V. Smoldering multiple myeloma

Diagnostic work-up

Initial investigation of a patient with suspected SMM should include the tests shown in Table 2, which are coincidental with those used for a correct diagnosis of symptomatic MM [5]. However, because of the updated IMWG criteria for the diagnosis of MM, there are some specific assessments to which physicians have to pay attention in order to make a correct diagnosis of SMM [2].

1. With respect to the evaluation of bone disease, the IMWG recommends that one procedure from skeletal survey, [6]F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT), or low-dose whole-body CT be carried out in all patients with suspected SMM, with the exact modality determined by availability and resources. The aim is to exclude the presence of osteolytic bone lesions, currently defined by the presence of at least one lesion (≥5 mm) revealed by X-ray, CT or PET-CT. In addition, whole-body MRI of the spine and pelvis is a necessary component of the initial work-up. It provides detailed information about not only bone marrow involvement but also the presence of focal lesions that predict more rapid progression to symptomatic myeloma. Hillengass et al. reported in 2010 that the presence of more than one focal lesion in whole-body MRI was associated with a significantly shorter median time to progression (TTP) to active disease of 13 months, compared with the period when no focal lesions were present [7]. Kastritis and colleagues reported similar results after the analysis of a subgroup of patients who underwent spinal MRI and were followed up for a minimum of 2.5 years. The median TTP to symptomatic disease was 14 months when more than one focal lesion was present [8]. Therefore, if more than one focal lesion in MRI are present in SMM patients, this entity should no longer be considered as SMM but as MM, according to the current IMWG criteria.
2. With respect to bone marrow infiltration, the Mayo Clinic group evaluated BMPC infiltration in a cohort of 651 patients and found that 21 (3.2%) had an extreme infiltration (≥60%) [9]. This group of patients had a median TTP to active disease of 7.7 months, with a 95% risk of progression at 2 years. This finding was subsequently validated in a study of 96 patients with SMM, in whom a median TTP of 15 months was reported for the group of patients with this extreme infiltration [10]. In a third study, six of 121 patients (5%) with SMM were found to have ≥60% BMPC, and all progressed to MM within 2 years [11]_ENREF_10. Therefore, if ≥60% of clonal plasma cell infiltration is present either in bone marrow aspirate or biopsy, the diagnosis of SMM should be replaced by MM. Additional assessments, for example, by flow cytometry or by identifying cytogenetic abnormalities in SMM patients, are not obligatory but can help estimate the risk of progression to active disease.
3. With respect to the serum free-light chain (FLC) assay, Larsen et al. studied 586 patients with SMM to determine whether there was a threshold FLC ratio that predicted 85% of progression risk at 2 years. They found a serum involved/uninvolved FLC ratio of at least 100 in 15% of patients and a risk of progression to symptomatic disease of 72% [12]. Similar results were obtained in a study by Kastritis and colleagues from the Greek Myeloma Group. In their study of 96 SMM patients, 7% had an involved/uninvolved FLC ratio of ≥100 and almost all progressed within 18 months [10]. In a third study, the risk of progression within 2 years was 64%_ENREF_11. Therefore, physicians must consider the sFLC assay at the moment SMM is first suspected and, if the involved/uninvolved ratio is ≥100, they should discount a diagnosis of SMM because MM is the correct diagnosis under these circumstances.

Once a diagnosis of SMM has been made, considering the specific assessments mentioned above, the serum and urine M-component, hemoglobin, calcium and creatinine levels should be re-evaluated 2-3 months later to confirm the stability of these parameters. The subsequent follow-up involves the same evaluation, but the frequency should be adapted on the basis of risk factors for progression to symptomatic MM (see below).

Risk factors predicting progression to active MM

Most patients diagnosed with SMM will progress to symptomatic MM and will need to start treatment. However, SMM is not a uniform disorder, and once the diagnosis has been confirmed, the doctor should evaluate the risk of progression to symptomatic disease in order to plan an appropriate, risk-based follow-up, and to optimize the management of the SMM patient. The annual risk of progression from SMM to symptomatic MM is 10% per year for the first 5 years, 5% per year during the following 5 years and only 1% per year after 10 years [13].

