Tandem transplantS



Tandem transplants involve a second transplant done 2-3 months after the first autologous transplant. They are usually part of aggressive upfront therapy (= during the first 6-12 months of diagnosis), not in the salvage setting (= relapse).

For some experts, the use of tandem transplants remains a controversial issue. A French study published in 2003 involving 399 myeloma patients has shown that the probability of being alive at 7 years after a single autologous transplant was 21%, while it was 42% in the group treated with double transplant.

In order to consider a second transplant, 3 criteria should be fulfilled:
 1) Insurance approval (e.g., Medicare does not approve for >1 SCT).
 2) Myeloma has been responsive to the first transplant
 3) No serious complications during the first transplant

The use of tandem transplants pioneered in Arkansas has raised the true CR and it prolonged the duration of remission. With this approach, some patients can reach an operational cure (= a normal life span with persistent microscopic disease). Some patients return to a phase of MGUS.

As of 2014, 5 prospective trials compared the use of single vs tandem transplants. Progression-free survival was prolonged in 3 of them, and overall survival in 1 of them (the benefit was limited in those patients who did not achieve at least a very good partial remission after the first transplant). A meta-analysis did not show benefit.


Predicting long-term (> or = 5 years) event-free survival in multiple myeloma patients following planned tandem autotransplants.
Tricot G, Spencer T, Sawyer J, Spoon D, Desikan R, Fassas A, Badros A, Zangari M, Munshi N, Anaissie E, Toor A, Barlogie B.
Br J Haematol. 2002 Jan;116(1):211-7.
This study analyzed prognostic factors for long-term survival in 515 consecutive patients who underwent tandem transplants and had a follow up of at least 5 years. Multivariate analysis identified several factors associated with event-free survival of at least 5 years:
  - Beta-2 microglobulin = or < 2.5 mg/l at time of first transplant
  - Absence of chromosome 11 and 13 abnormalities
  - Less than 12 months of induction therapy
Follow-up data were consistent with cure in those myeloma patients in complete remission for at least 7 years post-transplant, and re-establishment of an MGUS status in those in partial remission at 7 years post-transplant.

Benefit and timing of second transplantations in multiple myeloma: clinical findings and methodological limitations in a European Group for Blood and Marrow Transplantation registry study.
J Clin Oncol. 2004 May 1;22(9):1674-81.
Morris C, Iacobelli S, Brand R, Bjorkstrand B, Drake M, Niederwieser D, Gahrton G; Chronic Leukaemia Working Party Myeloma Subcommittee, European Group for Blood and Marrow Transplantation.
This study reviewed 7,452 patients treated with autologous transplants, either planned tandem transplants or not. Results were analyzed on an intention-to-treat basis. Of note, the transplantation rate in the group of planned transplants was only 55% (1,469 of 2,655 patients). The median survival from transplant was 60 months for the "planned" group, vs 51 months for the remainder group. The authors found that, in order to improve survival of tandem autologous transplants, the second transplant should be performed before relapse and within 6-12 months of the first transplant.

Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients.
J Clin Oncol. 2010 Feb 10;28(5):800-7.
Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M.
In this study, 102 patients age 65-75 underwent the following treatment:
 1- Induction therapy with PAD (bortezomib, liposomal doxorubicin, dexamethasone) x 4 cycles
 2- Stem cell collection with cyclophosphamide 3 g/m2
 3- Tandem autologous stem cell transplantations with melphalan 100 mg/m2
 4- Consolidation therapy with Revlimid + Prednisone x 4 cycles
 5- Maintenance therapy with Revlimid until relapse
Results: the 2 year progression-free survival was 69%, and the 2-year overall survival was 86%.






IFM 94 trial (French)
399 patients.
After a median follow-up of 60 months:
EFS and OS were superior after 2 transplants compared with 1 transplant.
  - 7-year EFS: 10% with 1 transplant and 20% with 2 transplants
  - 7-year OS: 21% with 1 transplant and 42% with 2 transplants
Of note, the difference in survival became apparent only after 4 years of follow-up.

Single versus double autologous stem-cell transplantation for multiple myeloma.
N Engl J Med. 2003 Dec 25;349(26):2495-502.
Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R; InterGroupe Francophone du Myélome.
This is a randomized trial of 399 patients with newly diagnosed multiple myeloma, treated with high-dose chemotherapy followed by either 1 or 2 autologous stem-cell transplantations. Results favored the double transplant group:
  - Rate of complete or very good partial response was 42% with 1 transplant and 50% with 2 transplants
  - Event-free survival at 7 years was 10% with 1 transplant and 20% with 2 transplants
  - Overall survival at 7 years was 21% with 1 transplant and 42% with 2 transplants
The benefit of the second transplant was observed especially in those patients who did not have a very good partial response after the first transplant.


Bologna 96 trial
321 patients.
  - Median OS was 65 months after 1 SCT and 71 months after tandem SCT
  - 7-year survival was similar (43% vs 46%, p=0.90)
The Bologna 96 data suggest that patients who derive most benefit from second SCT are those who do not reach complete remission (or nCR) after the first SCT.

Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study.
J Clin Oncol. 2007 Jun 10;25(17):2434-41.
Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M.
This is a prospective, randomized study of single vs double autologous stem-cell transplantation.
321 patients with newly diagnosed myeloma were treated with VAD x4, mobilization chemotherapy with high-dose cyclophosphamide 7 grams/m2, and randomized to receive:
  - 1 transplant: melphalan 200 mg/m2 (arm A, 163 patients)
  - 2 transplants: melphalan 200 mg/m2 followed, after 3-6 months, by melphalan 120 mg/m2 + busulfan 12 mg/Kg (arm B, 158 patients)
In comparison with a single autologous transplant, double autologous transplants showed:
  - Superior CR or nCR rate (47% vs 33%, p=0.008)
  - Similar transplant-related mortality (4% vs 3%, p=0.70)
  - Superior median event-free survival (35 vs 23 months, p=0.001)
  - Median OS was 71 months in arm A and 65 months in arm B
  - Similar 7-year survival (43% vs 46%, p=0.90)
Of note, the administration of a second transplant at relapse in patients assigned to receive a single transplant probably contributed to prolong the survival. Benefits offered by double transplantation were more evident among patients who failed to reach at least nCR after the first transplant.


MAG95 trial
227 patients.
OS was superior after 2 transplants compared with 1 transplant.


HOVON 24 trial (Dutch-Belgian)
303 patients
RR and EFS were superior after 2 transplants compared with 1 transplant. OS was similar, but many patients in the single-transplant group underwent a second transplant as salvage therapy, upon relapse.

Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial.
Haematologica. 2007 Jul;92(7):928-35.
Sonneveld P, van der Holt B, Segeren CM, Vellenga E, Croockewit AJ, Verhoe GE, Cornelissen JJ, Schaafsma MR, van Oers MH, Wijermans PW, Westveer PH, Lokhorst HM; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON).
The Dutch-Belgian HOVON group performed a randomized trial in 303 patients with newly diagnosed MM. After induction chemotherapy with VAD x3, patients received either:
  - 2 cycles of non-myeloablative intermediate-dose melphalan (70 mg/m2) (group A)
  - Same regimen followed by cyclophosphamide 120 mg/kg  + TBI 9 Gy and autologous stem cell transplantation (group B)
Patient were given maintenance with interferon alpha-IIa until relapse or progression.
  - CR was higher in group B (32% vs 13%, p<0.001)
  - Group B had similar median EFS (22 vs 21 months) and better EFS at 6 years (15% vs 7% at 6 years)
  - Median overall survival was similar (55 months in group A vs 50 months in group B)
  - OS at 6 years was similar (36% in group A vs 39% in group B)
Achievement of CR had a favorable prognostic impact.


GMMG-HD2 trial (German)
358 patients
After a median follow-up of more than 11 years, single SCT was non-inferior to tandem SCT.

Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial.
Br J Haematol. 2016 Jun;173(5):731-41.
Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H.
This is a prospective study of 358 patients randomized to receive either a single transplant (188 patients) or tandem transplants (197 patients). Post-transplant maintenance was done with the use of interferon three times a week, a practice which was obsolete at the time of the publication. Of note, in the tandem arm, 26% of patients refused the second autologous transplant (p>0.05). In an intention-to-treat analysis, after a median follow-up of 134 months, results were as follows:
  - Response rate: 93% with single transplant, and 91% with tandem transplants
  - Median event-free survival: 25 months with single transplant, and 29 months with tandem transplants
  - Median overall survival: 73 months with single transplant, and 75 months with tandem transplants
  - 10-year overall survival: 34% with single transplant, and 33% with tandem transplants



[Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial.
Blood. 2008 Feb 15;111(4):1805-10.
Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaouï L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsaïri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group.
This study has been retracted in June 2009]




The philosophy behind the "Total Therapy" approach of Dr. Barlogie at the University of Arkansas is the aim at reaching CR with the goal of curing the disease (instead of disease control), by combining all available methods of therapy into front-line treatment. These protocols were intended only for newly diagnosed myeloma patients, and use a systematic approach which include induction therapy, tandem autologous transplants, and post-transplant consolidation/maintenance. These aggressive protocols have reached an unprecedented proportion of patients attaining CR, which is a prerequisite of cure.

Total Therapy I was the first study of tandem transplants to produce impressive results:
  - CR: 40%
  - EFS: 2.6 years
  - OS: 5.7 years
  - 15-year EFS: 7%
  - 15-year OS: 17%

Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma.
Blood. 1997 Feb 1;89(3):789-93.
Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G.
At the time of this publication, available standard therapies for myeloma were unable to improve survival for two decades. The introduction of this "Total Therapy" protocol improved outcomes. 123 patients with newly diagnosed myeloma recieved induction therapy with noncross-resistant drugs, tandem autologous transplants, and maintenance with interferon. RR was 85%, with 40% CR (52% with conventional therapy). After a median follow-up of 31 months, median event-free survival was 49 months (22 months with conventional therapy), and overall survival was >62 months (48 months with conventional therapy).

