Tandem transplants with different high-dose regimens improve the complete remission rates in multiple myeloma. Results of a Grupo Español de Síndromes Linfoproliferativos/Trasplante Autólogo de Médula Osea phase II trial.
Br J Haematol. 2003 Jan;120(2):296-303.
Lahuerta JJ, Grande C, Martínez-Lopez J, De La Serna J, Toscano R, Ortiz MC, Larregla S, Conde E, Insunza A, Gonzalez-San Miguel JD, Bargay J, Cabrera R, García-Ruiz JC, Albó C, García-Alonso L, Solano F, Vivancos P, León A, San Miguel J; Grupo Español de Síndromes Linfoproliferativos/Trasplante Autólogo de Médula Osea.
88 myeloma patients were treated with tandem autologous stem cell transplants, using melphalan 200 mg/m2 with the first transplant, and CBV (cyclophosphamide, BCNU, and etoposide) with the second transplant. Complete remission was achieved in 26 patients (30%) after the first transplant, and in 16 of the remaining 48 evaluable patients (33%) after the second transplant (final CR rate 48%). The 5-year event-free survival was 28%, and the 5-year overall survival was 55%. The outcome of the patients in CR after 2 transplants was not different from that of patients in CR after the first transplant. In this study, the benefit of the second transplant depended on the induction of CR for those patients who did not reach CR after the first transplant.




At present time, the auto-allo SCT approach does not constitute standard of therapy for multiple myeloma. Despite high rates of complete remission, this strategy does not lead to improvement in overall survival, at least in standard-risk myeloma.

Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma.
Blood. 2002 Aug 1;100(3):755-60.
Kröger N, Schwerdtfeger R, Kiehl M, Sayer HG, Renges H, Zabelina T, Fehse B, Tögel F, Wittkowsky G, Kuse R, Zander AR.
In this study, 17 patients with myeloma underwent an autologous SCT with melphalan 200 mg/m2, followed by a mini-allogeneic SCT using fludarabine 180 mg/m2 + melphalan 100 mg/m2 + ATG. Transplant-related mortality at day 100 was 11%. CR increased from 18% after the autologous SCT to 73% after the mini-allogeneic SCT. After a median follow-up of 13 from the allogeneic SCT, 13 patients were alive and 12 of them were in remission.

Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma.
Blood. 2003 Nov 1;102(9):3447-54.
Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W, Storer B, Hegenbart U, Somlo G, Chauncey T, Bruno B, Appelbaum FR, Blume KG, Forman SJ, McSweeney P, Storb R.
This is a study of 54 patients with multiple myeloma treated with an autologous stem cell transplant (using melphalan 200 mg/m2) followed by a mini-allogeneic stem cell transplant from HLA-matched siblings (using TBI). 52% of patients had refractory or relapsed disease. RR: 83% (CR 57%, PR 26%). At a median follow-up of about 1.5 years, overall survival was 78%.

A Phase II trial of autologous stem cell transplantation followed by mini-allogeneic stem cell transplantation for the treatment of multiple myeloma: an analysis of Eastern Cooperative Oncology Group ECOG E4A98 and E1A97.
Biol Blood Marrow Transplant. 2009 Jan;15(1):83-91.
Vesole DH, Zhang L, Flomenberg N, Greipp PR, Lazarus HM; ECOG Myeloma and BMT Committees.

In this study, 32 MM patients received melphalan 200 mg/m2 with autologous HSCT, followed by a mini-allogeneic SCT from matched sibling donor, using fludarabine 30 mg/m2 daily x 5 + cyclophosphamide 1 g/m2 daily x 2. 23 patients (72%) completed both SCT. After a median follow up of 4.6 years, the median PFS was 3.6 years, and the 2-year OS was 78%. Response rate was 78%, including 30% CR. This approach failed to be curative, because a plateau in PFS or OS was not observed, even in patients achieving CR.

Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo.
Blood. 2009 Apr 2;113(14):3375-82.
Bruno B, Rotta M, Patriarca F, Mattei D, Allione B, Carnevale-Schianca F, Sorasio R, Rambaldi A, Casini M, Parma M, Bavaro P, Onida F, Busca A, Castagna L, Benedetti E, Iori AP, Giaccone L, Palumbo A, Corradini P, Fanin R, Maloney D, Storb R, Baldi I, Ricardi U, Boccadoro M.
These authors enrolled 100 newly diagnosed patients younger than 65 years in a prospective multicenter study. They used induction therapy with VAD-based chemotherapy and an autologous SCT with melphalan 200 mg/m2, followed by an allogeneic SCT from an HLA-matched sibling with a single dose of nonmyeloablative total body irradiation. CR rate was 53%. After a median follow-up of 5 years, OS was not reached, and EFS was 37 months. Acute GVHD was observed in 38% of patients, and chronic GVHD in 50% of them.

Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting.
Blood. 2009 Apr 2;113(14):3383-91.
Rotta M, Storer BE, Sahebi F, Shizuru JA, Bruno B, Lange T, Agura ED, McSweeney PA, Pulsipher MA, Hari P, Maziarz RT, Chauncey TR, Appelbaum FR, Sorror ML, Bensinger W, Sandmaier BM, Storb RF, Maloney DG.
102 MM patients received auto SCT with high-dose melphalan and allogeneic SCT from HLA-matched siblings, using 2-Gy total body irradiation. 42% of patients developed grade 2-4 acute GVHD, and 74% chronic GVHD. After a median follow-up of 6.3 years, the 5-year nonrelapse mortality was 18%, mostly due to GVHD or infections. CR was observed in 59 of 95 patients. Median OS was not reached, and median progression-free survival (PFS) was 3 years. Five-year OS was 64%, and 5-year PFS was 36%. Overall, these results do not compare favorably with tandem autologous transplants, due to nonrelapse mortality, frequent GVHD, and relatively inadequate long-term disease control.

Tandem autologous non-myeloablative allogeneic transplantation in patients with multiple myeloma relapsing after a first high dose therapy.
Bone Marrow Transplant. 2011 Feb;46(2):250-6.
Karlin L, Arnulf B, Chevret S, Ades L, Robin M, De Latour RP, Malphettes M, Kabbara N, Asli B, Rocha V, Fermand JP, Socie G.
This is a retrospective study of 23 patients with myeloma in relapse after an autologous stem cell transplant. Patients received salvage tandem transplants, with an autologous SCT followed by a mini-allogeneic SCT. Results:
  - Median event-free survival 36.8 months
  - Median overall survival: 60 months
  - Overall survival at 2 years: 61%
Compared with patients who did not receive allogeneic SCT, these patients had a significant survival advantage.

Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation.
Bone Marrow Transplant. 2016 Apr;51(4):529-35.
Ahmad I, LeBlanc R, Cohen S, Lachance S, Kiss T, Sauvageau G, Roy DC, Busque L, Delisle JS, Bambace N, Bernard L, Sabry W, Roy J.
In this study, 92 patients with newly diagnosed multiple myeloma younger than 65 were treated with an autologous stem cell transplant followed by a non-myeloablative allogeneic stem cell transplant, 2-3 months after the autologous one. The conditioning regimen for the allogeneic stem cell transplant consisted of fludarabine 30 mg/m2 IV and cyclophosphamide 300 mg/m2 IV, both of them for 5 days. The donors were 6/6 HLA-matched siblings. GVHD prophylaxis included tacrolimus and MMF. There was no maintenance therapy. Median follow-up was 8.8 years.
Despite the suboptimal induction chemotherapy (most patients received VAD, which was obsolete and considered inferior therapy at the time of the publication), the results were excellent, because the 10-year overall survival was 62%, and the 10-year progression-free survival was 41%, which suggested the potential for sure for a subset of patients treated with this approach. Unfortunately, the incidence of chronic GVHD was high (79%), but the non-relapsed mortality was low (10%).




It seems that patients undergoing allo-SCT do worse in the first 1-2 years, but prolonged follow-up shows a benefit for patients treated with the allo-SCT. In fact, survival curves for autologous SCT show a continuous drop, whereas those for allo-SCT show stabilize with time, indicating a potential for definitive cure for a subset of patients.
However, as of 2014, only
one of 5 trials (Bruno et al.) reported an improvement of overall survival.



Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma.
Blood. 2006 May 1;107(9):3474-80.
Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P.
In 1999, the Intergroupe Francophone du Myélome (IFM) initiated 2 trials in patients with high-risk myeloma:
  - IFM99-03: autologous stem cell transplant with melphalan 200 mg/m2 followed by RIC allogeneic stem cell transplant, in patients with HLA-identical sibling donor
  - IFM99-04: tandem autologous stem cell transplant with melphalan 200 mg/m2, in patients without HLA-identical sibling donor
This study included 264 patients, 65 in the IFM-03 trial and 219 patients in the IFM99-04 trial.
On an intent-to-treat analysis, overall survival and event-free survival were similar:
  - In IFM99-03, median OS was 35 months, and median EFS was 25 months
  - In IFM99-04, median OS was 41 months, and median EFS was 30 months
TRM was 5% for the tandem autologous group and 11% for the autologous-allogeneic group.
In this study, autologous SCT followed by allogeneic SCT was not superior to tandem autologous SCT in patients with high-risk MM.



