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Myeloma

Myeloma

Over the past decade, remarkable advances have been made in the biology and treatment of multiple myeloma.[1] In most, if not all, patients, myeloma evolves from a precursor stage called monoclonal gammopathy of undetermined significance (MGUS); MGUS is asymptomatic, but progresses to myeloma or a related disorder at a rate of 1% per year.[2] Although precise pathogenetic mechanisms remain elusive, recent studies show that a primary translocation, usually involving the immunoglobulin heavy chain locus on chromosome 14q32, or in some cases the immunoglobulin lambda light chain locus, can be detected at the MGUS stage in 60- 65% of individuals.[3] Progression of MGUS to myeloma appears to be a random event often accompanied by secondary translocations (eg, c-myc), mutations in RAS or other genes, as well as changes in the microenvironment including the induction of angiogenesis. The diagnostic criteria for myeloma have been recently refined, to ensure uniformity. Diagnosis of myeloma requires 10% or more plasma cells in the bone marrow, presence of a monoclonal (M) protein in the serum and/ or urine, and evidence of hypercalcemia, renal insufficiency, anemia, or bone lesions.[ 4] A new international staging system has been developed and several important prognostic factors such as deletion of chromosome 13 have been identified. Major advances have also occurred in therapy, including the use of single or tandem autologous stem cell transplantation as initial therapy for appropriate patients.[5,6] As a result, the current approach to treatment requires newly diagnosed patients to be initially stratified based on eligibility for stem cell transplantation. Patients who are candidates for the procedure are treated with nonalkylating containing regimens such as vincristine/doxorubicin (Adriamycin)/ dexamethasone (VAD), thalidomide (Thalomid) plus dexamethasone, or dexamethasone alone for approximately 4 months to reduce tumor burden prior to stem cell harvest and transplantation. On the other hand, patients who are not candidates for transplantation because of advanced age, poor performance status, or comorbidity are treated with melphalan (Alkeran)/prednisone chemotherapy. Enrollment in clinical trials is encouraged for all patients. Perhaps the most important advance for both physicians and patients alike has been the arrival of new, active agents. Until 1998, alkylators and corticosteroids were the only agents known to have significant singleagent activity in myeloma. Since then, thalidomide, bortezomib (Velcade), and CC-5013 have all emerged as active drugs, significantly transforming the therapy of multiple myeloma. These drugs are now being studied, alone and in combination, for the treatment of all stages of the disease. Improvements have also occurred in supportive care. Increased RANKL expression by osteoblasts and a reduction in the level of its decoy receptor, osteoprotegerin (OPG), are now recognized as key pathogenetic factors for the development of lytic bone lesions. Better understanding of the biology of bone disease in myeloma and results of randomized trials have led to the routine use of bisphosphonates to prevent the occurrence and progression of lytic bone lesions. Out of numerous exciting abstracts presented at the 2003 Annual Meeting of the American Society of Hematology, a few key abstracts that highlight additional progress made in the diagnosis, prognosis, and treatment of myeloma are presented in this supplement to ONCOLOGY. In the second half of the supplement, Dr. Hagop Kantarjian will provide discussion on several important biologic and therapeutic studies in leukemia that were reported at ASH 2003.

References

1. Rajkumar SV, Gertz MA, Kyle RA, et al: Current therapy for multiple myeloma. Mayo Clin Proc 77:813-822, 2002.
2. Kyle RA, Therneau TM, Rajkumar SV, et al: A long-term study of prognosis of monoclonal gammopathy of undetermined significance. N Engl J Med 346:564-569, 2002.
3. Kuehl WM, Bergsagel PL: Multiple myeloma: Evolving genetic events and host interactions. Nat Rev Cancer 2:175-187, 2002.
4. The International Myeloma Working Group: Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group. Br J Haematol 121:749-757, 2003.
5. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335:91-97, 1996.
6. Attal M, Harousseau JL, Facon T, et al: Single versus double autologous stem-cell transplantation for multiple myeloma [see comment]. N Engl J Med 349:2495-2502, 2003.
 
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