Myeloma

April 1, 2004

Over the past decade, remarkable advanceshave been made in the biology and treatmentof multiple myeloma.[1] In most, if not all,patients, myeloma evolves from a precursorstage called monoclonal gammopathy of undeterminedsignificance (MGUS); MGUS isasymptomatic, but progresses to myeloma ora related disorder at a rate of 1% per year.[2]Although precise pathogenetic mechanismsremain elusive, recent studies show that aprimary translocation, usually involvingthe immunoglobulin heavy chain locus onchromosome 14q32, or in some cases theimmunoglobulin lambda light chain locus,can be detected at the MGUS stage in 60-65% of individuals.[3] Progression of MGUSto myeloma appears to be a random eventoften accompanied by secondary translocations(eg, c-myc), mutations in RAS or othergenes, as well as changes in the microenvironmentincluding the induction of angiogenesis.

Over the past decade, remarkable advanceshave been made in the biology and treatmentof multiple myeloma.[1] In most, if not all,patients, myeloma evolves from a precursorstage called monoclonal gammopathy of undeterminedsignificance (MGUS); MGUS isasymptomatic, but progresses to myeloma ora related disorder at a rate of 1% per year.[2]Although precise pathogenetic mechanismsremain elusive, recent studies show that aprimary translocation, usually involvingthe immunoglobulin heavy chain locus onchromosome 14q32, or in some cases theimmunoglobulin lambda light chain locus,can be detected at the MGUS stage in 60-65% of individuals.[3] Progression of MGUSto myeloma appears to be a random eventoften accompanied by secondary translocations(eg, c-myc), mutations in RAS or othergenes, as well as changes in the microenvironmentincluding the induction of angiogenesis.The diagnostic criteria for myeloma havebeen recently refined, to ensure uniformity.Diagnosis of myeloma requires 10% or moreplasma cells in the bone marrow, presence ofa monoclonal (M) protein in the serum and/or urine, and evidence of hypercalcemia,renal insufficiency, anemia, or bone lesions.[4] A new international staging systemhas been developed and severalimportant prognostic factors such as deletionof chromosome 13 have been identified.Major advances have also occurred in therapy,including the use of single or tandemautologous stem cell transplantation as initial therapy for appropriate patients.[5,6]As a result, the current approach to treatmentrequires newly diagnosed patients tobe initially stratified based on eligibility forstem cell transplantation. Patients who arecandidates for the procedure are treatedwith nonalkylating containing regimens suchas vincristine/doxorubicin (Adriamycin)/dexamethasone (VAD), thalidomide (Thalomid)plus dexamethasone, or dexamethasonealone for approximately 4 months toreduce tumor burden prior to stem cell harvestand transplantation. On the other hand,patients who are not candidates for transplantationbecause of advanced age, poorperformance status, or comorbidity are treatedwith melphalan (Alkeran)/prednisonechemotherapy. Enrollment in clinical trialsis encouraged for all patients.Perhaps the most important advance forboth physicians and patients alike has beenthe arrival of new, active agents. Until 1998,alkylators and corticosteroids were the onlyagents known to have significant singleagentactivity in myeloma. Since then, thalidomide,bortezomib (Velcade), and CC-5013have all emerged as active drugs, significantlytransforming the therapy of multiplemyeloma. These drugs are now being studied,alone and in combination, for the treatmentof all stages of the disease.Improvements have also occurred in supportivecare. Increased RANKL expressionby osteoblasts and a reduction in the level ofits decoy receptor, osteoprotegerin (OPG),are now recognized as key pathogenetic factorsfor the development of lytic bone lesions.Better understanding of the biology ofbone disease in myeloma and results of randomizedtrials have led to the routine use ofbisphosphonates to prevent the occurrenceand progression of lytic bone lesions.Out of numerous exciting abstracts presentedat the 2003 Annual Meeting of the AmericanSociety of Hematology, a few keyabstracts that highlight additional progressmade in the diagnosis, prognosis, and treatmentof myeloma are presented in this supplementto ONCOLOGY.In the second half of the supplement, Dr.Hagop Kantarjian will provide discussionon several important biologic and therapeuticstudies in leukemia that were reportedat ASH 2003.

References:

1. Rajkumar SV, Gertz MA, Kyle RA, et al: Current therapyfor multiple myeloma.

Mayo Clin Proc

77:813-822, 2002.
2. Kyle RA, Therneau TM, Rajkumar SV, et al: A long-termstudy of prognosis of monoclonal gammopathy of undeterminedsignificance.

N Engl J Med

346:564-569, 2002.
3. Kuehl WM, Bergsagel PL: Multiple myeloma: Evolvinggenetic events and host interactions.

Nat Rev Cancer

2:175-187,2002.
4. The International Myeloma Working Group: Criteria forthe classification of monoclonal gammopathies, multiple myelomaand related disorders: A report of the International MyelomaWorking 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 andchemotherapy in multiple myeloma. Intergroupe Francais duMyelome.

N Engl J Med

335:91-97, 1996.
6. Attal M, Harousseau JL, Facon T, et al: Single versusdouble autologous stem-cell transplantation for multiple myeloma[see comment].

N Engl J Med

349:2495-2502, 2003.