Parameswaran Hari, MD
Professor of Medicine
Section Head - Hematological Malignancies and BMT
Division of Hematology Oncology
Medical College of Wisconsin
Milwaukee, Wisconsin

The Patient:

A 57-year-old woman (NB) presented to her primary care doctor for a routine annual visit and physical. A CBC and chemistry panel were obtained during her evaluation and showed an elevated total protein level of 9.3 g/dL. Further work up including serum protein electrophoresis (SPEP) and immunofixation (IFE) indicated the presence of an IgG lambda monoclonal spike (M spike) of 2.52 g/dL.   As a reminder, the diagnostic work-up required for multiple myeloma as well as tests that are useful under certain circumstances can be found in table 1.a and 1.b, respectively as listed in the NCCN Guidelines for multiple myeloma.

Baseline Results in 2007:

Hemoglobin was 13.2 g/dL, with hematocrit 39%.  Platelets were 287 k/μL. White cell count was 11,000 μL, with a normal differential. The patient's calcium was 9.5 mg/dL, creatinine 0.7 mg/dL. Beta2 microglobulin levels were 2 mg/mL. Albumin was 3.6 g/dL (see table 2a). 

Bone marrow aspirate and biopsy showed a marrow plasmacytosis of 30% against an overall background of normal to mildly increased marrow cellularity, myeloid and erythroid precursors were unremarkable. Overall plasmacytosis was estimated at 30% after CD138 staining. Flow cytometry showed the presence of CD56 positive, CD19 negative, lambda light chain restricted plasma cells. 

Metastatic bone survey: NO evidence of osteolytic or osteoblastic bone lesions.

IgG levels were 4075 mg/dL. IgA and IgM were 63 mg/dL and 61 mg/dL respectively. Repeat protein electrophoresis confirmed a 2.77 g/dL M-spike consisting of IgG lambda (see table 2b). Urine protein electrophoresis positive for small faint IgG lambda excretion by immunofixation. 

Cytogenetics and myeloma specific FISH studies were performed on the bone marrow biopsy showed a normal karyotype and 4.5% cells with monosomy 13 abnormality by FISH alone. 

Patient denied any symptoms and specifically had no constitutional, neuropathic or infection related issues. She had been worked up for a high ESR 2 years prior and no obvious cause was discovered. Other concomitant medical problems included hyperlipidemia and degenerative joint disease.

Questions for the clinician:

Does my patient have Multiple Myeloma, Smoldering (Asymptomatic) Myeloma or Monoclonal Gammopathy of undetermined significance (MGUS)?

The most widely followed classification of plasma cell disorders is the IMWG schema from 2003 and 2010 which divided the spectrum of clonal PC disorders into MGUS, SMM and symptomatic MM. This classification is based on the overall disease burden and the presence of symptoms or signs of organ injury attributable to clonal PCs.

Multiple Myeloma requiring treatment (or active MM or symptomatic MM) is diagnosed based on the presence of PC related end-organ damage in the setting of laboratory evidence of a clonal PC process (M-protein and or monoclonal PC). End-organ damage in plasma cell disorders is indicated by hypercalcemia, renal insufficiency, anemia, bone lesions (the so called “CRAB” criteria). It is well recognized that other types of end organ damage (such as severe osteoporosis, neuropathy, amyloidosis, recurrent infections and hyperviscosity) can sometimes be attributed to clonal PCs. Table 3 summarizes the most recent definition of end organ damage from IMWG 2010 and NCCN criteria.

The pre MM states of MGUS and SMM are defined on laboratory criteria and the absence of end organ damage. Smoldering (asymptomatic) multiple myeloma is characterized by an M protein level of > 3 g/dl or a clonal marrow plasmacytosis of > 10% with no evidence of end-organ damage attributable to PC proliferation. MGUS is defined by an M protein <3 g/dl, <10% clonal PCs in the bone marrow (BM) and the absence of end-organ damage.

Based on these criteria, the patient in question carries a diagnosis of SMM. The key management issues in this scenario are 1) identifying MM precursor disease states vs. MM needing treatment based on clinical, laboratory and imaging criteria 2) defining risk of progression in those with MM precursor states 3) identifying pts who might benefit from early treatment 4) defining a follow up schedule. Emerging data and biological insights have raised the possibility of identifying those at the highest risk for imminent progression or might benefit from early treatment (while still not meeting current definitions of end organ damage criteria). 

End Organ Damage and Limitations of CRAB criteria:

Since the differentiation between SMM and MM relies entirely on the detection of end-organ damage, detailed multidisciplinary clinical assessment is critical in addition to CBC, chemistry and traditional skeletal X-rays. The clinician’s responsibility to exclude impending problems and stratify risk is greater in patients with SMM who do not receive therapy. Detection of early skeletal involvement is especially difficult.

