Smoldering myeloma (SMM) is a clinically heterogeneous disease, with some patients having a slow clinical progression similar to monoclonal gammoplasmosis of undetermined significance (MGUS) and others having a more aggressive course described as “early myeloma”.
The diagnosis of SMM requires a serum M protein ≥3 g/L or ≥10% plasma cells in the bone marrow, and there are no molecular markers to detect risk factors associated with disease progression, and currently the recommended treatment remains follow-up or voluntary enrollment of patients in clinical trials. However, the International Myeloma Working Group (IMWG) has agreed on a new definition of active multiple myeloma that may change the timing of SMM treatment.
Based on the available data on patient care, it will become an increasingly hot topic to recommend treatment for patients with SMM. Ghobrial et al. at the Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA, review the existing knowledge of this disease and the risk factors associated with disease progression, while examining the molecular biological insights and alterations in clonal tumor cells and the bone marrow stromal microenvironment. Finally, the results of clinical trials in patients with SMM are reviewed and recommendations for the follow-up of patients with this unique disease are presented. The paper was published in BLOOD on November 27, 2014.
Although effective targeted therapy for multiple myeloma (MM) has been available for the past decade, the clinical utility of targeted therapy has been hampered by drug resistance, clonal evolution, and disease progression, requiring us to further explore this elusive disease. However, the controversial view is that starting treatment when MM is symptomatic is equivalent to treating solid tumors when they metastasize.
Thus, even with the best current drug combination regimens in clinical practice, most patients are still not cured. Therefore, most have begun to address the question of whether treatment is needed in the prodromal asymptomatic phase of MM, with the ultimate goal of halting disease progression and achieving a cure.
MM can progress from the prodromal state of MGUS and SMM, which indicates that the tumor load remains a continuously progressive process in the absence of symptoms or signs of end-organ damage.
The authors review the current understanding of SMM, including the clinical risk factors that can contribute to disease progression. The recommended treatment for most patients is still long-term follow-up observation or clinical registration trials. However, the definition of active MM and indications for treatment were recently agreed upon by the IMWG.
Based on the available treatment SMM data, long-term and sustained remission has been shown to significantly improve progression-free survival (PFS) and overall survival (OS). Based on the above reasonable presentation, it is reasonable to believe that treatment of SMM will become a hot topic in the near future.
1. Case description
A 42-year-old pediatrician presented to the clinic with blood tests that revealed the presence of monoclonal protein in the serum. He was in good health and had frequent sinus infections in the past year, which he thought were caused by work exposure to infected children. Routine laboratory tests revealed an elevated protein level of 9.5 g/dL (reference range: 6.0-8.0 g/dL). Serum protein electrophoresis showed immunoglobulin (Ig) A κ light chain of 3.5 g/dL. There was no bone pain, fever, or weight loss. Serum creatinine level and calcium ion concentration were within the normal range. κ light chain was elevated and κ/λ ratio was 30. Serum IgG and IgM levels were decreased. Further examination did not reveal osteolytic lesions, and MRI did not show focal damage.
Bone marrow biopsy revealed 30% plasma cells in a single, clustered, sheet-like distribution. Immunophenotyping allowed the isolation of 95% of abnormal plasma cells that expressed CD38, CD138, CD56 by flow cytometry, had excessive cytoplasmic secretion of κ light chains, and had abnormal staining. Cytogenetics and fluorescence in situ hybridization showed an increase in the long arm of chromosome 1.
2. How is a patient with SMM diagnosed and initially evaluated?
SMM is a clinically heterogeneous disease with a higher risk of disease progression than MGUS, and the timing of treatment is unclear because of the lack of end-organ damage that meets the diagnostic criteria for MM. In 2003, the IMWG developed a uniform definition of MGUS and SMM, with MGUS defined as serum M protein <3 g/dL with <10% monoclonal plasma cells in the bone marrow, and SMM defined as serum M protein ≥3 g/dL or ≥10% monoclonal cells in the bone marrow (Table I), both without end-organ damage.
Criteria for end-organ damage CRAB definition: hypercalcemia (serum calcium ≥11.5 mg/dL), renal failure (creatinine ≥1.95, excluding other causes), anemia (hemoglobin ≤10 g/dL or more than 2 g/dL below the low limit of normal), and bone damage (osteolytic changes, pathologic fractures, spinal cord compression).
The tests required for grading of patients with SMM are similar to those required for the diagnosis of MM (Table II), which requires an adequate tumor cell load and monoclonal protein in the bone marrow, but lacks symptoms or signs of end-organ damage.
