Smoldering multiple myeloma (SMM) was initially described as a separate clinical entity in 1980 by Kyle and Greipp at the Mayo Clinic (N Engl J Med 1980;302(24):1347-1349). They observed a group of six patients who met laboratory criteria for multiple myeloma, but did not have any signs of hypercalcemia, renal disease, anemia, or lytic bone lesions on plain radiograph (CRAB symptoms).
These patients were monitored for 5-16 years without progression of their disease. As a result of this indolent natural history, they concluded that there exists subgroup of patients with laboratory evidence of plasma cell dyscrasia who will not develop end organ damage and can potentially be spared treatment.
Since then, our understanding of SMM has evolved. While none of the original six patients progressed to multiple myeloma, we now recognize that many patients with SMM will progress to multiple myeloma and ultimately require treatment. As a result, there has been ongoing research in order to better understand who is at risk for progression to multiple myeloma ultimately requiring treatment and who can be monitored with low likelihood of developing clinically relevant disease.
Risk stratification is important because the question remains as to whether early disease recognition and treatment will prevent future complications and change its natural history. In multiple myeloma patients, renal impairment at diagnosis, even if it improves with treatment, predicts for inferior overall survival compared to those with no renal disease (PLoS One 2014;9:e101819; Blood Cancer J 2015;5:e296). In addition, the genetic landscape of SMM is less complex than multiple myeloma (Nat Rev Clin Oncol 2017;14:100-113), potentially resulting in fewer resistant mutations, and thus SMM may be more treatment responsive. However, further investigation is still needed to understand whether early intervention will lead to less morbidity, improved responses to treatment, and an overall survival benefit in this patient population.
Defining Smoldering Multiple Myeloma
When originally described, SMM was defined as individuals who had bone marrow plasma cell (BMPC) percentage ≥10 percent, M-Spike ≥3gm/dL, and urine monoclonal protein 500mg/24h in the absence of CRAB symptoms (N Engl J Med 1980;302(24):1347-1349). Given the known clinical heterogeneity of this entity, the rate of progression from SMM to multiple myeloma changes over time with the highest risk within the first few years of diagnosis.
Risk stratification criteria has changed over time in order to identify those at highest risk for progression within the first 2-5 years of diagnosis. In 2014, the International Myeloma Working Group (IMWG) revised its guidelines expanding the definition of multiple myeloma to include those patients with one of the following: BMPC percentage ≥60 percent and/or free light chain ratio (FLCr) ≥100 or ≤0.01 and/or >1 focal bone lesion seen on MRI, even in the absence of CRAB symptoms. This change was motivated by evidence that these patients have a greater than 90 percent risk of progression to symptomatic multiple myeloma within 2 years of diagnosis (N Engl J Med 2011;365(5):474-475).
As a result, the current definition of SMM is a BMPC percentage between 10 and 60 percent and/or M-Spike of ≥3gm/dL, FLCr ≤ 100 or ≥0.01, no CRAB symptoms (if MRI obtained, fewer than or equal to 1 bone lesion under 5 mm allowed), or other myeloma defining events (Lancet Oncol 2014;15(12):e538-e548).
Risk Factors for Progression
Unlike Monoclonal gammopathy of undetermined significance (MGUS) in which the rate of progression to multiple myeloma for the population as a whole is stable at 1 percent per year, in SMM, the rate of progression to multiple myeloma changes over time—10 percent over the first 5 years, 3 percent over the next 5 years, and 1 percent for the following 10 years (N Engl J Med 2007;356(25):2582-2590).
In SMM, this landmark study concluded that BMPC percentage, M-protein level, immunoparesis (reduction of uninvolved immunoglobulins), immunoglobulin heavy chain type, and histologic pattern of bone marrow involvement all contributed to risk for progression (N Engl J Med 2007;356(25):2582-2590). Through this work a clinical risk model was developed to determine risk of progression to multiple myeloma (Table 1). It was recognized that the low-risk group was similar to MGUS with a stable rate of progression to multiple myeloma over time. However, the high-risk group had a high rate of progression in the first few years, but the rate of progression decreased over time. This change in rate of progression of the high-risk group is indicative of the limitations of the clinical risk model in that some “high-risk” patients, ultimately had more indolent disease. In 2008, serum FLCr was added to this risk model (Blood 2008;111(2):785-789) (Table 1).