A comparison of allografting with autografting for newly diagnosed myeloma.
N Engl J Med. 2007 Mar 15;356(11):1110-20.
Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, Omedè P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo A, Storb R, Ciccone G, Boccadoro M.
This is a trial of 162 patients with newly diagnosed multiple myeloma, age 65 or younger. The authors compared tandem autologous-autologous SCT (82 patients) vs tandem autologous-allogeneic SCT (80 patients). Patients without an HLA-identical sibling received two autologous SCT using melphalan 100-200 mg/m2, whereas patients with an HLA-identical sibling underwent a second SCT with a nonmyeloablative allogeneic protocol using TBI 200 cGy (19% received DLI). Median follow-up was 45 months (range, 21-90). Results:
  - Treatment-related mortality was similar
  - Disease-related mortality was 43% in the auto-auto group, and 7% in the auto-allo group (p <0.001)
  - Median OS was 54 months in the auto-auto group, and 80 months in the auto-allo group (p= 0.01)
  - Median EFS was 29 months in the auto-auto group, and 35 months in the auto-allo group (p= 0.02)
  - OS at 4 years was 53% in the auto-auto group, and 75% in the auto-allo group
The authors concluded that in patients with newly diagnosed myeloma, outcomes of tandem autologous-allogeneic SCT are superior to those of tandem autologous-autologous SCT. Some experts have criticized this conclusion, because of the relatively poor outcome of the auto-auto group in this trial. Other series of tandem autologous transplants have reported better median overall survival.



A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma.
Blood. 2008 Nov 1;112(9):3591-3.
Rosiñol L, Pérez-Simón JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ, González JD, Díaz-Mediavilla J, Hernández B, García-Frade J, Carrera D, León A, Hernández M, Abellán PF, Bergua JM, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas y Grupo Español de Mieloma (PETHEMA/GEM).
110 patients with multiple myeloma not in CR/nCR after a first autologous transplant received a second transplant, either second autologous transplant (85 patients) or a RIC allogeneic transplant (25 patients), depending on the availability of a matched sibling donor. Results:
  - Transplantation-related mortality: 16% in the auto-allo group and 5% in the auto-auto group (p= 0.07)
  - CR: 40% in the auto-allo group and 11% in the auto-allo group (p =0.001)
  - Median PFS: not reached in the auto-allo group and 31 months in the auto-auto group (trend: p= 0.08)
  - Median EFS and OS: no statistical difference
  - OS at 5 years: 60% in the auto-auto group, and 62% in the auto-allo group
  - Chronic GVHD: 66%
The auto-allo group reached an encouraging plateu of PFS, but the allogeneic transplant was associated with high morbidity and mortality, as expected.



Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up.
J Clin Oncol. 2011 Aug 1;29(22):3016-22.
Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Musto P, Beksac M, Bosi A, Milone G, Corradini P, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Gahrton G.
357 patients with multiple myeloma were treated with:
  - Tandem auto-SCT and mini-allo-SCT (108 pts), if a matched sibling was available
  - Single autologous SCT (145 pts)
  - Tandem auto-STC (104 pts)
Median follow-up time was 61 months. Results:
  - Rate of complete remission was higher with auto-allo than with auto (51% vs 41%), p= 0.02
  - Progression-free survival at 5 years was better (35% vs 18%, p= 0.001)
  - Relapse incidence was lower (49% vs 78%)
  - Overall survival at 5 years was higher (65% vs 58%)
Of note, this study included only allo-SCT with HLA-matched sibling donors.

Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study.
Blood. 2013 Jun 20;121(25):5055-63.
Gahrton G, Iacobelli S, Björkstrand B, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Carella AM, Beksac M, Bosi A, Milone G, Corradini P, Schönland S, Friberg K, van Biezen A, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Garderet L, Kröger N; EBMT Chronic Malignancies Working Party Plasma Cell Disorders Subcommittee.



Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial.
Lancet Oncol. 2011 Dec;12(13):1195-1203.
Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; on behalf of the Blood Marrow Transplant Clinical Trials Network (BMT CTN).
This is a phase III trial that randomized 625 patients with standard-risk myeloma (age <70) into two groups: one received tandem autologous transplants (366 evaluable patients), and the other received an autologous transplant followed by a mini-allogeneic transplant, if an HLA-matched sibling donor was available (156 evaluable patients). Patients of the auto-auto group were also randomized to maintenance with dexamethasone and thalidomide (219 patients, but only 77% completed it) vs observation (217 patients).
  - The 3-year progression-free survival was 46% in the auto-auto group, and 43% in the auto-allo group (p=0.67)
  - The 3-year overall survival was 80% in the auto-auto group, and 77% in the auto-allo group (p=0.19)
  - More than half of patients of the auto-allo group developed chronic GVHD
  - Progression-free survival and overall survival did not differ between the group receiving maintenance and the group followed with observation
The conclusion is that the auto-allo transplant strategy is not superior to the auto-auto one for standard-risk myeloma.


