A tandem autologous transplant, also known as a double autologous transplant, requires the patient to undergo two planned autologous stem cell transplants within 6 months. Stem cells are collected once before the initial transplant and half are used for each procedure. The second transplant is performed after recovery from the first procedure.

Although the relative merit of double transplantation has yet to be definitively determined, several studies have shown improved response rates and survival with the highly-demanding tandem regimen compared with single transplantation. However, it has yet to be determined which patients benefit most from a tandem transplant, and strategies to improve survival rates are still needed. Various strategies are being evaluated to improve the outcome of tandem transplants. One such strategy is intensification of therapy, such as that implemented in the Total Therapy program (see below), which is showing promising results. Another strategy is the incorporation of novel agents, such as thalidomide, Velcade, or Revlimid, into the treatment regimen either before or after transplant.

One of the first published reports of the use of tandem transplants in a large number of patients showed that the procedure was feasible and that the complete response (CR) rate increased from 24% after the first transplant to 43% after the second transplant. (Vesole et al. Blood. 1994;84:950-956.) Results of several tandem therapy trials are described below.

Total Therapy I. One of the first studies to show that a tandem autologous transplant can improve response rates and survival over that seen with standard therapy or a single transplant was Total Therapy I. (Barlogie et al. Blood. 1997;89(3):789-793; Barlogie et al. Blood. 1999;93:55-65.) Two hundred thirty-one patients with symptomatic myeloma were enrolled in Total Therapy I between 1990 and 1995.

The Total Therapy I regimen included induction therapy with 3 cycles of VAD (vincristine, doxorubicin, dexamethasone). High-dose cyclophosphamide plus granulocyte-macrophage colony-stimulating factor (GM-CSF) was then used to mobilize stem cells prior to peripheral blood stem cell (PBSC) collection. After stem cell collection, EDAP (etoposide, dexamethasone, cytarabine, cisplatin) was given to enhance reduction of tumor cells prior to high-dose therapy (melphalan 200 mg/m²) and autologous transplant. The second course of high-dose therapy and transplant was performed 3 to 6 months later. Patients then received interferon maintenance until disease recurrence.

In the study, 71% of patients completed the treatment through the second transplant. Mortality rates were 3% during induction, 1% with the first transplant, and 4% with the second transplant. There was a progressive increase in response rates after each treatment phase. The complete response rate was 5% after VAD, 26% after the first transplant, and 41% after the second transplant. In comparison with matched historical controls receiving standard chemotherapy, patients receiving the Total Therapy regimen had a significantly higher response rate and survival (see table below). Ten-year data presented at ASH 2003 show that in comparison to standard chemotherapy, the tandem transplant regimen used in the Total Therapy I trial offered superior 10-year event-free and overall survival. (Barlogie et al. Blood. 2003;102(11). Abstract 136.)

Results of Total Therapy I Compared with Historical Controls*

Parameter Total Therapy I Historical Controls Response (≥ PR) 86% 52% Median EFS† 49 mos. 22 mos. Median OS† >62 mos. 48 mos. 10-year EFS 15% 5% 10-year OS 33% 15%

An important observation made from this trial and the various single autologous transplant studies noted earlier is that achieving a complete response-by whatever means-is associated with longer overall survival.

IFM-94. The final analysis of the landmark French IFM-94 trial demonstrated that double transplantation led to improved survival compared with single transplantation in patients with previously untreated myeloma. (Attal et al. N Engl J Med. 2003;349(26):2495-2502.) The randomized study included 399 patients under the age of 60. The percentage of patients achieving a complete or very good partial response was similar among the single (42%) and double transplant (50%) groups. However, after 7 years, the probabilities of event-free and overall survival with double transplants were twice that seen with single transplants (see figures below). The benefits of double transplantation were not evident until after 4 years of follow up. Double transplantation appeared to be particularly beneficial to those patients who did not achieve a very good response following the first transplant. However, 7-year EFS was 20%, indicating that there is much room for improvement in survival rates.



Other randomized trials.Preliminary results of several randomized trials comparing tandem and single autologous transplants, which have not been followed as long, have also shown superior event-free survival with the tandem regimen in most studies (see table). In one study (Bologna 96), significantly improved event-free survival with double transplants was seen among patients <60 years of age, particularly those who had not achieved a near CR after the first transplant. However, only the IFM-94 study has demonstrated improvement in overall survival with the tandem approach. The designs of these studies vary, so comparisons are difficult. In addition, it has yet to be determined which patients benefit most from a tandem transplant. It appears that in patients with poor prognostic features, outcome is not improved with tandem transplants, so additional strategies need to be evaluated in this patient population.

Preliminary Results: Randomized Single Versus Double Transplant Studies

CR rate (%) EFS (months) OS (months) Study # Pts Age (yrs) Follow up (yrs) Single vs Double p Single vs Double p Single vs Double p IFM94 399 < 61 7 42 vs 50 0.1 25 vs 30 0.03 48 vs 58 0.01 MAG95¹ 227 < 56 4 39 vs 37 NS 31 vs 33 NS 49 vs 73 0.14 Bologna96² 220 < 61 3 31 vs 43 NS 21 vs 31 0.02 56 vs 60 NS GMMG³ 261 < 66 – – – 23 vs NR 0.03 – – Hovon224 303 < 66 4 13 vs 28 0.002 20 vs 22 0.01 55 vs 50 NS

Results of a prospective trial conducted by the Spanish Group of Multiple Myeloma that analyzed the effect of age on survival following tandem transplants suggest that they may be less effective in patients over 60 years of age. (Sureda et al. Blood. 2004;104(11). Abstract 930.)

