In this review, Landgren and colleagues from NCI updated our knowledge of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), focusing on advances in their definition and pathogenesis, with clinical implications. Specifically, they described the evolution in the definition of these entities by the International Myeloma Working Group (IMWG) as well as of distinct subtypes and their clinical sequelae. They focused on predictive models for progression to active MM, based upon parameters such as serum M protein concentration, Ig isotype, and free light-chain ratio, as well as multiparameter flow cytometric evaluation of normal versus aberrant bone marrow (BM) plasma cell ratio. Finally, they outlined the clinical implications of these advances, including opportunities for clinical trials to block progression and related complications.
Since the original recognition of benign monoclonal gammopathy by Waldenström and of MGUS by Kyle, long-term clinical annotation has allowed for more precise definitions of MGUS and SMM. Specifically, the most recent iteration by the IMWG defines MGUS as serum M protein < 3 g/dL; BM clonal plasma cells < 10 percent; and absence of end-organ damage including hypercalcemia (> 11.5 mg/dL), abnormal creatinine (> 2.0 mg/dL), or creatinine clearance (< 40 mL/min); normochromic normocytic anemia (Hb < 10 g/dL); bone lesions (lytic lesions, osteopenia, pathologic fractures); recurrent bacterial infections (< 2 in 12 months); amyloidosis; or symptomatic hyperviscosity. Moreover, distinct non-IgM, IgM, and light-chain subtypes evolve to MM, Waldenström macroglobulinemia, and light-chain lymphoproliferative diseases, respectively. In parallel, SMM is characterized by serum M protein of > 3 g/dL and/or clonal BM plasma cells > 10 percent without end-organ damage. Such uniform definition is essential to assure that epidemiologic and interventional studies evaluate similar patient populations and likely will continue to evolve, as does active MM, into genomic subtypes.
Having uniformly defined these entities, it is then essential to identify factors predictive of progression both in preclinical and clinical studies. It now appears that all MM evolves from precursor MGUS, but the genetic or epigenetic correlates remain to be defined. To date, most genetic subtypes and abnormalities defined in active MM appear to be present in MGUS, and no common genetic signature correlates with progression to active disease. Moreover, although epigenetic (i.e., IL-6 transcription and secretion from the BM milieu) or host (i.e., immune effector cells) factors have been correlated with progression, no causative factors are identified as of yet. Since MGUS does not progress to active MM in many patients with these precursor conditions even over a long period of time, defining host factors that control proliferation of clonal cells has great promise.
In Brief
Although current treatment guidelines include expectant follow-up in most cases, the ability to define patients at high risk to progress to active MM, coupled with the advent of novel therapies with acceptable adverse side effect profiles, is now making it possible to evaluate treatment strategies directed to prevent progression to active disease. These interventions include immunomodulatory drugs or other efforts to enhance host anti-tumor immunity and must be evaluated not only for their ability to delay time to progression, but also on their ultimate capacity to extend overall survival. Moreover, such treatments may be long-term, and a particular focus on complications of chronic therapy must be balanced against any potential benefits. Nonetheless, the opportunity to intervene earlier in the disease course and ultimately prevent the development of complications attendant to active MM is now a real possibility to be evaluated in ongoing and future clinical trials.
Competing Interests
Dr. Anderson indicated no relevant conflicts of interest.