Total therapy with tandem transplants for newly diagnosed multiple myeloma.
Blood. 1999 Jan 1;93(1):55-65.
Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J.
231 patients with newly diagnosed myeloma were enrolled in the Totasl Therapy 1 protocol (1990-95), which included:
1) Induction therapy with non-cross-resistant regimens (VAD, cyclophosphamide for mobilization)
2) First autologous transplant with melphalan 200 mg/m2
3) Second autologous transplant (with TBI or CTX if <PR) - 71% of patients
4) Post-transplant maintenance with interferon-2b
  - Mortality rate was 3% during induction, 1% with the first transplant, and 4% with the secon transplant
  - Response rate (PR + CR) was 75% after the first transplant and 83% after the second transplant
  - Median time to disease progression or relapse was 52 months
  - Median event-free survival was 43 months
  - Median overall survival was 68 months
  - 5-year event-free survival was 42%
  - 5-year overall survival was 58%

Long-term outcome results of the first tandem autotransplant trial for multiple myeloma.
Br J Haematol. 2006 Oct;135(2):158-64.
Barlogie B, Tricot GJ, van Rhee F, Angtuaco E, Walker R, Epstein J, Shaughnessy JD, Jagannath S, Bolejack V, Gurley J, Hoering A, Vesole D, Desikan R, Siegel D, Mehta J, Singhal S, Munshi NC, Dhodapkar M, Jenkins B, Attal M, Harousseau JL, Crowley J.
Results after a median follow-up of 12 years:
  - 10-year OS 33%, 10-year EFS 15%
  - 15-year OS 17%, 15-year EFS 7%

With Total Therapy 2:
  - CR: 43-62%
  - EFS: 4.8 years
  - OS: 8.0 years
  - 5-year EFS: 44-56%
  - 5-year OS: 65%
  - 8-year estimate of OS: 56% in the thalidomide group and 45% in the control group (p=0.09)
  - The survival benefit of thalidomide was limited to patients with cytogenetic abnormalities

Thalidomide and hematopoietic-cell transplantation for multiple myeloma.
N Engl J Med. 2006 Mar 9;354(10):1021-30.
Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, Fassas A, Zangari M, Hollmig K, Pineda-Roman M, Lee C, Talamo G, Thertulien R, Kiwan E, Krishna S, Fox M, Crowley J.

Total Therapy 2 (1998-2004) is one of the largest trials conducted in multiple myeloma. 668 patients with newly diagnosed myeloma were treated with induction therapy, tandem autologous transplants using melphalan, consolidation chemotherapy, and maintenance therapy. Patients were randomized to receive thalidomide continuously, until disease progression or unacceptable toxicity (323 patients), or no thalidomide (345 patients). Results:
  - Rate of complete response was 62% in the thalidomide group, and 43% in the control group (p<0.001)
  - 5-year event-free survival was 56% in the thalidomide group, and 44% in the control group (p=0.01)
  - 5-year overall survival was 65% in both groups (P=0.90)
  - Median survival after relapse was inferior in the thalidomide group (1.1 vs 2.7 years, p=0.001)
As expected, toxicities were more frequent in the thalidomide group, particularly severe peripheral neuropathy and deep venous thrombosis.
In conclusion, after a median follow-up of 42 months, thalidomide increased response rate and event-free survival, but did not improve overall survival.

Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of total therapy 1.
Br J Haematol. 2008 May;141(4):433-44.
Zangari M, van Rhee F, Anaissie E, Pineda-Roman M, Haessler J, Crowley J, Barlogie B.
This study reports the rusults of Total Therapy 2, with longer follow-up. Results were better than those achieved with Total Therapy 1, in terms of CR duration, EFS, and OS. Event-free survival was 4.8 years and overall survival was 8.0 years. In patients without cytogenetic abnormalities, improved results were mainly related to post-transplant consolidation therapy, whereas in patients with cytogenetic abnormalities, improved results were mainly related to the use of thalidomide. With longer follow-up, Total Therapy 2 revealed an apparent separation of the survival curves between the two randomized groups (thalidomide vs non-thalidomide), and it did not confirm the previously observed shorter post-relapse survival of the thalidomide group.

With Total Therapy 3:
  - CR/nCR: 83% at 2 years (59% CR)
  - 2-year EFS: 84%
  - 2-year OS: 86%

Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3.
Br J Haematol. 2007 Jul;138(2):176-85.
Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr.
303 patients with newly diagnosed patients received induction chemotherapy, tandem autologous transplants, consolidation chemotherapy, and maintenance therapy, integrating bortezomib during the various phases of the protocol. Results:
  - Treatment-related mortality was 5%
  - At 2 years, 83% of patients achieved at least a near-complete remission
  - 2-year estimate of event-free survival was 84%
  - 2-year estimate of overall survival was 86%

Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2.
Br J Haematol. 2008 Mar;140(6):625-34.
Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F, Crowley J, Shaughnessy JD Jr, Barlogie B.
After a median follow-up of 2 years and among 303 patients enrolled in TT3, 92% of patients who reached CR sustained their remission at 2 years. Superior outcomes of TT3 compared with TT2 are presumably due to the addition of bortezomib.



Giampaolo Talamo, M.D.