Modern imaging such as low dose CT bone scans, MRI scans or functional imaging with PET-CT or PET-MRI may detect bone damage earlier in the disease course. Among SMM patients with no bone lesions on skeletal X-rays up to 50% may have bony abnormalities on MRI of the lower spine. Whole body MRI techniques offer an overview of BM disease burden and specific patterns of marrow involvement (diffuse vs. focal). It has been reported that SMM patients with >2 focal bone lesions on MRI have a shorter median time to symptomatic MM. Similarly up to a third of SMM pts may have a diffuse pattern of marrow involvement comparable to MM pts. It is important to recognize that lack of insurance coverage, specialized radiologic expertise and implantable devices in patients may limit wide spread use of WB-MRI. PET-CT may be superior with regard to many of these limitations and is especially useful in excluding active MM.

Natural History and the risk of progression to MM:

Long term follow up data from the Mayo group suggest that the natural history and long term cumulative progression rate of SMM is about 10% per year for the first 5 years following diagnosis, thereafter reducing to 3% per year for the next 5 years and 1% per year for the remainder who have had no progression at 10 years. Thus the lowest risk end of the SMM spectrum consists of a significant proportion of patients (more than 20%) with a risk profile similar to that of MGUS. Thus SMM is best thought of as a heterogeneous grey area between MGUS and active MM. Majority of patients with SMM are in a pre-MM state, eventually progressing to therapy (as opposed to MGUS where the annual progression rate is 1%).

Some of highest risk patients in currently defined SMM state may have annual progression rates up to 40% (based on a variety of risk factors) and survival rates similar to those with symptomatic myeloma. Numerous risk factors and different schema have been proposed. Some of the risk factors used in various schema for SMM progression models include: IgA isotype, involved FLC >8 times that of uninvolved FLC, circulating plasma cells detected by immunofluorescence, high plasma cell proliferation index, suppression of uninvolved immunoglobulin subtypes and a high fraction PCs with aberrancy. Should the highest risk SMM pts be reclassified as active MM or considered candidates for treatment in order to reduce imminent morbidity and avoid unnecessary treatment delay?

Early intervention strategies entail the risk of unnecessary therapy and side effects and the benefits of any such strategy depends on the validity of the risk stratification scheme. On the one hand, for those with >60% BM PCs at diagnosis, the median time to progression was 7 months and almost all of them (95%) progressed to MM eventually. It is very reasonable to reclassify this group (>60% PCs) in the category of MM requiring treatment.

Identifying SMM patients with high risk of progression to MM:

The Mayo Clinic group has proposed a model that includes 1 point each for each of the following risk factors: M-protein level ≥3 g/dL, BM PCs ≥10%, and an FLC ratio (of < 0.125 or >8).  The risk of progression to active MM at 5 years was 25%, 51%, and 76% those with 1, 2 or 3 risk factors respectively. A model developed by the Spanish PETHEMA group uses ≥ 95% aberrant BM PC (CD19 negative and/or CD45 expression, CD56 positivity, or weak CD38) detected by flow cytometry and uninvolved immunoglobulin suppression as independent risk factors. Progression rates at 5 years were 4%, 46%, and 72% for those with 0,1 or 2 risk factors, respectively. Concordance in risk assignment between the 2 models was found to be low in a recent study by NIH group. Models incorporating gene expression profiling (GEP) and proteomic profiling have also been proposed. The 2 most common models are compared in Table 4.

Cytogenetic abnormalities:

In terms of the risk of progression to MM, deletion 17p or t(4;14), gain of 1q21 and chromosomal trisomy have all been shown to be risk factors, with greater impact among those with a low disease burden at diagnosis. Survival after progression to active MM is similar to the established data in MM - poor OS for deletion 17p or t(4;14) anomalies but not for trisomy. In contrast, a recent GEP analysis indicates that SMM and MGUS share the same GEP abnormalities seen in active multiple myeloma (MM) but only the proliferation subtype was predictive of progression.

Time to revise the “CRAB” criteria:

Revision of current end organ damage criteria has been proposed by several groups including the IMWG. Some of the proposed criteria for re-classifying asymptomatic individuals as active MM pts needing therapy include: BM plasmacytosis ≥ 60%, involved free light chain >100 times the uninvolved or focal BM lesions detected by PET or MRI imaging. Newest NCCN criteria (version 2.2014) also recognize the need for reclassification of high risk SMM (Table 3).

PETHEMA – Qui REDEX Study and early treatment of SMM:

The established standard of care in SMM is close observation and treatment only after progression to active MM. This recommendation is based on the lack of survival or PFS benefit for agents such as melphalan, bisphosphonates or thalidomide in prior randomized trials. These findings have been recently challenged by the PETHEMA sponsored QUIREDEX study (NCT00480363) reported by Mateos et al. They randomized a strictly defined high risk sub group of SMM patients to Lenalidomide/low dose dexamethasone vs. observation. High risk was defined by 2 sets of inclusion criteria – one group included those with BM PC >10% AND a high M spike which was set as ≥3 g/dl for IgG, ≥2 g/dl for IgA and >1 g of urine M protein per 24 hours. Another group (40% of all pts) included those with only one of the above marrow or M spike criteria and > 95% phenotypically aberrant BM PCs detected by multi-parameter flow cytometry AND suppression of either of the uninvolved immunoglobulins (i.e IgA or M if IgG SMM) by at least 25%.

