From myeloma precursor disease to multiple myeloma: new diagnostic concepts and opportunities for early intervention.
ABSTRACT 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: Targeted modulation of microenvironmental regulatory pathways may be essential to control myeloma and other genetically/clonally heterogeneous cancers. Here we report that human myeloma-associated monocytes/macrophages (MAM), but not myeloma plasma cells, constitute the predominant source of interleukins (IL)1β, IL10 and TNFα at diagnosis, whereas IL6 originates from stromal cells and macrophages. To dissect MAM activation/cytokine pathways, we analyzed Toll-like receptor (TLR) expression in human myeloma CD14+ cells. We observed co-regulation of TLR2 and TLR6 expression correlating with local processing of versican, a proteoglycan TLR2/6 agonist linked to carcinoma progression. Versican has not been mechanistically implicated in myeloma pathogenesis. We hypothesized that the most readily accessible target in the versican-TLR2/6 pathway would be the MAP3-kinase, TPL2 (Cot/MAP3K8). Ablation of Tpl2 in the genetically-engineered in vivo myeloma model, Vκ*MYC, led to prolonged disease latency associated with plasma cell growth defect. Tpl2 loss abrogated the "inflammatory switch" in macrophages within nascent myeloma lesions and licensed macrophage repolarization in established tumors. MYC activation/expression in plasma cells was independent of Tpl2 activity. Pharmacologic TPL2 inhibition in human monocytes led to dose-dependent attenuation of IL1β induction/secretion in response to TLR2 stimulation. Our results highlight a TLR2/6-dependent TPL2 pathway as novel therapeutic target acting non-autonomously through macrophages to control myeloma progression.Blood 04/2014; · 9.78 Impact Factor
Article: Indolent mantle cell lymphoma[Show abstract] [Hide abstract]
ABSTRACT: Over the past decade, it has become increasingly clear that mantle cell lymphoma (MCL) is a more heterogeneous disease than originally recognized. Several groups have reported on a subgroup of patients with a less aggressive course than expected resulting in the term “indolent MCL”. Unlike the recognized histologic variants, the definition of indolent mantle cell lymphoma is unclear, and patients with indolent MCL are often identified only after having undergone prolonged periods of observation. In this review, we will discuss clinical and biologic features and provide a framework for the approach in identifying patients with indolent MCL.Leukemia and Lymphoma 03/2014; 55(4). · 2.61 Impact Factor
- Journal of Clinical Oncology 07/2014; · 17.88 Impact Factor