Total Therapy II. The ongoing Total Therapy II trial is evaluating a double transplant regimen that incorporates a more intensive chemotherapy regimen than Total Therapy I and includes thalidomide (see figure below).

TOTAL THERAPY II FLOWCHART

Preliminary results show improved response and survival rates over that seen in Total Therapy I in patients without chromosomal abnormalities. (Barlogie et al. Blood. 2003;102(11). Abstract 136.)

Preliminary Results of Total Therapy II Compared with Total Therapy I

Parameter Total Therapy II Total Therapy I Rate of CR + Near-CR 66% 43% 4-yr estimate of continuous CR, no CA 75% 36% 4-yr estimate of continuous CR, with CA 35% 35% 4-yr. EFS, no CA* 70% 37% 4-yr. OS, no CA 80% 64%

Additional results from this study suggest that the high intensity therapy as applied in TT-2 results in greater tumor cytoreduction as reflected by a higher molecular CR rate than previously reported with autotransplantation, even in patients with abnormal cytogenetics. (Tricot et al. Blood. 2004;104(11). Abstract 933.) The rate of molecular CRs achieved appears to be equivalent to that observed after allotransplantation.

Total Therapy III. Total Therapy 3 (TT 3) represents a further development of the Total Therapy concept. TT 3 incorporates Velcade into a DT-PACE (dexamethasone, thalidomide, cisplatin, Adriamycin, cyclophosphamide, and etoposide) chemotherapy regimen. (Barlogie et al. Blood. 2004;104(11). Abstract 538.) Preliminary data on the first 57 patients enrolled in the study show that 26% of patients achieved at least a near CR after the second cycle of treatment (prior to first transplant) and 40% achieved at near CR or better after the first transplant. Bone marrow suppression was the most common side effect; non-hematologic toxicities appeared to be similar to those seen with DT-PACE previously. Stem cell harvest was possible in most cases.

Maintenance. Researchers are investigating ways of maintaining response after tandem transplantation. Maintenance treatment with thalidomide and pamidronate (Aredia®, Novartis and others) after high-dose therapy and tandem autologous transplant may prolong response duration and reduce the number of bone events. (Attal et al. Blood. 2004;104(11). Abstract 535.) Preliminary results from a large IFM study comparing outcome following no maintenance treatment, maintenance treatment with pamidronate, and maintenance with thalidomide and pamidronate showed that the 3-year progression-free survival was significantly improved with the combination (56%) compared with 34% in the group receiving no treatment and 37% in the group receiving pamidronate alone. The 3-year risk of bone events was reduced in the two groups receiving pamidronate and overall survival was similar in the three groups.

Second salvage transplants. A second autologous stem cell transplant is sometimes performed in patients who have relapsed after an initial stem cell transplant. Some myeloma centers automatically collect enough stem cells for two transplants and reserve them for a possible second transplant. Analysis of data on 96 myeloma patients who received a second transplant following relapse, which was presented at the IXth International Workshop on Myeloma, showed that a second (salvage) transplant is a feasible option for refractory/relapsed disease. (Powles et al. Hematology J. 2003;4(suppl 1):S62. Abstract P10.3.1.) The median survival in patients receiving the salvage transplant (6.4 years) was equivalent to that typically seen with a planned tandem transplant. However, these patients represent a select subgroup of patients with relatively good prognosis.

Ongoing Tandem Autologous Stem Cell Transplant Trials in Myeloma as of August 2005 Tandem Autologous Stem Cell Transplantation with Or Without Maintenance Therapy After the Second Transplantation Compared with Autologous Stem Cell Transplantation Followed by Matched Sibling Allogeneic Stem Cell Transplantation in Patients with Stage II Or Stage III Multiple Myeloma •  View trial information A Trial of Tandem Autologous Stem Cell Transplants +/- Post Second Autologous Transplant Maintenance Therapy versus Single Autologous Stem Cell Transplant Followed by Matched Sibling Non-myeloablative Allogeneic Stem Cell Transplant for Patients with Multiple Myeloma •  View trial information SWOG 0204, Phase II Trial of Thalidomide/Dexamethasone Induction Followed by Tandem Melphalan Transplant and Prednisone/Thalidomide Maintenance in Newly Diagnosed Multiple Myeloma Patients •  View trial information Phase III Study of DTPACE followed by Tandem Transplant with MEL 200 versus MEL/DTPACE Hybrid and DTPACE Consolidation in Patients with Active Multiple Myeloma •  View trial information UARK 2003-33, Total Therapy III: A Phase 2 Study Incorporating Bone Marrow Microenvironment (ME) - Co-Targeting Bortezomib into Tandem Melphalan-Based Autotransplants with DT PACE for Induction/Consolidation and Thalidomide + Dexamethasone for Maintenance •  View trial information Phase I study of Bortezomib with "DT-PACE" for induction and Stem Cell collection of Newly Diagnosed Multiple Myeloma patients •  View trial information