Over the past decade, remarkable advances
have been made in the biology and treatment
of multiple myeloma. 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.
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. 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
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.
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,
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.