Several studies have reported possible predictors of progression to symptomatic MM, and this information is useful for physicians and could also be used to help explain to patients their risk of progression to active MM (Table 3).

Management of SMM patients

The standard of care for the management of SMM patients has been under observation until MM develops. However, several groups evaluated the role of early intervention in this group of patients using conventional and novel agents.

There have been different trials evaluating the role of early treatment with melphalan and prednisone (MP), or novel agents, such as thalidomide or even bisphosphonates.

None of these trials provided evidence favoring the early treatment of patients with SMM. However, they were conducted without considering the differences in the risk of progression to active disease, and while the high-risk subgroup of patients may have benefited, this could have been counterbalanced by the absence of benefit in low-risk patients. The Spanish myeloma group (GEM/Pethema) has conducted a phase 3 randomized trial in 119 SMM patients at high risk of progression to active disease (according to the Mayo and/or Spanish criteria) that compared early treatment with lenalidomide plus dexamethasone as induction followed by lenalidomide alone as maintenance versus observation. The primary end-point was TTP to symptomatic MM, and after a median follow-up of 40 months, the median TTP was significantly longer in patients in the early treatment group than in the observation arm (not reached vs. 21 months; hazard ratio, HR = 5.59; p < 0.001). Secondary end-points included response, OS and safety. The PR or better after induction was 82%, including 14% of cases of stringent complete response (sCR) plus CR, and after maintenance the sCR/CR rate increased to 26%. The safety profile was acceptable, and most of the adverse events reported were grade 1 or 2. The OS analysis showed that the 3-year survival rate was also higher for the group of patients who received early treatment with lenalidomide-based therapy (94% vs. 80%; HR = 3.24; p = 0.03) [14]. A recent update of this trial confirmed the efficacy of early treatment in terms of TTP (HR = 6.21; 95% CI: 3.1–12.7, p < 0.0001) and the benefit to OS was even more evident with longer follow-up (HR = 4.35, 95% CI: 1.5–13.0, p = 0.008) [15]. This study showed for the first time the potential for changing the treatment paradigm for high-risk SMM patients based on the efficacy of early treatment in terms of TTP to active disease and of OS. Moreover, several trials currently underway are focusing on high-risk SMM patients using novel agents.

Managing SMM patients in clinical practice

Given the extensive background to this disease described above, the first step in clinical practice is to identify the risk of progression to active disease for each newly diagnosed SMM patient. The key question is which risk model is better for evaluating the risk of progression to symptomatic disease for each individual SMM patient. The Mayo Clinic and Spanish models enable initial risk stratification of SMM and, in fact, both were validated in a prospective trial. However, new risk models are emerging that incorporate new clinical and biological features [6, 11, 13, 16-20] (Table 4). The components of these models are not identical, and each patient's risk should probably be defined on the basis of all the available data rather than through the use of a restricted model (Table 3).

SMM patients should be classified as follows:

1. Patients at low risk of progression who are characterized by the absence of the aforementioned high-risk factors (using the validated Mayo and Spanish risk models), with a probability of progression at 5 years of only 8%. The patients in this group behave similarly to MGUS-like patients and should be followed annually.
2. The second group includes patients at intermediate risk of progression, and they only display some of the aforementioned high-risk factors. These are probably the true SMM patients. They have a risk of progression at 5 years of 42%, and they must be followed up every 6 months.
3. The third group includes high-risk patients classified on the basis of one of the risk models mentioned above. Half of them will progress during the 2 years following diagnosis. This group of patients need a close follow-up every 2–3 months. The key question is whether this high-risk group should be treated. Although the Spanish trial showed significant benefit from the early treatment in high-risk SMM patients, there are some limitations that prevent the results being generally applicable at present; these may be resolved when the results of the ongoing clinical trials become available. The best approach for these patients should be to refer them to centers that specialize in MM therapy and to include them in clinical trials to better understand their biology and to confirm the survival benefit of early treatment in this cohort [21].