumumab in transplant-eligible newly-diagnosed MM patients, SLiM-only MM patients (n = 81) were slightly fitter and had lower-risk profiles compared with CRAB-MM patients (n = 1004)[17]. However, treatment outcomes, including response rates, minimal residual disease negativity rates, and progression-free survival, were comparable between the two groups. Furthermore, a retrospective study from Australia and New Zealand reported that patients with SLiM-only MM (n = 257) exhibited a lower incidence of advanced stage, and prolonged progression-free and overall survival (OS) compared to CRAB-MM patients[18]. Therefore, to better understand the outcomes of SLiM-MM patients who would have been observed without treatment prior to the updated 2014 criteria, additional data are needed. Moreover, no subsequent studies have addressed patients with > 1 one focal lesion on MRI.

To further clarify the clinical impact of the SLiM biomarkers, we conducted a nationwide retrospective analysis in Korea.

Thirty-five patients (49%) patients were managed with active surveillance (group 1), while the other thirty-seven patients (51%) received immediate treatment (group 2). There was no significant difference in whether patients underwent active surveillance or initiated treatment immediately according to the time of diagnosis.

In group 1, the median age was 60 years (range, 36–78). Three patients (9%) and one patient (3%) were classified as ISS stage III and R-ISS stage III, respectively. Regarding the SLiM criteria, one patient met all three criteria, whereas the remaining 34 patients met only one criterion: 10 patients (29%) had BMPC ≥ 60%, 13 patients (37%) had an FLCr ≥ 100, and 14 patients (40%) had > 1 focal lesion on MRI. At a median follow-up of 59.9 months (95% confidence interval [CI], 29.0–90.8), 10 patients (29%) progressed to CRAB-MM. The median TTP to CRAB-MM was 75.8 months, and the 2-year risk of progression was 19.6% (95% CI, 18.8–24.9%)(Fig. 1A). After excluding the one patient who met all three SLiM criteria, patients with > 1 focal lesion on MRI showed a significantly longer TTP to CRAB-MM (median not reached) compared with those with BMPC ≥ 60% (median, 33.2 months; 95% CI, 21.7–44.7) or an FLCr ≥ 100 (median, 28.0 months; 95% CI, 17.2–38.8) (p = 0.014). The 2-year risks of progression for each group were 28.6% (95% CI, 8.0–74.3%), 36.4% (95% CI, 12.7–77.9%), and 0.0% (no events before 2 years), respectively (Fig. 1B). The 2-year risk of progression was significantly higher in younger patients (≤ 65) (20.6% [95% CI, 2.6–38.6] vs. 0.0%, p = 0.046) (Fig. 2); however, other prognostic factors, including stage, cytogenetics, did not impact on TTP to CRAB-MM. Of the 10 patients who progressed to CRAB-MM, their median TTP to CRAB-MM was 22.6 months (95% CI, 14.4–30.8), and the median PFS1 for first-line treatment was 62.6 months (95% CI, 43.7–81.5). A total of 8 patients died during follow-up: 6 from progressive disease and 2 from unrelated causes. The 5-year OS rate was 74.1% (± 9.6%).

In group 2, the median age was 68 years (range, 46–89). Nine patients (24%) and six patients (16%) were classified as ISS stage III and R-ISS stage III, respectively. Thirteen patients (35%) had met two or more SLiM criteria. Seventeen patients (46%) underwent autologous stem cell transplantation. The responses to first-line treatment were as follows: complete response, 60% (n = 22); very good partial response, 8% (n = 3); and partial response, 22% (n = 8). The estimated median PFS1 was 56.8 months (95% CI, 21.2–92.4). A total of 7 patients died during follow-up: 3 from progressive disease, 2 from treatment-related cause, 1 unrelated cause, and 1 unknown. The median OS was 96.0 months (95% CI, 30.5–161.5), and the 5-year OS rate was 57.3% (± 16.0%).

Advances in the molecular and clinical characterization of precursor lesions of MM have led to increasing interest in early detection as well as therapeutic intervention, aiming to prevent progression to overt disease and to improve survival outcomes. This approach has emerged as one of the most intensely debated topics in contemporary myeloma research.

SMM is an asymptomatic plasma-cell proliferative disorder associated with a high risk of progression to symptomatic MM or amyloidosis[5]. Given its heterogeneous clinical trajectories, multiple sets of criteria have been established to define patients at increased risk of progression to overt MM[19, 20, 5]. They have incorporated factors including the level of monoclonal protein, BMPC percentage, the presence of immunoparesis, and/or the serum FLCr, to define high-risk groups with a significantly increased probability of progression to overt MM. These efforts eventually led to the identification of specific criteria—namely, BMPC ≥ 60%, serum FLCr ≥ 100, and the presence of > 1 focal lesion on MRI to define “ultra high-risk” SMM. Multiple studies confirmed that patients with SMM who met these criteria had an approximately 80% probability of progression to overt MM within 2 years[9, 10, 13, 12, 11]. Consequently, in the 2014 International Myeloma Working Group (IMWG) criteria, these features were incorporated as myeloma-defining events[8]. This inclusion allows treatment initiation before end-organ damage occurs, potentially preserving the patient’s performance status and thereby improving clinical outcomes.

