ABSTRACT: The use of high-dose chemotherapy and autologous stem cell support in the past decade has changed the outlook for patients with multiple myeloma. In newly diagnosed patients, complete remission rates of 25% to 50% can be achieved, with median disease-free and overall survivals exceeding 3 and 5 years, respectively. Despite these results, autologous transplantation has not changed the ultimately fatal outcome of the disease, as there is no substantial evidence of "cure" in most published studies. An additional high-dose chemotherapy course (with tandem transplants) appears to improve progressionfree survival, although the effect is not discernible until 3 to 5 years posttransplant. The recent reports of tandem autologous transplant for maximum cytoreduction followed by nonmyeloablative allogeneic transplant for eradication of minimal residual disease appears promising and deserve further investigation. A central issue of tandem transplants, whether they involve autologous or allogeneic transplants, revolves around defining the subsets of patients who will benefit from the procedure. Good-risk patients (defined by normal cytogenetics and low beta-2-microglobulin levels), especially those who achieve a complete or near-complete response after the first transplant, appear to benefit the most from a second cycle. High-risk patients (defined by chromosomal abnormalities usually involving chromosomes 11 and 13 and high beta-2-microglobulin levels) whose median survival after tandem transplant is less than 2 years should be offered novel therapeutic interventions such as tandem "auto/allo" transplants. Until the efficacy and safety of this procedure is fully established, it should be limited to high-risk patients.
Newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and stem cell transplantation have a superior outcome in terms of eventfree and overall survival, compared with conventional chemotherapy recipients.[ 1-3] Although this has been proven in only one randomized trial, the results of several phase II studies provide a substantial body of evidence favoring the use of high-dose therapy (recently reviewed by Fassas and Tricot).[4] Despite this improvement in survival, it is clear that autologous stem cell transplant (auto- SCT) is not curative in the majority of patients. Allogeneic transplant (allo-SCT) is the only accepted curative therapy for multiple myeloma, given documented molecular remissions that are attributed to the graft-vs-myeloma effect, which appears to overcome chemotherapy resistance.
One approach to improving outcome in multiple myeloma patients is to administer additional cycles of high-dose therapy (usually two to three) with "tandem" transplants. Traditionally, autologous stem cells-and, more recently, allografts following administration of a nonmyeloablative conditioning regimen-have supported the second cycle. This review will focus on the prognostic factors that predict longterm event-free and overall survival following tandem auto-SCT and the potential for cure and benefit associated with tandem "auto/allo" transplantation.
Historical Background
High-dose therapy for multiple myeloma was introduced by the Royal Marsden Group.[5] These investigators reported an impressive 100% overall response rate in nine relapsed multiple myeloma patients following high doses of melphalan(Drug information on melphalan) (Alkeran), 100 to 140 mg/m2, without stem cell support. Subsequently, several trials demonstrated high-dose therapy to be superior to conventional chemotherapy in newly diagnosed multiple myeloma patients with response rates of 70% to 90%, complete remission (CR) rates of 25% to 50%, and median overall survivals of 4 to 5 years.
Results of Studies of Multiple Cycles of High-Dose Chemotherapy in Multiple MyelomaThe Intergroupe Français du Myélome was the first to randomize 200 previously untreated multiple myeloma patients to high-dose therapy with auto-SCT support (melphalan, 140 mg/m2, and total-body irradiation, 8 Gy) or conventional doses of chemotherapy.[1] The response rate in the high-dose therapy arm was 81% (CR = 22%), compared with only 57% in the standard group arm (CR = 5%, P < .001). The probability of achieving event-free and overall survival at 5 years was 28% and 52% in the high-dose therapy arm vs 10% (P = .01) and 12% (P = .03) in the conventional-dose arm. This trial confirmed the importance of complete response as a prognostic factor for overall survival.[6]
The use of peripheral blood stem cells, growth factors, and single-agent melphalan at 200 mg/m2 (vs totalbody irradiation) significantly reduced treatment-related mortality and improved the overall outcome of auto-SCT in multiple myeloma patients. In the 1980s, in an attempt to improve the results of auto-SCT, several groups used tandem high-dose therapy with auto-SCT.[7,8] Numerous phase II and III trials have shown that these strategies are feasible and well tolerated.[9-24] However, these studies were nonrandomized and contained a relatively small number of patients, making it difficult to prove that tandem transplant is more effective than single high-dose therapy and auto-SCT (Table 1).