Recent recommendations include spine and pelvis MRI or low-dose CT for more timely disease prediction (see SMM imaging studies section for details). Recently expanded clinical diagnostic and early treatment criteria for MM that are clearly progressive include bone marrow plasma cells ≥ 60%, an involved free light chain (FLC) to non-involved light chain ratio ≥ 100, and/or focal bone marrow lesions seen by functional imaging such as PET-CT and/or MRI ≥ 2.
3, SMM imaging studies
One of the CARB criteria defines symptomatic MM requiring the presence of osteolytic damage, which was previously assessed using skeletal plain radiographs, which, although safe and inexpensive, can only be detected when there is a 30%-50% reduction in bone mass. When patients with SMM present with ≥2 focal bone marrow lesions, they can progress to active MM in a very short period of time, making it a new criterion for initiating treatment of MM.
In addition, CT can detect bone damage earlier, and low-dose CT has been used in some studies as a means of detecting end-organ damage. In addition, functional techniques such as PET (PET-CT or PET-MRI), dynamic-enhanced MRI, and diffusion-weighted imaging MRI can provide information on functional disease activity.
4. SMM follow-up, assessment of risk factors and chance of progression
The incidence and prevalence of SMM is unclear and is estimated to account for 8% to 20% of MM. In a recent review of 2494 myeloma patients in the Swedish myeloma registry from 2008 to 2011, 360 (14.4%) were eligible for SMM. 104 (28.8%) of these SMM patients were of high-risk type (defined as M protein ≥3 g/dL and plasma cell infiltration ≥10%), representing 4.2% of all myeloma patients. Using the world population as a reference, the age-standardized incidence of SMM was 0.44 cases/100,000 persons and the incidence of high-risk types was 0.14 cases/100,000 persons.
Based on the Mayo Clinic retrospective study, the overall risk of SMM progressing to MM is 10%/year for the first 5 years, 3%/year for the next 5 years, and 1%/year for the last 10 years, indicating a high degree of biological and clinical heterogeneity in SMM as currently defined.
The frequency of follow-up of these SMM patients depends on the above mentioned risk factors for disease progression. 2010 IMWG guidelines suggest that SMM patients should be tested every 2 to 3 months in the first year, followed by 4 to 6 months per year, and eventually 6 to 12 months if clinically stable. The authors of this article recommend more intensive follow-up (at least every 3 months if not on treatment) for patients with high-risk SMM.
Indeed, SMM is a heterogeneous clinical disease, meaning that some patients are in a very inert process, similar to the MGUS-like stage, while others have a more aggressive clinical process, i.e. patients with myeloma described as early stage or CRAB-negative myeloma. There are currently no molecular factors to distinguish between these two clinically and biologically distinct subgroups, and further studies are needed to identify markers for these progressive patients.
Current risk factors associated with disease progression are based primarily on the level of tumor load in SMM patients, through analysis of tumor cell involvement in the bone marrow and quantification of peripheral blood monoclonal proteins. Both of these factors have been used extensively for risk stratification by the Mayo Clinic and by the Spanish Programa para et Tratamiento de Hemopatias Malignas (PETHEMA) study group for this disease.
The Mayo Clinic mainly based on serum protein marker levels (serum protein electrophoresis and FLC analysis) and the percentage of plasma cells in the bone marrow. the PETHEMA study group risk stratification focused on the application of bone marrow multiparametric flow cytometry to quantify the ratio of abnormal plasma cells in the bone marrow, and the reduction of uninvolved globulin. However, there were significant differences between the two organizations’ assessments, i.e., many patients had one criterion suggesting high risk and the other suggesting low risk.
Other detectable risk factors include IgA (vs IgG type) phenotype, proteinuria, peripheral blood plasma cell count, high rate of plasma cell proliferation in the bone marrow, and abnormal MRI presentation.
Recent studies have shown that plasma cell chromosomal abnormalities are also a key factor in the progression of SMM. Two studies have shown that 17q deletion or t(4;14) is associated with the shortest time to progression (TTP) and that triploidy is also a risk factor for progression. increased mutations in chromosome 1q21 also increase the risk of progression in SMM patients.
Therefore, patients diagnosed with SMM should first be risk stratified (applying both Mayo and PETHEMA criteria). In addition, other high-risk progression factors such as cytogenetics, peripheral plasma cell counts, changes in serum protein electrophoresis M spikes, and MRI imaging changes should be taken into account.
Clearly, the old classification of “ultra-high risk” should be reclassified as MM with a clear risk of progression requiring clinical intervention. These patients include: bone marrow plasma cells ≥ 60%, abnormal FLC ratio ≥ 100 (κ chain involvement) or < 0.01 (λ chain involvement), and/or focal bone lesions ≥ 2 on PET-CT and/or MRI imaging.
