Smoldering multiple myeloma: to treat or not to treat

Abstract

Introduction: Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of ≥ 30 g/l serum M-protein and/or ≥ 10% bone marrow plasma cell infiltration. The progression risk to active multiple myeloma (MM) is not uniform, and several prognostic parameters are useful for identifying patients at high risk of progression. A watch-and-wait approach has been the standard of care up to now. However, recently, it has been demonstrated that a subset of high-risk cases can benefit from early treatment with new drugs.

Areas covered: In this editorial, we focus on SMM and evaluate the diagnostic work-up and the prognostic factors predicting progression to symptomatic MM. We also review the studies in which the role of early treatment has been evaluated for patients with SMM.

Expert opinion: After the update performed by the International Myeloma Working Group regarding MM diagnosis, it is now time to change the therapeutic paradigm for this disease. While “ultra high-risk” myeloma should now be considered as active MM, for low-risk patients the “watch-and-wait” strategy is still recommended. More caution is needed for the high-risk group: physicians should continue monitoring patients using every tool now available while waiting for results from ongoing trials that will establish if this group will benefit from an early intervention.

Keywords:

• multiple myeloma
• prognosis
• smoldering
• therapy

1. Introduction

In 1980 Kyle and Greipp described six patients who met the criteria of multiple myeloma (MM), but who did not show an aggressive course. The authors defined this clinical entity as smoldering MM (SMM) [1]. In 2003, the International Myeloma Working Group (IMWG) defined SMM as a plasma cell disorder characterized by the presence of ≥ 3 g/dl serum M-protein and/or ≥ 10% bone marrow plasma cells (BMPCs), but without MM-related symptomatology (hypercalcemia, renal insufficiency, anemia or bone lesions) [1]. Subsequently, the Mayo Group clarified that the M-protein must be of the IgG or IgA subtype and that the PCs need to be clonal [1]. Thus, SMM represents an intermediate clinical stage between monoclonal gammopathies (MGUS) and MM. Genetic studies have highlighted that most genetic lesions typical of MM are already present in both MGUS and SMM patients. The most important difference between these three clinical entities is the number of clonal PCs with genetic abnormalities, which increases from MGUS to MM, suggesting a clonal expansion [1].

2. Diagnostic work-up

Initial investigation of patients with suspected SMM is the same used to perform a correct diagnosis of symptomatic MM. Medical history, physical examination, hemogram, creatinine, calcium value and protein studies including serum and urine protein electrophoresis, 24-h proteinuria, immunofixation in serum and urine, serum-free light-chains (sFLC) and their ratio, should be collected [2]. Although the skeletal survey remains the standard method for the bone disease evaluation, the IMWG consensus highly recommends that a spine and pelvis MRI be performed for this category of patients, with the aim of detecting occult lesions not visible from the conventional skeletal survey [2]. The role of 18F-fluorodeoxyglucose PET/CT is currently under investigation in SMM patients. Evaluation of PC infiltration is mandatory in the case of bone marrow aspirate/biopsy. FISH analysis is not mandatory, but it is highly recommended for all newly diagnosed patients. Similarly, flow cytometry can help to estimate the progression risk to active MM.

3. Risk factors predicting prognosis to active multiple myeloma

The Mayo Clinic group, analyzing data from 276 SMM patients, showed that the annual risk of progression to symptomatic MM was 10% per year for the first 5 years, 5% per year during the following 5 years, and 1% per year after the 10th year [3]. Moreover, on the basis of M-protein size and BMPC infiltration, three SMM subgroups were identified: group 1, with ≥ 3 g/dl of M-protein and ≥ 10% of BMPCs, with a median time to progression (TTP) to symptomatic MM of 2 years; group 2, with ≤ 3 g/dl of M-protein and ≥ 10% of BMPCs with a median TTP of 8 years; group 3, with ≥ 3 g/dl of M-protein and < 10% of BMPCs, with a median TTP of 19 years [3]. The addition of an sFLC ratio of < 0.125 or > 8 to the above-mentioned criteria was associated with an increase in the progression risk to SMM [4]. More recently, the presence of an involved/uninvolved sFLC ratio > 100 has been associated with shorter TTP (median of 15 months) [5]. Furthermore, the immunoparesis (a decrease in one or two of the uninvolved immunoglobulins to 25% below the lowest normal value) and the presence of ≥ 95% of phenotypically abnormal BMPCs have been identified as predictive factors for TTP [6]. Combining these two parameters, a scoring system was proposed: cases with both risk factors had a median TTP of 23 months, cases with one risk factor a median TTP of 73 months, cases with none of two risk factors did not reach the median [6]. The pattern of evolution of the M-protein during the clinical course also allowed us to identify two types of SMM with different prognosis: evolving and non-evolving. The evolving cases had a progressively increasing serum M-protein value until active MM developed, and a shorter TTP (median of 1.3 years) [7]. Similarly, the Southwest Oncology Group showed that SMM cases with an increase in the M-protein to ≥ 3 g/dl through the 3-month period had a progression risk of 33.3% at 2 years [8]. Moreover, Rajkumar et al. showed that SMM cases with > 60% of BMPCs had a progression risk of 95% at 2 years [9]. Subsequently, Bianchi et al. showed that high levels of circulating PCs were a significant risk factor for progression (progression risk of 71% at 2 years) [10]. Instead, the German group reported that abnormalities on whole-body MRI can also predict progression to symptomatic MM: patients with > 1 focal lesion had a progression risk of 70% at 2 years [11]. Furthermore, a recent study showed that the increase in number and/or size of focal lesions in follow-up MRI of SMM patients also had a predictive value for TTP [12]. Neben et al. showed that the presence of t(4;14), deletion 17p, +1q and hyperdiploidy by FISH analysis shortened the TTP independent of tumor burden in SMM cases [13]. Finally, the Southwest Oncology Group identified a 70-gene signature, which allowed us to prognostically stratify SMM cases [8].