The reclassification was subsequently challenged by several reports published after 2014, demonstrating a prolonged TTP to MM in contrast to prior findings. Wu et al., for instance, detailed the outcomes of 22 SMM patients with BMPC ≥ 60%[14]. With a median follow-up of 67 months, their median TTP to MM was 31 months, and 6 patients (27%) remained without progression to MM. While this paper is potentially the sole publication reporting the outcomes for SMM patients with BMPC ≥ 60% in the post-2014 era, there are more studies that have specifically analyzed the outcomes for SMM patients a FLCr ≥ 100. In the aforementioned study by Wu et al., the median TTP was 40 months among 72 patients with SMM and an FLCr ≥ 100, with 32 patients (44%) remaining progression-free to MM[14]. In a Danish population-based cohort study of 321 patients with SMM, 23 patients (11%) had an FLCr ≥ 100; however, this was not associated with a shorter TTP to MM[21]. More recently, a study analyzing 65 patients with an FLCr ≥ 100 reported a median TTP to MM of 32 months (95% CI, 25–59)[22]. To date, no study has reevaluated the impact of having > 1 focal lesion on MRI since the 2014 criteria update.

In the current study, we included 10 patients with BMPC ≥ 60%, with a median TTP to CRAB-MM of 33.2 months (95% CI, 21.7–44.7), and 13 patients with FLCr ≥ 100, with a median TTP to CARB-MM of 28.0 months (95% CI, 17.2–38.8). These outcomes are consistent with those reported in studies published after 2014, which showed improved TTP to CRAB-MM compared to the studies published before 2014. The apparently improved outcomes for SLiM-only MM patients who also meet other biomarker criteria, such as BMPC ≥ 60% or FLCr ≥ 100, may be attributable to the proactive early use of modern imaging modalities, including MRI and PET-CT[16]

Due to reports showing a longer TTP in SLiM-only MM patients compared with studies conducted before 2014, some suggest that rather than automatically diagnosing SLiM-only MM patients as candidates for anti-myeloma treatment, a more conservative approach should be applied when considering treatment initiation[16]. Conversely, several reports already indicate that early intervention in high-risk SMM prolongs survival[23, 24], and considering the studies showing that SLiM-only MM patients have a better survival outcome[18], proceeding with aggressive treatment is also considered a viable option. The answer to this question will likely come from ongoing studies prospectively analyzing the natural course of SMM patients, such as the IFM 2017-04 trial (CARRISMM, NCT04144387). The outcomes of trials described in Table 2.

In our study, the risk of progression to MM among patients with > 1 focal lesion on MRI was even lower than that reported in studies published before 2014. Since no subsequent study has re-evaluated this issue, further analysis is not possible. The apparently improved outcomes for SLiM-only MM patients who also meet other biomarker criteria, such as BMPC ≥ 60% or FLCr ≥ 100, may be attributable to the proactive early use of modern imaging modalities, including MRI and PET-CT[16]. Such active screening could identify patients who would previously have been classified as having SMM but are now diagnosed with symptomatic MM. Notably, the disease entity “multiple solitary plasmacytoma (MSP)” was included in the 2003 IMWG diagnostic criteria and encompassed patients with > 1 focal area of bone destruction or extramedullary clonal plasma cell tumors[25]. This entity was removed in the 2014 update, when the SLiM criteria were incorporated as myeloma-defining events, and is no longer investigated. Consequently, only historical records remain, with the largest study to date being a Chinese analysis of nine patients[26]. In that study, patients were relatively young (median age, 49) and received either bortezomib-containing regimens (n = 6) or conventional chemotherapy (n = 3). After a median follow-up of 28.5 months, none progressed to MM. Given the limited data on patients in this category, larger-scale studies are warranted for individuals with > 1 focal lesion on MRI.

Interestingly, the 2-year risk of progression was significantly higher in patients aged 65 years or younger (20.6% vs. 0.0%). This was also found in a US study, were the 4-year cumulative incidence of progression was 34% for patients under 60 years, which was significantly higher compared to 28% for those aged 60–70 years, and 18% for those over 70 years[27]. Potential explanations include competing risks in older populations, as they are more likely to have other comorbidities that may precede the development of active MM. Since the risk of precursor disease progressing to active MM varies over time[5], a significant number of elderly patients with identified precursor lesions may have already entered an indolent stage, resulting in a lower risk of progression to MM.

Although our study did not perform a direct comparison with CRAB-MM patients, the outcomes of the 37 patients in this study who were diagnosed with SLiM-only MM and immediately started treatment showed a numerical superiority (median PFS1, 56.8 months; median OS, 96.0 months) compared to the outcomes reported in a recently published nationwide population-based cohort study in Korea (median time to next treatment after the first-line treatment 26.61 months; median OS from the first-line treatment, 61.88 months)[28]. This also supports the benefit of early intervention.

Other than its retrospective nature, our study has several limitations. The relatively small number of patients and short follow-up duration limit the ability to draw definitive conclusions, including subgroup comparisons. MRI scans were not centrally reviewed. However, a central review is more crucial when confirming the absence of lesions; since once focal lesions were identified, a central review was deemed unnecessary. Unlike previous studies, 93% of our patients underwent MRI, which enabled us to detect both focal and disseminated bone lesions—representing a notable strength of our study.

In conclusion, our study demonstrated that patients diagnosed with SLiM-only MM exhibited an extended TTP without treatment compared to prior studies, particularly those with only focal MRI lesions. In addition, the treatment resulted in favorable outcomes, which may support the benefit of earlier initiation of treatment for the patients. Therefore, it is necessary to have a thorough discussion about the benefits and risks before initiating treatment of patients with SLiM-only MM.

Figure 1. Kaplan-Meier curves for progression to active (CRAB+) multiple myeloma in patients with SLiM-only multiple myeloma without immediate treatment. A, all patients; B, according to fulfilled SLiM criteria (BMPC, bone marrow plasma cell; FLCr, serum free light chain ratio; MRI, magnetic resonance imaging).

Figure 2. Kaplan-Meier curves for progression to active multiple myeloma according to their age.