Overview of the Advances in
the Treatment of Multiple Myeloma
In this issue of Cancer Control, we are privileged to include
four excellent manuscripts addressing recent advances made in the understanding of the
biology and treatment of multiple myeloma. Multiple myeloma is a neoplastic disease of
B-cell lineage resulting in the overproliferation of malignant plasma cells. The actual
origin of the malignant cell is unknown but may originate from pre-B cells. The annual
incidence of myeloma in the United States is approximately 4 to 5 per 100,000, with 14,000
estimated new cases diagnosed each year. American blacks have nearly double the incidence
compared to whites.
The clinical spectrum of myeloma includes bone damage, increased
infections, and anemia. The median survival of patients with myeloma depends on the stage
of disease at diagnosis, but it is approximately 3.5 years for all patients. Only
approximately 5% of patients will be alive at 10 years following diagnosis. Despite the
use of many different chemotherapeutic regimens, there has been little improvement in
outcome since the introduction of melphalan and prednisone over three decades ago.
Chemotherapy induces remissions in approximately 50% of cases with median remission times
of two years. In this issue, Drs Lust, Donovan, Oken, Shustik, and Bensinger review some
of the advances being made in the understanding of myeloma biology and how this
information may be translated into improved therapy.
Understanding the pathogenesis and progression of myeloma will
likely provide us with new approaches to treating the disease. In the report by Drs Lust
and Donovan, the progression from MGUS (a clinically benign condition associated with
monoclonal gammopathy) to overt symptomatic myeloma is discussed. MGUS is considerably
more common than myeloma, and as many as 25% of patients with this disorder will develop
myeloma or related plasma cell disorders. While the clinical evolution of MGUS to overt
myeloma has been well described, cellular mechanisms have been only recently described
that may be causally related to this progression. Studies have shown that the multistep
pathogenesis from MGUS to myeloma may be related to cytokines such as IL-6 and IL-1b, adhesion molecules, viruses, and certain oncogenes. If a causal
relationship is determined to exist for these factors, then new targets for therapy of
myeloma may emerge.
For over three decades, the standard treatment for myeloma has been
the combination of melphalan and prednisone (MP). Attempts to improve on results of MP by
using multiagent regimens have been disappointing overall. Clearly, some regimens may be
superior to others in certain situations, such as preference for the use of vincristine,
doxorubicin, and dexamethasone (VAD) in patients with acute renal insufficiency; however,
little improvement in overall survival is seen with combination chemotherapy compared to
MP. Difficulties in discerning whether combination chemotherapy is superior to MP are
discussed in the article by Dr Oken. He also points out that advances in supportive care
have been made recently, and these include the use of erythropoietin for anemia, G-CSF for
treatment-related myelosuppression, and pamidronate for the prevention of bone
destruction. Ultimately, however, newer agents with novel mechanisms of action will need
to be developed to improve treatment outcome for the majority of myeloma patients.
One approach to improving survival is to try to prolong treatment
response using biological modifiers such as interferon. Dr Shustik reviews the results of
multiple studies using interferon in the treatment of myeloma. He concludes that
interferon has, at best, a modest effect on overall survival when combined with induction
chemotherapy or when used as maintenance therapy. However, he also suggests that
recognizing certain subsets of patients who might benefit from interferon may be important
and that cost-benefit analyses combined with quality-of-life data must be considered when
developing guidelines for the use of interferon in the treatment of myeloma.
Perhaps the greatest advance in the treatment of myeloma has been
the use of very high-dose chemotherapy and autologous or allogeneic hematopoietic
stem-cell transplantation (HSCT). Dr Bensinger reviews the results of numerous trials
including prospective, randomized studies that demonstrate that autologous HSCT results in
superior response rates, progression-free survival, and disease-free survival when
compared to conventional-dose chemotherapy. Allogeneic HSCT may even result in long-term
survivals (cures?) but at significant cost, including high risk of early death due to
complications. Dr Bensinger highlights the challenges that must be met in order to improve
results and make the HSCT option available to more patients.
These four excellent reviews illustrate the current approach to the
treatment of myeloma. They also identify some of the most challenging issues that must be
met in order to improve treatment outcome. Our efforts must now focus on improving our
understanding of the biology of myeloma so that newer, more novel approaches may be
developed to treat this as yet incurable disease. Carpe diem!
William S. Dalton, PhD, MD
Associate Center Director for Clinical Investigations
H. Lee Moffitt Cancer Center & Research Institute
University of South Florida
Tampa, Florida
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Volume 5 Number 3