From Myeloma Precursor Disease to Multiple Myeloma: New Diagnostic Concepts and Opportunities for Early Intervention

Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Clinical Cancer Research (Impact Factor: 8.72). 03/2011; 17(6):1243-52. DOI: 10.1158/1078-0432.CCR-10-1822
Source: PubMed


Since monoclonal gammopathy of undetermined significance (MGUS) was first described more than 30 years ago, the definition of the entity has evolved. Today, 3 distinct clinical MGUS subtypes have been defined: non-immunoglobulin M (IgM; IgG or IgA) MGUS, IgM MGUS, and light chain MGUS. Each clinical MGUS subtype is characterized by unique intermediate stages and progression events. Although we now have strong evidence that multiple myeloma is consistently preceded by a precursor state at the molecular level, there is urgent need to better understand mechanisms that regulate transformation from precursor to full-blown multiple myeloma. In the future, if such knowledge was available, it would allow clinicians to define high-risk and low-risk precursor patients for a more tailored clinical management. Also, it would provide insights on the individual patient's disease biology, which, in turn, can be used for targeted and more individualized treatment strategies. On the basis of current clinical guidelines, patients diagnosed with MGUS and smoldering myeloma should not be treated outside of clinical trials. In the near future, it seems reasonable to believe that high-risk precursor patients will likely become candidates for early treatment strategies. In this review, we discuss novel insights from recent studies and propose future directions of relevance for clinical management and research studies.

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    ABSTRACT: Osteolytic bone disease is pathognomonic of multiple myeloma (MM) and affects more than 80% of patients. Bone disease results in skeletal-related events (SRE) such as vertebral compression fractures, which may cause cord compression, hypercalcemia, pathologic fractures that require radiation or surgical fixation, and severe pain. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. Osteolytic disease is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Bisphosphonates are a well-established treatment of myeloma-related skeletal disease and are the current standard of care. However, complications arising from their long-term use have prompted studies of schedule optimization and alternate strategies. Several novel agents are currently under investigation for their positive effect on bone remodeling via OC inhibition. The identification of negative regulators of OB differentiation has prompted the use of anabolic agents. In addition to restoring bone remodeling, these drugs may inhibit tumor growth in vivo. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from bone disease but also capitalizing on the resultant antitumor activity.
    Clinical Cancer Research 03/2011; 17(6):1278-86. DOI:10.1158/1078-0432.CCR-10-1804 · 8.72 Impact Factor
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    ABSTRACT: Treatment options for patients with relapsed myeloma have benefited from the development of new targeted agents. The use of bortezomib, thalidomide, and lenalidomide have dramatically changed outcomes for patients with relapsed myeloma. New agents are also in development, on the basis of preclinical rationale, as well as combinations of conventional and novel agents. Together each of these treatment approaches are being tested in phase I, II, and III clinical trials, with the goal of prolonged duration of remission and, ultimately, improved overall survival.
    Clinical Cancer Research 03/2011; 17(6):1264-77. DOI:10.1158/1078-0432.CCR-10-1805 · 8.72 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) is an example of rapid bench-to-bedside translation in new drug development. Bortezomib and lenalidamide target the tumor cell in the bone marrow microenvironment to overcome drug resistance in laboratory and animal models; each is effective to treat relapsed and/or refractory, relapsed, and newly diagnosed MM, and both are now showing promise as maintenance therapy. Major ongoing translational research efforts include improved classification and personalized therapies; identification and validation of next-generation agents targeting the tumor cell in its microenvironment; novel immune therapies; rationally based combination therapies; and use of novel agents to delay or prevent development of active MM. This paradigm of targeting the tumor in its microenvironment has already extended median survival in MM from 3 to 7 to 8 years and has great potential to improve patient outcome in other hematologic malignancies and solid tumors as well.
    Clinical Cancer Research 03/2011; 17(6):1225-33. DOI:10.1158/1078-0432.CCR-10-3366 · 8.72 Impact Factor
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