Tandem Transplantation in Multiple Myeloma

Tandem Transplantation in Multiple Myeloma

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 (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 Myeloma

The Intergroupe Franais du Mylome 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' Patients

In 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 (Adriamycin), and dexamethasone (VAD) * 4 cycles, etoposide, dexamethasone, cytarabine, and cisplatin, followed by high-dose 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' Patients

On 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.


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