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Novel Therapeutic Avenues in Myeloma: Changing the Treatment Paradigm

Novel Therapeutic Avenues in Myeloma: Changing the Treatment Paradigm

Our better understanding of the complex interaction of multiple myeloma (MM) cells with their bone marrow microenvironment and the signaling pathways that are dysregulated in this process has resulted in a dramatic increase in the therapeutic agents available for this disease. A number of these new agents have demonstrated significant activity in patients with MM. Over the past 5 years, three drugs have received approval from the US Food and Drug Administration for therapy in MM—bortezomib, thalidomide, and lenalidomide. To date, the choice of therapy for MM is not individualized according to the biologic characteristics of the disease, but future studies should enable us to identify patients who may benefit most from certain therapeutic interventions, and thus develop individualized therapy for MM. In this review, we will present some of the treatment algorithms currently developed for patients with MM and focus on established advances in therapy, specifically with thalidomide, bortezomib, and lenalidomide. We will also discuss some of the emerging novel therapeutic agents showing promise in phase I/II clinical trials in MM.

Multiple myeloma (MM) is characterized by the presence of a malignant clone of plasma cells in the bone marrow and a monoclonal protein in the serum or urine. It represents a spectrum of disease from monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma and symptomatic, active MM. MGUS and smoldering myeloma are asymptomatic, with MGUS requiring no therapeutic intervention other than observation. Similarly, the mainstay of management for smoldering myeloma is careful observation, although the selected use of erythropoietic agents for mild anemia, bisphosphonates for osteopenia, and participation in clinical trials are appropriate considerations in selected patients. Conversely, active MM characterized by the presence of hypercalcemia (C), renal insufficiency (R), anemia (A), or lytic bone lesions (B)—summarized by the acronym CRAB—requires treatment to prevent worsening complications and end organ damage.[1,2]

The rate of progression of MGUS to MM is 0.6 to 3% per year, with many patients never developing any symptoms from this plasma cell dyscrasia.[3] Patients with smoldering disease are at higher risk, with progression to active disease occurring from between 1 to 2 years to a median of 5 to 7 years in some series, reflecting considerable heterogeneity of disease biology in this population.

Once active MM develops, proper staging and evaluation is required to determine prognostic factors that may affect the choice of therapeutic agents to be used. Several factors have been associated with poor prognosis in MM, including decreased serum albumin, increased beta-2-microglobulin, interleukin (IL)-6, C-reactive protein, plasma cell labeling index, the presence of circulating plasma cells, and cytogenetic abnormalities.[4-8] Karyotyping is a key prognostic tool in MM, as it identifies numerical chromosomal abnormalities. Specifically, it is a sensitive technique of determining abnormalities of chromosome 13.[9]

More broadly, MM can be classified into hyperdiploid and nonhyperdiploid forms.[9] Aneuploidy occurs frequently in MM, with monosomies (including 13, 14, 16, and 22) being more frequent than trisomies (including 3, 5, 7, 9, 11, 15, 19, and 21). Hyperdiploid MM is associated with multiple trisomies and a low incidence of IgH translocations.[9] Nonhyperdiploid MM is characterized by a very high prevalence of IgH translocations, and five recurrent chromosomal partners are involved in IgH translocations occuring in about 40% of the patients,[10] including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (fibroblast growth factor receptor 3 [FGFR3] and multiple myeloma SET domain [MMSET]), 16q23 (c-maf), and 20q11 (mafB).[9,11] Identifying these changes has enhanced our understanding of the pathogenesis of MM, and in turn this has led to the development of agents that specifically target these abnormalities, such as FGFR3 inhibitors, which are discussed below.

Critically, the advances in our understanding of the complex interaction of the MM cells with the bone marrow microenvironment and the signaling pathways that are dysregulated in this process have been associated with a surge in the investigational agents tested for this disease. A number of these agents have demonstrated efficacy in MM patients, and specifically, in the past 5 years three of these drugs have received US Food and Drug Administration (FDA) approval for the treatment of MM: bortezomib (Velcade), thalidomide (Thalomid), and lenalidomide (Revlimid). Therapy for MM can now be tailored depending on the clinical disease characteristics. Future studies determining sensitive and specific molecular markers of response/resistance to specific anti-MM therapies should enable us to better identify patients who would benefit most from certain therapeutic interventions, and thus help develop individualized approaches to therapy for the disease.

In this review, we will focus on treatment algorithms currently developed for patients with MM and focus on established advances in therapy for MM, including the use of thalidomide, bortezomib, and lenalidomide. We will also discuss other novel therapeutic agents showing promising activity in early-phase clinical trials in MM.

Treatment Overview

After 20 years of relative inertia, where alkylator-based cytotoxic chemotherapy and glucocorticoids remained the backbone of therapy, the use of anthracyclines, the advent of high-dose therapy supported by stem cell transplant, and then the introduction of bisphosphonates punctuated the 1980s and 1990s.[12] Since the promising results of thalidomide for the treatment of relapsed MM reported in 1999,[13] and the accelerated approval of bortezomib for relapsed and refractory MM in 2003, the treatment algorithm has been continuously changing. As change has come to the relapse setting, upfront therapy has also changed. Clinical trials remain a cornerstone of management throughout the course of the illness; studies are of critical importance not only to determine the combinations and sequences that will lead to higher response rates and improved survival, but also to test the activity of new agents in MM.

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