Conditioning regimens for the allo-SCT:
  - IFM.............Fludarabine + Busulfan + ATG
  - Italian.........TBI 2 Gy
  - Pethema.........Fludarabine + Melphalan 140
  - EBTM............Fludarabine + TBI
Of note, the IFM trail included only patients with high-risk disease.




Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study.
Blood. 2012 Jun 28;119(26):6219-25.
Lokhorst HM, van der Holt B, Cornelissen JJ, Kersten MJ, van Oers M, Raymakers R, Minnema MC, Zweegman S, Janssen JJ, Zijlmans M, Bos G, Schaap N, Wittebol S, de Weerdt O, Ammerlaan R, Sonneveld P.
This is a prospective study of 260 patients with newly diagnosed myeloma. After a single autologous transplant, patients were divided into 2 groups, based on the availability of a HLA-identical sibling donor for allogeneic stem cell transplant: 138 patients did not have a sibling donor, and 122 patients had a donor. After a median follow-up of 77 months, complete remission, progression-free survival, and overall survival were similar:
  - PFS at 6 years: 22% in the no-donor group, and 28% in the donor group (p=0.19)
  - Overall survival at 6 years (from the autologous transplant): 55% in both groups
In the group of 99 patients who underwent the allogeneic transplant, the incidence of relapse was lower, but the nonrelapse mortality was higher. Therefore, the prologation of PFS did not translate into a survival benefit. This study suggests that mini-allogeneic stem cell transplant should not be routinely offered as part of frontline therapy in patients with multiple myeloma. The different outcomes and conclusion of this study compared to those of the Italian and EBMT trials are likely due to the worse outcomes of the no-donor group in those two trials.





Comparison of upfront tandem autologous-allogeneic transplantation versus reduced intensity allogeneic transplantation for multiple myeloma.
Bone Marrow Transplant. 2015 Jun;50(6):802-7.
Sahebi F, Iacobelli S, Biezen AV, Volin L, Dreger P, Michallet M, Ljungman PT, de Witte T, Henseler A, Schaap NP, López-Corral L, Poire X, Passweg J, Hamljadi RM, Thomas SH, Schonland S, Gahrton G, Morris C, KrÖger N, Garderet L.

This is a retrospective study comparing the outcomes of an early reduced intensity conditioning (RIC) allogeneic transplant (173 patients) vs tandem autologous-allogeneic transplant (517 patients). After a median follow-up of about 8 years, results favored the planned tandem auto-allo transplants:
   - 5-year progression-free survival: 22% in the allo group, and 34% in the auto-allo group (p<0.001)
   - 5-year overall survival: 42% in the allo group, and 59% in the auto-allo group (p<0.001)





Triple transplants are not standard therapy.

Triple MEL100 therapy in multiple myeloma.
Transplant Proc. 2009 Nov;41(9):3863-7.
Berz D, Colvin GA, McCormack EM, Winer ES, Karwan P, Colvin L, Rathore R, Lum LG, Elfenbein GJ, Quesenberry PJ.
In this study, 13 patients with multiple myeloma underwent triple transplant using melphalan 100 mg/m2 every 3 weeks. The average hospital stay for the 3 transplants was 18 days, and 3 patients were managed entirely as outpatients. Median progression-free survival was about 28 months, overall survival not reached.



Transplantation as salvage therapy for high-risk patients with myeloma in relapse.
Bone Marrow Transplant. 2002 Dec;30(12):873-8.
Lee CK, Barlogie B, Zangari M, Fassas A, Anaissie E, Morris C, Van Rhee F, Cottler-Fox M, Thertulien R, Muwalla F, Mazher S, Badros A, Tricot G.
76 consecutive patients with myeloma in relapse after tandem autologous stem cell transplants received a third transplant as salvage therapy. Transplant was autologous in 50 patients, sibling-matched allogeneic in 22 patients, and matched-unrelated allogeneic in 4 patients. Results:
  - Response rate: 59% (CR 11%, near-CR 18%, PR 30%)
  - Event-free survival at 2 years: 7%
  - Overall survival at 2 years: 19%


Giampaolo Talamo, M.D.