Major progress has been made in the last 20 years in the treatment of multiple myeloma. The introduction of high-dose therapy and, more recently, a variety of new agents including thalidomide (Thalomid) and other immunomodulatory drugs,[3,4] bortezomib (Velcade),[5,6] and immunologic approaches means patients have a variety of treatment strategies available today. Still, multiple myeloma remains incurable, and clinicians face unique challenges in placing new information into context, to determine a rational approach to the use of autologous and allogeneic stem cell transplantation for patients with the disease. Hari and colleagues distill the clinical questions surrounding transplantation for myeloma in a succinct yet thorough review. With their well-written assessment, the authors cover most of the key areas of controversy surrounding the role of autologous stem cell transplantation (ASCT) in this setting.
The desire to prospectively distinguish patients destined to have an indolent disease course from those with aggressive myeloma has led to the identification of a number of prognostic features, including beta-2 microglobulin, serum albumin, plasma cell labeling index, and several cytogenetic abnormalities.[8-12] As our genetic understanding of multiple myeloma becomes more sophisticated, new classifications will emerge. The challenge is how to best use available information to ensure that patients with good prognosis are not subjected to unnecessarily toxic therapies and patients with poor prognosis are treated aggressively and appropriately.
The Mayo Clinic definition of high-risk multiple myeloma includes patients with one or more of the following adverse prognostic factors: deletion 13 or hypodiploidy on conventional karyotypic analysis; t(4;14), t(14;16), or 17p on molecular genetic studies; or a plasma cell labeling index of at least 3%.[13,14] We have recommended that patients with high-risk myeloma be considered for novel treatment strategies.
Novel Induction Regimens
The development of novel active agents for multiple myeloma has resulted in a plethora of new combination regimens. The high response rates observed with these regimens have raised questions on whether we should still be offering ASCT to patients as initial therapy. The first new combination regimen to show such promise was thalidomide and dexamethasone (Thal/Dex), which has been shown to be superior to dexamethasone alone in the Eastern Cooperative Oncology Group (ECOG) E1A00 trial.
Combinations of thalidomide, lenalidomide (Revlimid), bortezomib, and traditional alkylating agents are summarized in Table 2 of the review by Hari and colleagues. Response rates in excess of 90% are not uncommon, rivaling responses seen with ASCT. Unfortunately, these high response rates do not equate with cure. No plateau is seen in survival curves in any of the trials, showing that the disease invariably relapses and patients can expect to be treated with multiple different regimens during the course of their illness. For this reason, we do not expect that ASCT will become obsolete any time soon.
High response rates are not the only factor determining the desirability of using ASCT. All new regimens have unique toxicities, and quality-of-life measures should be included in all future randomized trials. In transplant trials, some of the most important information to emerge has included recognition of the benefit to patients' quality of life with early transplant approaches. This was best quantified in the French Group Myelome-Autogreffe (MAG) trial comparing early to late transplant, which showed improved TWiSTT (time without symptoms, treatment, and toxicity) among patients transplanted early.
Autologous Stem Cell Transplantation
Two well-designed prospective randomized trials have demonstrated an advantage for ASCT over conventional chemotherapy, including improved complete remission (CR) rates, event-free survival, and overall survival.[17,18] Most studies that failed to show these benefits allowed salvage transplant at relapse or randomized only responding patients, as discussed in the review by Hari and colleagues. The MAG study, as well as the US Intergroup study, clearly show that survival is the same whether the transplant is done early or late, but the MAG study showed that the most compelling reason for early ASCT is superior quality of life.
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23. Maloney DG, Molina AJ, Sahebi F, et al: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102:3447-3454, 2003.