A Clinical Practice Guide to Diagnosing Multiple Myeloma with Expansion of Myeloma Defining Events to Include SLiM

The Managing Myeloma Accredited e-Newsletter Volume 2, Issue 1

Plasma cells are terminally differentiated B-lymphocytes whose function is to aid the immune system in fighting foreign pathogens via the production of antibodies. Plasma cell dyscrasias comprise a diverse collection of processes, which stem from malignant cell lines leading to the overproduction of neoplastic cells. These cells typically produce a monoclonal protein, which is the result of the rearrangement of immunoglobulin genes.1 Disorders of plasma cells run the gamut, from more benign entities, such as monoclonal gammopathy of undetermined significance, to incurable malignancies, such as multiple myeloma. Figure 1.

Monoclonal gammopathy of undetermined significance (MGUS) represents the most common plasma cell dyscrasia, affecting approximately 3% of the population aged 50 and older.2 The median age at diagnosis is about 70 years, with fewer than 2% of all cases being diagnosed in patients under the age of 40. There is a slight increase in the prevalence of MGUS in males over females, and in persons of African and African American descent over Caucasian.3

MGUS is defined as having a detectable monoclonal gammopathy that exhibits less than 3 gm/dL of monoclonal protein in the serum and fewer than 10% clonal plasma cells on bone marrow evaluation. Furthermore, the disorder is characterized as having no evidence of plasma cell-related end-organ dysfunction, no hypercalcemia, anemia, lytic bone disease, or renal dysfunction. Whereas patients may have one or more of these symptoms on initial presentation, further investigation must be completed to determine if the abnormality may be due to another disorder such as iron deficiency or parathyroid dysfunction.

The cause of MGUS is not known. The rate of progression to a symptomatic malignancy, such as multiple myeloma or Waldenström’s macroglobulinemia is approximately 1%.2 Although the majority of patients with MGUS will never undergo malignant transformation, there have been cases of progression to symptomatic myeloma after several decades of quiescence. Figure 2.

The recommended evaluation and testing, for patients with a monoclonal gammopathy, is as follows:


Table 1. Evaluation for patients suspected of monoclonal gammopathy*
History and physical examination
Complete blood count (with attention to the hemoglobin)
Serum chemistry evaluation (with attention to the albumin, globulin, calcium and creatinine)
Serum protein studies:
  Serum protein electrophoresis and immunofixation
  Quantitative immunoglobulins
  Free light chain analysis with free light chain ratio
24-hour urine protein collection:
  Total protein excretion
  Urine protein electrophoresis and immunofixation
Examination of bone marrow (aspirate and biopsy)
Skeletal survey
*Berenson JR, et al. Br J Haematol. 2010;150(1):28-38.



Although the overall rate of progression of MGUS to a symptomatic plasma cell dyscrasia is approximately 1% per year, there are factors that contribute to the rate of progression. These factors include the size of the M-protein, the type of the immunoglobulin, and the serum free light chain ratio.4

The size of the M-protein may, in fact, be the most important risk factor in progression of MGUS.5 The risk of progression of a patient with an M-spike of 1.5 gm/dL is almost twice that of a patient with a spike of 0.5 gm/dL. Work by Blade and others has shown that non-IgG gammopathies have a high tendency to progress, specifically IgA.6

There have been a number of studies looking into the relevance of bone marrow plasma cell infiltration as a risk factor for progression. Overall, despite varying techniques and cutoff values, a higher percentage of plasma cell infiltration is associated with a higher risk of progression. Cesana reported a cutoff value of 5%, with those patients demonstrating more robust infiltration having a higher progression rate.7 In another study, the overall progression rate was found to be 6.8% when the bone marrow plasma cell percentage was less than 10%, and 37% when the plasma cells comprised 10-30%.8 Although this now crosses into the realm of smoldering myeloma, the correlation between plasma cell burden and progression rate holds.

The free light chain (FLC) and free light chain ratio have become standard tools in the evaluation of plasma cell dyscrasias, especially in patients with renal insufficiency. Clonal plasma cells exert their clonality through light chain restriction. As a result, the magnitude of the elevation of the involved FLC can act as a surrogate for disease burden. The relevance of the FLC ratio is seen even in the more benign gammopathies such as MGUS. Patients with an abnormal FLC ratio have a higher risk of progression compared to those with a normal ratio.9 This finding is independent of the size or immunophenotype of the para-protein.

The management of MGUS involves observations and not any particular therapy. The interval with which to follow these patients typically ranges from every 6 to every 12 months. These intervals can be increased in patients with low-risk MGUS (M-spike less than 1.5 gm/dL, normal FLC ratio, IgG subtype). Depending upon stability, these patients can potentially be followed once every 2 to 3 years. If there is any clinical change in the patient or concern for an evolving plasma cell malignancy, the patient should be brought back sooner for further evaluation.