Nonrandomized Trials of Tandem Auto-SCT
Outcome in 'Total Therapy' PatientsIn the early 1990s, Barlogie's group in Little Rock, Arkansas, adopted a "total therapy" program for newly diagnosed multiple myeloma patients. The program consisted of a series of intensive induction regimens using the non-cross-resistant drugs vincristine, doxorubicin(Drug information on doxorubicin) (Adriamycin), and dexamethasone(Drug information on dexamethasone) (VAD) * 4 cycles, etoposide(Drug information on etoposide), dexamethasone, cytarabine(Drug information on cytarabine), and cisplatin(Drug information on cisplatin), followed by high-dose cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) and stem cell collection, followed by tandem auto-SCT (irrespective of the response to induction). Upon hematologic recovery, patients received maintenance therapy with interferon.
Several updates of these data have been published.[3,7,24,25] The investigators noted a progressive increase in complete and partial response rates with each stage of the study: from 5% and 34% after VAD, to 15% and 65% at the end of induction, to 26% and 75% after the first auto-SCT, and to 41% and 83% after the second. Median event-free and overall survivals were 68 and 43 months, respectively. Median time to disease progression was 52 months (Figure 1).
Survival Curves for 'Total Therapy' PatientsOn multivariate analysis, superior event-free and overall survivals were observed in the absence of unfavorable karyotype (11q breakpoint abnormalities, -13 or 13q) and low beta-2-microglobulin levels (Figure 2). Median CR duration was 50 months, and CR was significantly longer with early onset of remission and favorable karyotype. Time-dependent analysis suggested that administration of the second auto-SCT within 6 months after the first extended both eventfree and overall survivals significantly, independent of karyotype or beta- 2-microglobulin levels.
The outcome in 1,000 multiple myeloma patients who received tandem auto-SCT was recently reported by Barlogie's group.[23] One factor associated with prolonged event-free survival (> 5 years), in addition to the absence of chromosome 11 or 13 abnormalities and low beta-2-microglobulin levels (< 2.5 mg/L) was pretransplant chemotherapy of less than 12 months at the time of first auto- SCT. Recently, Tricot et al reported that a small group of patients (n = 46) remained in continuous remission up to 7 years after auto-SCT. Of 515 patients, those without unfavorable risk factors (25%) had an event-free survival rate exceeding 35%, compared with 15%, 10%, and 0% for patients with one (43%), two (27%), or three (5%) risk factors, respectively.[ 26] These data show that patients with high-risk features should be considered for novel therapeutic interventions, as tandem auto-SCT does not significantly improve eventfree or overall survival.
Other studies using tandem auto-SCT reported similar long-term survival rates.[27] The European Group for Blood and Marrow Transplantation recently updated its transplantation registry data on a total of 8,362 multiple myeloma patients.[19] Only a subset of newly diagnosed patients (n = 441) received tandem cycles of high-dose therapy (their selection criteria were not reported). The investigators noted a trend toward improved survival at 7 years among patients receiving one vs two auto-SCTs (39% vs 57%, P = .1). The median overall survival following auto-SCT was 7.1 years in the tandem group and 5.6 years in the single auto-SCT groups. Although the majority of patients relapsed within the first 5 years after auto-SCT, a plateau was noted in event-free and overall survival after 7 to 8 years, thus supporting the possibility of "cure" in a small subset of patients.