Independent of clinical parameters, chromosomal abnormalities have also been shown to be prognostic for progression to symptomatic multiple myeloma (J Clin Oncol 2013;31:4325-4332). Abnormalities such as 17p, t(4:14), and +1q21 were shown to be predictors for progression. Other parameters such as immunoparesis, IgA SMM, >95 percent clonal BMPC, evolving M-protein level, and high levels of circulating plasma cells (absolute peripheral blood plasma cells >5 x 106 cells/L) have also been described as risk factors for progression (Br J Haematol 2009;148(1):110-114; Eur J Haematol 2016;97(3):303-309; Leukemia 2013;27(3):680-685; Leukemia 2018;32(6):1427-1434).
No single risk model comprehensively incorporates all the clinical and pathologic variables listed above; however, some of the models are highlighted in Table 1. It should be noted that many of these models were developed before the revised IMWG guidelines for the definition of SMM (Lancet Oncol 2014;15(12):e538-e548) and so newer thresholds for some of these risk factors (i.e., FLCr) are being proposed (Blood Cancer J 2018; doi:10.1038/s41408-018-0077-4). In addition, as we learn more about the transcriptional landscape of multiple myeloma through gene expression profiling, genomics are now being incorporated into these risk models as well (Table 1) (Blood 2014;123(1):78-85).
Progression to multiple myeloma from normal bone marrow to its precursor state (MGUS or SMM) to clinically evident disease involves clonal evolution and subclonal heterogeneity (Nat Rev Clin Oncol 2017;14:100-113).
Initiating events for this process usually include copy number variations (i.e., hyperdiploidy) or translocations involving the immunoglobulin heavy chain (IgH) located on chromosome 14 (i.e., t(11:14); t(4:14); t(14:16)). While these cytogenetic abnormalities occur early in the disease course and are primarily mutually exclusive events, they are not sufficient for progression to clinically symptomatic disease (Nat Rev Clin Oncol 2017;14:100-113; Blood 2002;100(4):1417-1424).
Secondary events, acting as driver mutations, typically affect one or more of the following pathways: NF-κB pathway, MAPK pathway, DNA repair pathway, and plasma cell differentiation. These driver mutations tend to associate with unique primary events; however, some overlap does occur—mutations in DIS3 and FGFR3 with t(4:14), KRAS, NRAS, DIS3, IRF4 with t(11:14), and KRAS, NRAS, FAM46C, BRAF, EGR1, CYLD with hyperdiploidy (J Clin Oncol 2015;33:3911-3920).
While the complex genomic landscape of multiple myeloma and its precursor disease states are being increasingly characterized, they have only minimally added to clinical risk stratification for progression of disease. The SWOG S0120 study used gene expression profiling with a distinct genetic signature as a risk factor for progression (Blood 2014;123(1):78-85). As discussed, 17p deletion/p53 mutation, t(4:14), and +1q21 were known to be independent risk factors for progression of SMM.
Mutations in the RAS and NF-κB pathway are prognostically neutral. Changes in the DNA repair pathway such as 17p deletion/TP53 mutations, ATM mutations confer a poor prognosis, which is consistent with existing data. IRF4 and EGF1 are notable in that they confer a favorable prognosis (J Clin Oncol 2015;33:3911-3920).
Given some of the limitations of analyzing genomics at a static point in time, another mechanism for utilizing genomics to predict risk for progression is to trend the predominance of the mutational burden of clonal cells to predict emergence of clinical disease. A case study analyzing the emergence of a predominant clone over time demonstrated the emergence of a subclone containing loss of 1p and rearrangement of MYC resulting in rapid progression to symptomatic multiple myeloma (Haematologica 2009;94:1024-1028).
This strategy was reinforced by a larger study examining the clonal expansion of genetically abnormal plasma cells (Clin Cancer Res 2017;17(7):1692-1700). Further studies need to be conducted to validate this approach and multiple considerations such as cost, frequency of monitoring, and predictive correlation to clinical parameters need to be examined before it can be considered a standard of care.
Treatment options for SMM, to a large extent, are still investigational; no one treatment paradigm exists and multiple ongoing clinical trials are trying to determine the best treatment approach.
The first trial for treatment of SMM, published in 1993, examined the role of melphalan and prednisone (Eur J Haematol 1993;50(2):95-102). The study enrolled 50 patients with smoldering myeloma and were randomized 1:1 to treatment versus deferred treatment until progression. The study concluded that there was no benefit to early treatment. However, with a median follow-up of 5 years, there was an increased risk for complications with cytotoxic chemotherapy, including development of acute leukemia in the early treatment arm (two patients–8%).
