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In the previous decade, younger patients with newly diagnosed myeloma were typically treated with induction therapy based on high-dose dexamethasone (dex) (i.e., vincristine/doxorubicin/dexamethasone [VAD] or dex alone) followed by autologous stem cell transplantation (ASCT), whereas older individuals received 6–12 cycles of oral melphalan and prednisone (MP). Results from randomized trials indicated that an approach of VAD and a single ASCT produced an overall response rate (≥ partial remission [PR]) of 80% with up to 20% complete or nearly complete (CR/nCR) remission, a progression-free survival (PFS) rate of around 24 months, and an overall survival rate of 4–5 years. MP in older patients resulted in overall response rates on the order of 50% with few CR/nCRs; a PFS of approximately 12–15 months and an overall survival of 3–4 years could be anticipated.1 More recently, an improved understanding of the biology of myeloma and the identification of new drugs have improved the therapeutic approach to myeloma. Genomic techniques have provided insights into the different molecular subtypes of this disease with differing natural histories. In the clinic, application of the International Staging System (based on the serum levels of beta-2 microglobulin and albumin) and FISH cytogenetics has allowed the definition of different myeloma risk groups with readily available laboratory tests. Several investigators have reported that the presence of t(4;14), t(14;16) and deletion 17p identifies patients with a poorer outcome. More recently, both 1q gains, as well as deletions of 1p22 and 1p32, have been associated with an adverse prognosis in analyses of patients treated on Intergroupe Francophone du Myelome (IFM) studies involving ASCT.2,3 Following the introduction of the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib, a series of phase II and III studies in both younger and older patients with myeloma has evaluated the integration of these novel agents into first-line therapy. Other recent developments have included an appreciation of the toxicity of the older schedule of “pulse” dexamethasone (high-dose dex [HD-dex] = 40 mg/day for day 1 through 4, 9–12, and 17–20 of a 28-day cycle) and the benefit of low-dose dex = 40 mg/week (LD-dex.)4 In addition, the incidence and severity of peripheral neuropathy associated with bortezomib can be reduced by weekly, rather than twice weekly, dosing as well as by the subcutaneous, rather than intravenous, route of administration.5,6 Finally, various maintenance strategies have been evaluated in both younger and older patients in an attempt to improve the duration of remission and overall survival.5,7 In Europe and Canada, a strategy that maintains the division of newly diagnosed patients into two categories—those who are designated for upfront ASCT and those who are transplant-ineligible on the basis of age and comorbidities—is still in place. In contrast, some U.S. specialists have recommended treating younger individuals, particularly those with standard-risk disease, with regimens based on novel agents for variable periods of time; ASCT is considered optional based on patient preference and other unknown factors. Some of these approaches advocate ASCT at the time of relapse. Although delayed ASCT may ultimately be shown to produce results comparable to first-line ASCT, phase III trials evaluating the two strategies have not yet been completed. Moreover, most reports describing the efficacy of 2-, 3- or even 4-drug regimens include a mix of transplant and nontransplant patients, with a focus on response rates; information regarding longer term outcomes such as PFS is often limited and the contribution of ASCT difficult to assess. To more accurately ascertain the results of different therapeutic strategies, the current discussion will, therefore, emphasize the results of randomized trials in which the distinction between ASCT and nontransplant therapy is determined from the onset of study. |
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