Smoldering (asymptomatic) multiple myeloma (SMM) is an intermediary disorder between MGUS and symptomatic multiple myeloma. It represents a disorder associated with a higher tumor burden than MGUS but without the “end-organ” dysfunction associated with symptomatic myeloma. Patients with SMM have either greater than 10% clonal plasma cells on bone marrow evaluation or serum M-spike of greater than 3.0 gm/dL.

The classic “end-organ” dysfunction which characterizes the difference between asymptomatic and symptomatic disease has been defined as the “CRAB criteria” C=calcium, R=renal dysfunction, A=anemia, B=bone disease. Hypercalcemia is defined as calcium levels greater than 11 mg/dL or greater than the upper limit of normal. Renal dysfunction is considered diagnostic once the serum creatinine rises above 2 mg/dL. Symptomatic anemia is characterized as a hemoglobin concentration of less than 10 gm/dL or greater than or equal to a 2 gm drop in hemoglobin from baseline. Bone sequelae of myeloma are defined as the presence of osteolytic lesions seen on skeletal radiography or the presence of osteoporosis (in patients with greater than or equal to 30% marrow plasmacytosis) with no other explanation for the demineralization.

Just as with MGUS, there are distinct features of SMM that are associated with risk of progression to symptomatic disease. The main risk factors associated for progression are abnormal serum FLC ratio (outside the range of 0.26-1.65 ratio of kappa/lambda),* bone marrow plasma cells greater than or equal to 10%, and serum M-protein greater than or equal to 3 gm/dL. Patients with 1, 2, or 3 of these risk factors have 5-year progression rates of 25%, 51%, and 76% respectively. This translates into median times to progression of 10, 5.1 and 1.9 years, respectively.4 Figure 3.
*Katzmann JA, et al, Clin Chem. 2002;48:1437-1444.

Management of SMM primarily consists of close monitoring of disease burden and evaluation of potential development of CRAB symptoms. Initial monitoring is recommended every 2 to 3 months. Baseline skeletal surveys and bone marrow biopsies are mandatory. PET/CT or spine and pelvis MRI may be of significance, and are used to rule out early signs of symptomatic disease. For those patients who maintain long-term stability, the interval of evaluation may be extended to every 4 to 6 months. If any concerns exist about evolving bone disease, skeletal or focal imaging may be repeated.

The advent of more sophisticated genetic analysis of plasma cell dyscrasias has enhanced our ability to discern discrete risk stratifications amongst phenotypically similar disease processes. Classically, routine karyotyping and FISH studies have aided in defining the specific genetic abnormalities within the plasma cell disorders. CD138-selected FISH has enhanced the technique to increase the relative yield of malignant cells to evaluate. Dhodapkar, et al., have utilized a 70-gene micro-array (GEP-70) based profile to more thoroughly characterize genetic risk. In this study, a GEP-70 score of greater than or equal to 0.26 functioned as an independent risk factor for progression of asymptomatic myeloma to symptomatic disease.10 Nearly 30% of the genes in the GEP-70 are associated with chromosome 1, which is consistent with studies implicating chromosome 1q21 in the pathogenesis of multiple myeloma.11 There is also a correlation between GEP-70 risk score and the proliferation index. Functionally, this may simply describe that plasma cell tumors with a greater proliferative/turnover rate, have a higher rate of progressing towards a symptomatic malignancy.

Ultimately, the dividing line, from a clinical standpoint, continues to be defined by the need (or lack thereof) to treat. The current standard of care for asymptomatic gammopathies such as MGUS and SMM is to monitor without directed therapy. Alternatively, symptomatic disease such as multiple myeloma requires treatment. As improved techniques are better able to discern which patients are more likely to progress from asymptomatic to symptomatic disease, it has become clear that a subgroup of “high-risk” smoldering patients exists. Some of these patients are statistically so likely to progress to symptomatic disease that the impetus to treat has been to wait for clinical decline (potentially life threatening), in the form of renal failure, marrow failure, bony fracture, or hypercalcemia. In 2014, Rajkumar, et al., published an updated set of criteria to separate those who needed therapy from those who did not. The classic “CRAB” paradigm was updated to include additional myeloma defining events (MDEs), referred to by Rajkumar as biomarkers of malignancy, but which may be more readily recalled by the descriptive acronym “SLiM”: S=equal to or greater than (≥) Sixty percent bone marrow plasmacytosis, Li=free Light chain ratio (involved:uninvolved) equal to or greater than 100 (≥100), and M=greater than 1 (>1) focal lesion seen on MRI (each greater than or equal to 5 mm).12 These new criteria allow for the treatment of patients with classically defined high-risk smoldering disease, prior to the ramifications of potentially irreversible end organ dysfunction. Figures 4 and 6.