As a result, the treatment paradigm was to observe patients until progression to multiple myeloma before considering treatment. However, this study did not risk stratify patients and the inclusion of low- and intermediate-risk patients may have masked a potential benefit that would have been seen if they had selected only high risk patients.
It was not until 2013 that the paradigm of observation for SMM was questioned (N Engl J Med 2013;369(5):438-447). One hundred twenty-five patients were randomized in 1:1 fashion to receive lenalidomide/dexamethasone followed by lenalidomide maintenance up to 2 years (9 months of 28-day cycles of lenalidomide 25 mg/day days 1-21 and dexamethasone 20 mg days 1-4 and 12-15 followed by 15 months of single-agent lenalidomide [10 mg days 1-21 every month]) versus observation.
The primary endpoint of the study was progression-free survival (PFS). Long-term follow-up (median 75 months) revealed a significant PFS difference in favor of the treatment arm versus observation (median not reached vs. 23 months). While the initial publication of this study (median follow-up of 40 months) showed a significant survival benefit at 3 years (94% vs. 80% p=0.03), at long-term follow-up, median survival was not reached in either group.
While these results are significant and suggest treatment for high-risk SMM should be the standard of care, the generalizability of its findings with the current definition of SMM has been questioned. About 19 percent of the patients in the observation arm had biological progression to the current definition of multiple myeloma, but were not treated until CRAB symptoms developed, resulting in what currently would be considered a delay in treatment.
In addition, the protocol allowed for escalation of therapy in the treatment arm if there was biological progression during the maintenance phase. While it was not standard of care at the time of study design, it is not clear whether treatment for biochemical progression in the observation arm would have abrogated some of the PFS or overall survival benefit observed. Since intervention in SMM remains investigational, NCCN guidelines still recommend observation versus enrollment in a clinical trial.
Another study evaluated the safety and efficacy of carfilzomib-lenalidomide-dexamethasone for newly diagnosed multiple myeloma and high-risk SMM (according to PETHEMA criteria—Table 1). Twelve of 57 participants (21%) had a diagnosis of high-risk SMM. The primary endpoint of this study for the SMM arm was very good partial response (VGPR) or better. Minimal residual disease (MRD) was also assessed. All SMM patients achieved at least a VGPR. Ninety-two percent and 75 percent were MRD-negative by multiparametric flow cytometry and next-generation sequencing, respectively (JAMA Oncol 2015;1(6):746-754).
Other studies such as one evaluating elotuzumab-lenalidomide-dexamethasone also showed significant response rates in patients with high-risk SMM (Blood 2016;128:976). However, long-term follow-up and future trials are needed to assess whether these high response rates translate into a survival benefit.
Ongoing studies are being conducted in order to best understand what the optimal treatment regimen is, when the best time to initiate treatment is, and which population would benefit most from treatment. One of the challenges of these studies is that, as individuals are living longer with multiple myeloma, investigators need long-term follow-up to conclude whether early treatment has a real effect on improving overall survival.
PFS and overall response rate are often the primary outcomes in these trials, but they are not necessarily the strongest predictors of improved overall survival. This has made MRD an interesting surrogate endpoint as that has been shown to be more correlative with overall survival in multiple myeloma as compared to other response criteria (J Clin Oncol 2017;35:2900-2910; JAMA Oncol 2017;3(1):28-35).
However, different modalities exist to assess MRD and it has not yet been standardized across institutions or clinical trials. While some trials are evaluating MRD, they are not currently using it as the primary endpoint. However, this will likely change in the near future. Some of the trials that are actively recruiting include the following: NCT02916771, NCT03301220, NCT02960555, NCT02943473, NCT03236428, NCT01572480, NCT02726750, NCT02269592.
Our understanding of SMM has improved dramatically since it was originally described by Kyle and Greipp in 1980. We continue to improve upon our risk stratification and are beginning to develop optimal treatment strategies for this patient population.
The clinical heterogeneity of this patient population makes it critical that we distinguish between those who are unlikely to progress and have no clinical sequelae and those who will progress, where early intervention could potentially avoid debilitating clinical symptoms, improve overall survival, and potentially cure patients of their disease.
ADAM BINDER, MD, is Assistant Professor of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia. PIERLUIGI PORCU, MD, is Professor of Medical Oncology, Dermatology, and Cutaneous Biology, and Director, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Sidney Kimmel Cancer Center, Thomas Jefferson University.
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