Based on the presence of these prognostic factors, we can identify patients at an elevated risk of progression (Table 1). Among these, a subgroup of cases, defined “ultra-high risk” patients, has been identified that have a ≥ 80% probability of progression at 2 years.

Table 1. Parameters for identifying SMM at elevated risk of progression to active myeloma.

High-risk SMM patients (50 – 79% of progression risk at 2 years)

Parameters correlated with tumor burden: a + b or a + b + c

(a) ≥ 10% clonal plasma cell bone marrow infiltration; (b) ≥ 3 g/dl of serum M-protein; (c) serum-free light chain ratio > 0.125 or < 8;

Parameters correlated with immunophenotyping characterization and immunoparesis: a + b

(a) > 95% of aberrant bone marrow plasma cells measured by flow cytometry; (b) 25% decrease in one or both uninvolved immunoglobulins with respect to the lowest normal value;

Parameters correlated with primary molecular cytogenetic abnormalities and GEP signature: the presence of one of the following

(a) presence of t(4;14); (b) presence of del17p; (c) gains of 1q24; (d) hyperdiploidy; (d) GEP-70 risk;

Parameters correlated with levels of peripheral blood circulating plasma cells: the presence of one of the following

(a) absolute peripheral blood PCs > 5000 × 10^6/l; (b) > 5% cytoplasmic Ig positive PCs per 100 mononuclear cells;

Ultra-high risk SMM patients (≥ 80% of progression risk at 2 years)

Parameters for identifying this category of patients: the presence of one of the following

(a) > 1 focal lesion plus diffuse pattern in whole-body MRI; (b) ≥ 60% of clonal plasma cells in bone marrow biopsy; (c) involved/uninvolved serum-free light-chain ratio > 100.

4. Treatment of smoldering multiple myeloma

To date, the standard of care for SMM patients has been close follow-up without treatment until MM symptoms develop. Several trials have looked at early intervention with conventional and novel agents, in an attempt to prolong the survival in this group of patients [14]. Few small studies comparing early treatment with melphalan and prednisone versus a delayed intervention did not result in a significant benefit in terms of TTP or overall survival (OS).

The same results were observed with thalidomide in monotherapy or associated with bisphosphonates. The combination of thalidomide with pamidronate in a single-arm Phase II trial showed a response rate of 42%, but patients who achieved at least a partial response had a shorter median time to treatment (< 2 years) compared with not-responder patients (i.e., response not reached in 8 years). The authors hypothesized a possible selection of aggressive clones due to this drug. In another Phase III study, patients treated with thalidomide plus zoledronic acid did not have any significant benefit compared to those who received bisphosphonates as a single agent [15].

Bisphosphonates as single agents have been studied in three different trials. Although a reduction in the incidence of skeletal-related events have been noted using pamidronate or zoledronic acid, none of these studies showed a survival advantage [16].

In summary, all attempts to anticipate treatment in SMM failed to give a benefit, but it should be taken into account that discrimination according to the risk of progression was not considered [14]. The first study that reported significant results in SMM was the Phase III trial performed by the Pethema Group, where 119 high-risk patients were randomized between treatment with lenalidomide-dexamethasone versus observation. The definition of “high-risk disease” was based on the presence of unfavorable features considered in both the Mayo Clinic and Spanish models: BMPC infiltration of at least 10% and an M-protein (IgG ≥ 3 g/dl, IgA ≥ 2 g/dl, or urine Bence Jones protein > 1 g per 24 h), or only one of these criteria and ≥ 95% aberrant PC by flow cytometry and immunoparesis [17]. Recently, updated data have shown that after a median follow-up of 64 months, median TTP was significantly longer with lenalidomide-based therapy compared with observation (not reached vs 21 months; hazard ratio, 6.21; p < 0.0001). Importantly, the 5-year survival rate also continued to be higher in the treatment than in the observation group (93 vs 67% at 5 years; hazard ratio, 4.35; p = 0.008) [18].