The patient mentioned above was diagnosed as high risk according to Mayo Clinic and PETHEMA evaluation criteria. Therefore, this patient may have a more rapid clinical progression with a 5-year progression rate of 70% to 80%.
5. Choosing SMM treatment options: observation or early treatment
The standard treatment for patients diagnosed with SMM today is a watchful waiting strategy. However, clinical trials showing different PFS and OS in patients with SMM may make this standard of care subject to change.
The SMM patient mentioned above showed rapid progression after one year of follow-up, with a bone marrow biopsy suggesting 70% plasma cells. Based on CRAB criteria, this patient showed no other evidence of symptomatic MM, but needed to be started on treatment based on the current redefinition of high-risk SMM patients as myeloma with a “myeloma-defining event (MDE)” with a clear risk of progression.
Therefore, the latest classification change treats patients who meet the criteria for MDE as symptomatic MM. Such patients should be excluded from future SMM clinical trial studies.
The idea that early intervention may significantly improve outcomes has been tested for many years. There are two main ideas for interventional therapy, the first is to stop disease progression and the second is etiologic therapy, which attempts to eradicate subclonal cells at an early stage of the disease to achieve complete remission or even a cure.
The main obstacle to early intervention is how to define the population of patients who can really benefit from early treatment. In fact, if SMM is a mixture of early-stage myeloma and MGUS-like myeloma, early-stage MM is the only patient that really needs intervention. Unfortunately, there are no biological markers of SMM disease progression, except for tumor load indicators in risk stratification.
In the 1990s, the first application of marfalan and prednisone to test the early intervention hypothesis did not show an advantage in terms of survival. Subsequent SMM studies with bisphosphonates (including 2 randomized controlled studies) showed no improvement in OS or time to progression, but a reduction in bone-related events.
The next drug in the trial was thalidomide. The thalidomide/zoledronic acid group significantly improved PFS compared with the zoledronic acid-only group, at 29 and 14 months, respectively, but there was no difference in PFS (49 and 40 months, respectively) or OS (6-year OS, 70%) as defined by CRAB events between the two groups.
The results of the most important study on SMM, the PETHEMA Study Group, which designated lenalidomide and dexamethasone as the intervention treatment group and compared it with the observation group, have generated great interest. The treatment group had higher 3-year progression-free survival (77%, 30%, respectively) and OS (94%, 80%, respectively).
However, enrollment required meeting 1 or more of 2 sets of high-risk disease definition (Mayo Clinic or PETHEMA risk stratification criteria) criteria. However, there are some concerns about the generalized findings of this trial, and care needs to be taken to compare the results of different clinical trials and trials. Therefore, every effort should be made to collect information on all risk factors for disease progression. In addition, the study was not clear about the asymptomatic biological progression in both groups, the transient OS in the dropout group, and the salvage treatment in the dropout group.
For these reasons, further studies are needed before implementing interventional treatment criteria for high-risk SMM. However, this study was challenging enough to inspire the development of many clinical trials investigating the treatment of high-risk SMM. Many drugs have been tested, including carfilzomib/lenalidomide in combination with dexamethasone, and the latest immunotherapies such as 7-elotuzumab, a member of the targeted signaling lymphocyte activation molecule family, CD38-targeting antibodies, and programmed cell death-1 targeting antibodies.
6. Recommendations
Based on the current definition of SMM, SMM is not a unique biological disease, but rather a step in the ongoing clonal evolution and progression of tumor cells in the bone marrow microenvironment that eventually leads to symptomatic MM. However, the understanding of SMM gives us the opportunity to understand the biological steps of disease progression and therefore to stop/delay disease progression or even cure the disease by targeting tumor cells before significant clonal heterogeneity occurs, immune disorders and abnormal regulation of the bone marrow microenvironment, thus intervening therapy.
Previous attempts to test the hypothesis of early intervention to halt progression or cure myeloma have failed. It was not until lenalidomide in combination with dexamethasone showed promising findings that early intervention had a survival advantage. However, more pilot studies are needed before the results of this study can be adopted in the clinic.
The biggest current practice change in SMM is the reclassification of a subset of patients with high-risk SMM as MM at significant risk of progression with MDE, and the treatment of these patients should be equivalent to that of symptomatic patients. For all other SMM patients, the authors suggest that they should also be carefully monitored or enrolled in clinical trials to better assess the role of early intervention in this disease.
We believe that a more meaningful molecular profile could be used to identify patients with early stage myeloma who are at high risk of progression to symptomatic MM and MGUS-like stages that do not benefit from treatment. Although formal testing and confirmation are needed, we suspect that early stage myeloma is less genetically unfavorable and that some patients can achieve a cure with the available effective drugs. Ongoing and future studies are expected to provide answers to these questions.