Multiple myeloma precursor disease: current clinical and epidemiological insights and future opportunities.

Benign monoclonal protein was first described by Waldenstrm in 1960 after abnormal narrow hypergammaglobulinemia bands were noted in the serum of healthy individuals on serum protein electrophoresis.[1] In 1978, Kyle coined the term “monoclonal gammopathy of undetermined significance (MGUS)” after observing that asymptomatic patients with monoclonal protein have a higher risk of developing multiple myeloma, Waldenstrm macroglobulinemia, light-chain amyloidosis, and related disorders.[2] Since then, definitions of MGUS have undergone several revisions. Today, three distinct clinical subtypes of MGUS (non-IgM MGUS, IgM MGUS, and light-chain MGUS) have been delineated.[3,4] The review by Kyle et al discusses these subtypes and their epidemiological relationships with corresponding malignancies. In addition, the paper sheds light on recent discoveries regarding etiologic risk factors, complications, and clinical predictors of transformation from a precursor state to full-blown malignancy. In 1980, Kyle and Greipp were the first to describe SMM as a distinct entity: as an “illness that met the criteria of multiple myeloma but has not had a progressive course”—a corollary to smoldering leukemia.[5] In their case series of six patients, all six patients had ≥ 10% bone marrow plasma cells and ≥ 3 g/dL of monoclonal (M) protein without progression to multiple myeloma for at least 5 years.[5] Following this initial description, several other studies of SMM were completed using criteria that ranged from inclusion of patients with mild anemia, to the requirement that the M protein be < 4.5 g/dL and the marrow plasma cells > 15% with the percentage of marrow plasma cells ignored entirely, to the requirement that Bence Jones proteinuria be present.[6-8] In 2003, the International Myeloma Working Group (IMWG) developed consensus definitions of the known monoclonal gammopathies.[9] MGUS was defined as the presence of serum M protein < 3 g/dL with fewer than 10% monoclonal plasma cells in the bone marrow; SMM was defined as either serum M protein ≥ 3 g/L or ≥ 10% monoclonal plasma cells in the bone marrow. In contrast to these laboratory-based definitions, a diagnosis of multiple myeloma is based on the clinical assessment of myeloma-related end-organ impairment in the presence of an M protein and/or monoclonal plasma cells. In the 2003 IMWG criteria, end-organ damage was defined using the classic “CRAB” criteria of hypercalcemia (serum calcium level > 11.5 mg/dL), renal failure (defined by a creatinine level >1.95 mg/dL with no other cause of the renal failure identified), anemia (hemoglobin level <10 g/dL), or skeletal lesions (lytic lesions by skeletal survey, osteoporosis with pathologic fractures, or cord compression).[9] In the updated 2010 IMWG diagnostic criteria, plasma cell MGUS is defined as having serum M protein < 3 g/dL, clonal plasma cell population in bone marrow < 10%, and absence of end-organ damage (CRAB criteria of multiple myeloma).[10] The CRAB criteria have also been slightly revised in the 2010 version; these now include: hypercalcemia with calcium level > 11.5 mg/dL, renal insufficiency with serum creatinine level > 2.0 mg/dL or estimated creatinine clearance < 40 mL/minute, normochromic normocytic anemia with a hemoglobin value < 10 g/dL (or a hemoglobin value more than 2 g/dL below the lower limit of normal), and bone lesions (lytic lesions, severe osteopenia, or pathological fractures).[10] Reflecting its greater disease burden, SMM is distinguished from MGUS by higher cut-off values, although a lack of end-organ damage remains one of the criteria. IMWG diagnostic criteria from 2010 define SMM as having serum M protein > 3 g/dL and/or clonal plasma cell population in bone marrow > 10%, and lack of end-organ damage (CRAB criteria).[10] Based on retrospective data from the Mayo Clinic, risk of progression from SMM to