Dr. Jewell is a hematology/oncology fellow, Dr. Xiang, Dr. Kunthur, and Dr. Mehta are staff hematologist/oncologists, all in the Division of Hematology/Oncology, Department of Internal Medicine, at the John L. McClellan Memorial Veterans Hospital in Little Rock, Arkansas. Dr. Xiang and Dr. Mehta are also faculty members at the University of Arkansas for Medical Sciences in Little Rock.
References
Two MM precursor syndromes are worth noting: MGUS and SMM. In evaluating a patient for possible MM, it is important to differentiate between MGUS, asymptomatic SMM, and MM that requires treatment. 4 Monoclonal gammopathy of undetermined significance is diagnosed when a patient has a serum M protein that is < 3 g/dL, clonal bone marrow plasma cells < 10%, and no identifiable end organ damage. 5 Smoldering MM is diagnosed when either the serum M protein is > 3 g/dL or bone marrow clonal plasma cells are > 10% in the absence of end organ damage.
Symptomatic MM is characterized by > 10% clonal bone marrow involvement with end organ damage that includes hypercalcemia, renal failure, anemia, or bone lesions. The diagnostic criteria are summarized in Table 1. The International Myeloma Working Group produced updated guidelines in 2014, which now include patients with > 60% bone marrow involvement of plasma cells, serum FLC ratio of > 100, and > 1 focal lesions on an MRI study as symptomatic MM. 5,6
Most patients with MM will have a M protein produced by the malignant plasma cells detected on an SPEP or UPEP. The majority of immunoglobulins were IgG and IgA, whereas IgD and IgM were much less common. 2 A minority of patients will not have a detectable M protein on SPEP or UPEP. Some patients will produce only light chains and are designated as light-chain-only myeloma. For these patients, the FLC assay is useful for diagnosis and disease monitoring. Patients who have an absence of M protein on SPEP/UPEP and normal FLC assay ratios are considered to have nonsecretory myeloma. 7
Staging and Risk Stratification
Two staging systems are used to evaluate a patient’s prognosis: the Durie-Salmon staging system, which is based on tumor burden (Table 2); and the International Staging System (ISS), which uses a combination of serum beta 2 microglobulin (B2M) and serum albumin levels to produce a powerful and reproducible 3-stage classification and is more commonly used by hematologists due to its simplicity to use and reliable reproducibility (Table 3).
In the Durie-Salmon staging system, patients with stage I disease have a lower tumor burden, defined as hemoglobin > 10 g/dL, normal calcium level, no evidence of lytic bone lesions, and low amounts of protein produced (IgG < 5 g/dL; IgA < 3 g/dL; urine protein < 4 g/d). Patients are classified as stage III if they have any of the following: hemoglobin < 8.5 g/dL, hypercalcemia with level > 12 mg/dL, bony lytic lesions, or high amounts of protein produced (IgG > 7 g/dL; IgA > 5 g/dL; or urine protein > 12 g/d). Patients with stage II disease do not fall into either of these categories. Stage III disease can be further differentiated into stage IIIA or stage IIIB disease if renal involvement is present. 8
In the ISS system, patients with stage I disease have B2M levels that are < 3.5 mg/dL and albumin levels > 3.5 g/dL and have a median overall survival (OS) of 62 months. In this classification, stage III patients have B2M levels that are > 5.5 mg/dL and median OS was 29 months. Stage II patients do not meet either of these criteria and OS was 44 months. 9 In a study by Mayo Clinic, OS has improved over the past decade, with OS for ISS stage III patients increasing to 4.2 years. Overall survival for both ISS stage I and stage III disease seems to have increased as well, although the end point has not been reached. 10