“The designation of myeloma warranting therapy now includes patients that were formally classified as high-risk smoldering and now fall under the rubric of fitting criteria for treatment under the ‘SLiM-CRAB’ nomenclature.”

Multiple myeloma represents a malignant plasma cell disorder that comprises approximately 10% of hematologic malignancies and about 1% of all cancers.13,14 The disease is defined in patients having greater than or equal to 10% clonal plasma cells on bone marrow evaluation, or greater than or equal to 3 gm/dL of M-protein in the serum as well as evidence of end-organ dysfunction “CRAB” symptoms. The designation of myeloma warranting therapy now includes patients that were formally classified as high-risk smoldering, and who now meet criteria for treatment under the “SLiM-CRAB” nomenclature.

The workup to establish symptomatic myeloma from its asymptomatic counterparts is outlined in Figure 1 and includes history and physical, laboratory testing and radiographs. More advanced imaging modalities such as MRI or PET/CT may be needed to help confirm the need for therapy.

There is mounting evidence that symptomatic myeloma arises from a more benign gammopathy such as MGUS.15 Figure 5. The exponential growth of knowledge both in the lab and in the clinic over the last decade has transformed our knowledge about these diseases. With greater insight, we are on the precipice of understanding who really needs treatment, who does not, and exactly what therapy is warranted for each patient. Advances in immunotherapy and transplant techniques have ushered in a new age of novel approaches, which may provide the framework for a cure in our lifetime.

Implications for Practice

The field of multiple myeloma is evolving at a rapid pace. As clinicians, we must utilize the most up-to-date knowledge base to manage our patients. Previously, myeloma therapy was restricted only to patients who were exhibiting symptoms of plasma cell related end-organ dysfunction or CRAB symptoms. This guidance has now been updated to SLiM-CRAB, to include a previously untreated group of patients. Utilization of the newer criteria is vital to ensure that appropriate patients do not go without treatment. In order to ensure that our patients’ gammopathies are appropriately delineated, thorough and complete physical, laboratory, and imaging examinations are required. The NCCN and IMWG recommendations are summarized and available in the “Tools” section on ManagingMyeloma.com. Wide variations in clinical management have been observed at the academic and community levels alike. Utilizing tools such as the NCCN and IMWG guidelines has been shown to have a positive impact on quality of care and survival.16 Greater universal utilization and adherence to these resources, particularly in the realm of the diagnostic evaluation of monoclonal gammopathies, will result in a significant and measurable benefit to patients.

Figure 1

Kyle RA, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356:2582-2590.

Figure 2

Kyle RA, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356:2582-2590.

Figure 3

RA Kyle, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24:1121-1127.

Figure 4

Rajkumar SV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-548.

Figure 5

Walker BA, et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia. 2014;28:384-390.

Figure 6

Managing Myeloma International Myeloma Working Group (IMWG) Updated Criteria for the Diagnosis of Multiple Myeloma Reference Resource Tool. Available at www.ManagingMyeloma.com.

References

  1. Bergsagel PL, Kuehl WM. The molecular biology of multiple myeloma. In: Malpas JS, Bergsagel DE, Kyle RA, Anderson KC, eds. Myeloma: Biology and management. 3rd ed. Philadelphia: Saunders, 2004:35-58.
  2. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362-1369.
  3. Blade J. Monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;355:2765-2770.
  4. RA Kyle, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24:1121-1127.
  5. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. [see comment]. New Engl J Med. 2002;346:564-569.
  6. Blade J, Lopez-Guillermo A, Rozman C, et al. Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Br J Haematol. 1992;81:391-394.
  7. Cesana C, Klersy C, Barbarano L, et al. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J Clin Oncol. 2002;20:1625-1634.
  8. Baldini L, Guffanti A, Cesana BM, et al. Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy. Blood. 1996;87:912-918.
  9. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106:812-817.
  10. Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014;123(1)78-85.
  11. Hanamura I, Stewart JP, Huang Y, et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood. 2006;108(5):1724-1732.
  12. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-548.
  13. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351:1860-1873.
  14. Rajkumar SV, Kyle RA. Plasma cell disorders. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine, 23rd ed. Philadelphia, PA: Saunders; 2007;1426-1437.
  15. Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113:5412-5417.
  16. Rifkin RM, Abonour R, Terebelo H, et al. Connect MM Registry: The Importance of Establishing Baseline Disease Characteristics. Clin Lymphoma Myeloma Leuk. 2015;15(6):368-376.