Final results from a Phase II pilot study have just illustrated that a three-drug combination of carfilzomib, lenalidomide and dexamethasone is a very effective association in this setting. All patients treated (n = 12) achieved a CR and 92% were negative for minimal residual disease by multi-color flow cytometry, with a manageable safety profile [19].

Interesting new approaches could have a key-role in the history of SMM. Based on promising results obtained with PVX-410, a cancer vaccine, in a Phase I/II dose-escalation trial, this agent is now given in association with lenalidomide. This therapy could reinforce the quality of response and improve the outcome, due to a synergistic effect of these two compounds with immunomodulatory properties [20]. The published Phase III studies are summarized in (Table 2).

Table 2. Selected Phase III trials for treatment of SMM.

Authors	Treatment	Schedule	N	Disease	End points	Response	TTE	Key toxicities (% of patients)
Musto et al. (2008) [16]	ZA versus observation	ZA: 4 mg every month	163	SMM	Primary: 5-year PFS Secondary: TTP, SREs, AEs	NA	Median TTP: 67 versus 59 months (p = NS) PFS and OS: not different	SREs: 55 versus 78% (p = 0.04)
Witzig et al. (2013) [15]	T- ZA versus ZA	ZA: 4 mg every 28 days T: 200 mg continuously	68	SMM	Primary: TTP Secondary: ORR, 1-year PFS, DOR, AEs	ORR: 37% versus 0	Median TTP: 2.4 versus 1.2 years (p = 0.02) Median OS: not different	Grade ≥ 3 hematologic: 20 versus 6% Grade ≥ 3 fatigue: 3 versus 9% Grade ≥ 3 venous thromboembolism: 3 versus 3%
Mateos et al. (2013, 2014) [17,18]	RD versus observation	R: 25 mg days 1 – 21 of 28-day cycle for the first 9 cycles, then 10 mg same days for 2 years D: 40 mg on days 1 – 4, 12 – 15 for the first 9 cycles	119	HR SMM	Primary: TTP Secondary: ORR, OS, AEs	RD arm: ORR: 90% CR: 26% sCR: 12%	Median TTP: NR versus 21 months (p <0.0001) 5-year OS: 93 versus 67% (p = 0.008)	Grade ≥ 3 hematologic: 9% versus 0 Grade ≥ 3 infection: 6% versus 0 Grade ≥ 3 rash: 3% versus 0 Grade ≥ 3 asthenia: 6% versus 0 Grade ≥ 3 diarrhea: 2% versus 0

AEs: Adverse events; CR: Complete response; D: Dexamethasone; DOR: Duration of response; HR: High risk; NA: Not applicable; NR: Not reached; NS: Not significant; ORR: Overall response rate; OS: Overall survival; PFS: Progression free survival; R: Lenalidomide; sCR: Stringent complete response; SMM: Smoldering multiple myeloma; SREs: Skeletal-related events; T: Thalidomide; TTE: Time to event; TTP: Time to progression; ZA: Zoledronic acid.

5. Expert opinion

For many years, in accordance with the guidelines of the IMWG published in 2003, SMM patients were managed with a “watch-and-wait” strategy. Although for the first time in the history of SMM, a therapy demonstrated a significant delay in TTP improving OS, other studies did not find similar results and more data from randomized, multicenter trials are needed before identifying this approach as a standard of care [17]. In addition to efficacy, safety and cost of intervention have to be considered. If patients seem to gain benefit from a long exposition to lenalidomide, continuous treatment may lead to a potential increased risk of secondary malignancies.

Recently the IMWG have proposed new criteria to indicate in which MM patients lacking the traditional CRAB features (hypercalcemia, renal failure, anemia and bone lesions) therapy should be started. As described in this paper, smoldering myeloma is not a homogeneous disease and the evaluation of several biomarkers allows us to appropriately select patients who will obtain a clear benefit from an early treatment [2].

Patients traditionally called “ultra high-risk” SMM should now be re-classified as having an MM, and treatment should be started immediately, before the development of myeloma-related symptomatology. This subgroup includes patients with BMPCs ≥ 60%, and/or a serum involved/uninvolved FLC ratio of ≥ 100, and/or > 1 focal lesion on MRI. Thus, an sFLC assay, a BM aspirate and biopsy, as well as an MRI at least of the spine and pelvis, should be performed before making the decision to start therapy. It is noteworthy that the presence of bone disease at baseline may also be evaluated through low-dose CT or PET-CT instead of MRI, according to the available resources to the patient. However, taking into account limitations in its sensitivity, the skeletal survey is no longer considered the standard method for the initial workup in suspicion of MM.

If patients at low- or standard-risk of progression are to be followed by observation only, particular attention must be paid to those patients with the aforementioned “high-risk features” (Table 1). For this group, the appropriate approach may be enrollment in clinical trials. However, initiation of therapy based only on the presence of these prognostic factors is not recommended in clinical practice. Additional studies on risk factors are needed to better understand the most reliable indicators of progression and consequently further stratify SMM patients.

Declaration of interest

M Offidani & S Gentili honoraria from Celgene and Amgen. The other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.