Those randomized to lenalidomide / low-dose dexamethasone arm had superior rates of freedom from progression to active MM (77% progression free at 3 yrs vs. 30%, p<0.001) and surprisingly a superior OS (94% alive at 3yrs vs. 80%, p=0.03) compared with the cohort randomized to observation.

This is the first randomized study to suggest survival advantage for early therapy in asymptomatic individuals with SMM albeit in a selected high risk subgroup. Several limitations of this study have been pointed out. Most importantly the sophisticated flow cytometry technique used limits the widespread use of these criteria in current practice. The unexpected observation of inferior survival among untreated SMM pts have led to speculation about the causes. Notably, those in the observation arm did not appear to receive uniform therapy with Lenalidomide based induction at clinical progression or initiation of therapy for asymptomatic biochemical progression which might explain why their 3 yr OS (80%) was not as impressive as current pts with newly diagnosed MM. The lack of genetic risk information and the older median age of the observation cohort could mean that baseline risks between cohorts could have been different. Once treatment is initiated should the high risk SMM pts just be considered active MM and receive standard induction, consolidation, autotransplant and maintenance approaches? The study actually raises more questions than answers.

Nevertheless, the principle that at least a subset of SMM pts benefit from early intervention is an important shift from the established paradigm. The subset of high risk pts stratified by M protein size and PC numbers alone has been estimated to be about 30% of the overall SMM group. Based on a Swedish population registry analysis, out of 360 pts diagnosed with SMM, 30% were defined as high risk by these criteria of whom 57% had progressed to active MM in 2 yrs and 70% by 30 months.  The overall worldwide incidence of SMM of 0.44 cases per 100,000 persons means an incidence of high risk SMM in 0.14 cases per 100,000 persons. In terms of therapy costs, this could entail substantial costs to society.

Does my patient need treatment for SMM – rethinking the timing of therapy in SMM?

The exact intervention needed (e.g. reframe the diagnosis and treat as active MM vs. use a disease slowing drug) and an defining who needs therapy (flow cytometry, FISH abnormalities, disease burden markers, proteomics, genomics, advanced bone imaging) are all works in progress being tested in trials. Reclassification of disease staging is always fraught with the risk of “stage migration bias” which leads to spurious improvements in stage-specific prognosis. When previously lower risk patients are classified into the more severe disease stage on the basis of new early detection technology etc, an apparent improvement in survival can be seen in both groups. This limits the use of epidemiologic / registry data to analyze the benefit of early intervention for lower risk disease. National guidelines emphasize the importance of treating SMM pts as far as possible in prospective trials of intervention vs. no intervention.

A current US intergroup study (NCI E3A06, NCT01169337) randomizes pts with asymptomatic high risk SMM defined as BM PCs >10% or an abnormal FLC ratio to Lenalidomide vs. observation. Another current US trial (NCT01572480) explores the use of Carfilzomib/Lenalidomide/Dexamethasone induction in high risk pts defined by either the Mayo or PETHEMA criteria. It should be mentioned that neither lenalidomide or carfilzomib are approved by the US FDA for the treatment of smoldering myeloma and remain investigational at this time for this population of patients.  Other agents are also undergoing investigation or are planned in this setting.  While the benefits of early treatment and preventing early morbidity are clear for some pts, the potential risks include overtreatment of patients who may never need therapy or those who could have deferred therapy for years. Identification of risk and prediction of end organ damage are not exact at this time and prospective studies with longitudinal observation of larger cohorts of patients are needed.

Most recent NCCN consensus guidelines do NOT RECOMMEND treating all SMM pts, nor those considered at high risk based on PETHEMA study criteria. The consensus of the panel recommends observation at 3 to 6 mo intervals or enrollment in a clinical trial. In an era of changing diagnostic criteria and uncertainty re: treatment initiation, referral to a specialized center for evaluation and trial / treatment recommendations is appropriate.

Follow Up of Patient:

Mrs. NB has continued on follow up for the past 6 years with no further change in disease status. A follow up marrow was performed 1 year after diagnosis and multicolor flow cytometry identified aberrant plasma cells to be 100%. Most recent M spike and Igs are summarized below. Patient remains on clinical follow up with CBC, chemistry panels and biochemical myeloma markers every 6 months. Most recent M spike was 2.53 g/dl (see table 5).

Table 5. Immunoglobulin and free light chain component monitoring 2007 and 2013.

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