"Early" stem cell transplant is done upfront, within 6-12 months from the initial diagnosis of myeloma. "Late" stem cell transplant is done later during the course of the disease, as a salvage modality.

Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma.
Cancer. 2012 Mar 15;118(6):1585-92.
Kumar SK, Lacy MQ, Dispenzieri A, Buadi FK, Hayman SR, Dingli D, Gay F, Sinha S, Leung N, Hogan W, Rajkumar SV, Gertz MA.
This is a retrospective study of 290 patients with newly diagnosed myeloma.
  - 178 patients underwent "early" transplant, i.e., transplant was done within 12 months of diagnosis
  - 112 patients underwent "delayed" transplant
The rate of overall survival at 4 years was similar, 73% in both groups.
In my personal opinion, the results of this study may be biased by the nature of the myeloma population at Mayo Clinic: patients with clinically aggressive myeloma, for example requiring hemodialysis for renal failure, or using a wheelchair because of spinal cord compression, were unlikely to travel to the Mayo Clinic. Maybe this is a selected population of patients with relatively indolent myeloma. In fact, only 16% of patients in the group of delayed transplant had a stage III disease. Therefore, the results of this study should be interpreted with caution, as it does not indicates that transplant can safely be delayed in all patients with multiple myeloma. Even a prospective study done at the Mayo Clinic may not be reflective of the real population of myeloma patients, as patients who travel to the Mayo Clinic are usually healthier and wealthier than in other parts of the world.

Early versus delayed autologous stem cell transplant in patients receiving novel therapies for multiple myeloma.
Leuk Lymphoma. 2013 Aug;54(8):1658-64.
Dunavin NC, Wei L, Elder P, Phillips GS, Benson DM Jr, Hofmeister CC, Penza S, Greenfield C, Rose KS, Rieser G, Merritt L, Ketcham J, Heerema N, Byrd JC, Devine SM, Efebera YA.
The authors compared clinical outcomes of 102 myeloma patients who received an "early" autologous transplant (= within 12 months of diagnosis) and 65 patients who received a "late" transplant. The 5 year survival rate was similar in both groups (63%). However, I am not convinced that this study demonstrates that "late" transplant has the same benefit than upfront transplant, and that it can be safely delayed in all patients until conventional therapies fail: the median time to transplant in the "late" group was 18 months, which means that 50% of patients received it within 18 months of diagnosis (this is not really "late", in my point of view).

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.
Blood Cancer J. 2016 Sep 2;6(9):e466.
Biran N, Jacobus S, Vesole DH, Callander NS, Fonseca R, Williams ME, Abonour R, Katz MS, Rajkumar SV, Greipp PR, Siegel DS.

In the E4A03 clinical trial, 431 patients with newly diagnosed multiple myeloma had the option of proceeding to an autologous stem cell transplant upfront, vs continuing the treatment with lenalidomide and dexamethasone and leave the transplant for later, as a salvage modality. 21% of patients decided to undergo an upfront autologous transplant. The overall survival at 5 years was superior in the group of patients with upfront transplant: 80% vs 57%. 



The role of second autografts in the management of myeloma at first relapse.
Haematologica. 2006 Jan;91(1):141-2.
Alvares CL, Davies FE, Horton C, Patel G, Powles R, Morgan GJ.
These authors performed an intention-to-treat analysis on 383 patients with newly diagnosed myeloma,  and reviewed the outcomes of a second autologous stem cell transplant with high dose melphalan done at relapse. SCT at relapse did not improve overall survival, and therefore data did not support the use of salvage SCT. One of the most important prognostic factor was a relapse-free survival after the first transplant >18 months.

Second autologous or allogeneic transplantation after the failure of first autograft in patients with multiple myeloma.
Cancer. 2006 Mar 1;106(5):1084-9.
Qazilbash MH, Saliba R, De Lima M, Hosing C, Couriel D, Aleman A, Roden L, Champlin R, Giralt SA.
This study analyzes the outcomes of salvage autologous or mini-allogeneic transplants in myeloma patients who relapsed after an autologous transplant.
  - In 14 pts treated with salvage autologous SCT: median PFS 6.8 months, median OS 29 months (median f/u 18 months)
  - In 26 pts treated with salvage mini-allogeneic SCT: median PFS 7.3 months, median OS 13 months (median f/u 30 months)

Prolonged overall survival with second on-demand autologous transplant in multiple myeloma.
Am J Hematol. 2006 Jun;81(6):426-31.
Elice F, Raimondi R, Tosetto A, D'Emilio A, Di Bona E, Piccin A, Rodeghiero F.
In this study, 130 patients with multiple myeloma were treated with an up-front autologous stem cell transplant, followed by a second autologous transplant at the time of disease relapse/progression. 107 (82%) patients completed the first transplant. Median EFS was 27.7 months, and median OS was 65.4 months. 26 of 70 patients with disease relapsed or progression received a second transplant, at a median time of 20.4 months from the first transplant. RR was 69%. After the second autologous transplant, median event-free survival was 14.8 months, and median overall survival was 38.1 months. Transplant-related mortality was 1.9% after the first transplant, and 0% after the second transplant.

Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma.
Bone Marrow Transplant. 2009 Mar;43(5):417-22.
Olin RL, Vogl DT, Porter DL, Luger SM, Schuster SJ, Tsai DE, Siegel DL, Cook RJ, Mangan PA, Cunningham K, Stadtmauer EA.
This is a study of 41 MM patients who received a salvage auto-SCT, with a median time between transplants of 37 months (range 3-91). The overall response rate was 55%. After a median follow-up of 15 months, the median PFS was 8.5 months and the median OS was 20.7 months.

Predictive factors for successful salvage high-dose therapy in patients with multiple myeloma relapsing after autologous blood stem cell transplantation.
Leuk Lymphoma. 2011 Aug;52(8):1455-62.
Fenk R, Liese V, Neubauer F, Bruns I, Kondakci M, Balleisen S, Saure C, Schröder T, Haas R, Kobbe G.
55 patients with multiple myeloma previously treated with autologous stem cell transplantation underwent another stem cell transplant at relapse. Conditioning regimens consisted of melphalan, melphalan + busulfan, or melphalan + bortezomib. Transplant-related mortality was 5%. Median event-free survival was 14 months, and median overall survival was 52 months.

Second autologous stem cell transplantation as salvage therapy for multiple myeloma: impact on progression-free and overall survival.
Biol Blood Marrow Transplant. 2012 May;18(5):773-9.
Jimenez-Zepeda VH, Mikhael J, Winter A, Franke N, Masih-Khan E, Trudel S, Chen C, Kukreti V, Reece DE.
In this study, 81 patients with myeloma underwent a second autologous stem cell transplantation as a salvage therapy, for relapsed myeloma. The median time to relapse after the second transplant was 19 months. The benefit of second transplant was observed especially in those patients who experienced relapse >24 months after the first transplant (median PFS was 9.8 months and 17.3 months in patients who experienced relapse <24 and >24 months after the first autologous transplant, respectively).

Autologous stem cell transplantation: an effective salvage therapy in multiple myeloma.
Biol Blood Marrow Transplant. 2013 Mar;19(3):445-9.
Lemieux E, Hulin C, Caillot D, Tardy S, Dorvaux V, Michel J, Gastinne T, Rossi C, Legouge C, Touzeau C, Planche L, Loirat M, Lafon I, Moreau P.
In this retrospective study, 81 patients with myeloma relapsed after the first autologous transplant received a second autologous transplant as salvage therapy. The median progression-free survival after the first transplant was 40 months, and the median progression-free survival after the second transplant was 18 months. After multivariate analysis, the prognostic factors which predicted worse progression-free survival after the second transplant were:
  - Short duration of remission (less than 24 months) after first transplant
  - Suboptimal response (less than VGPR) after salvage therapy
  - No maintenance therapy after the second transplant
This study supports the view that duration of remission with a second autologous transplant done as salvage therapy is about half of that reached after the first transplant. From a practical point of view, these results seem to imply that a second autologous transplant should not be offered as salvage therapy to a relapsed patient unless the remission with the first transplant lasted more than 2 years.

Second auto-SCT for treatment of relapsed multiple myeloma.
Bone Marrow Transplant. 2013 Apr;48(4):568-73.
Gonsalves WI, Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Dingli D, Hogan WJ, Kumar SK.
98 patients with relapsed myeloma underwent a second autologous transplant as salvage strategy. Transplant-related mortaity was 4%. Median progression-free survival after the second stem cell transplant was 10 months. Shorter PFS was predicted by:
  - Higher number of previous treatment regimens
  - Failure to achieve complete remission after the second transplant
  - Shorter remission after the first transplant

Salvage second hematopoietic cell transplantation in myeloma.
Biol Blood Marrow Transplant. 2013 May;19(5):760-6.
Michaelis LC, Saad A, Zhong X, Le-Rademacher J, Freytes CO, Marks DI, Lazarus HM, Bird JM, Holmberg L, Kamble RT, Kumar S, Lill M, Meehan KR, Saber W, Schriber J, Tay J, Vogl DT, Wirk B, Savani BN, Gale RP, Vesole DH, Schiller GJ, Abidi M, Anderson KC, Nishihori T, Kalaycio ME, Vose JM, Moreb JS, Drobyski W, Munker R, Roy V, Ghobadi A, Holland HK, Nath R, To LB, Maiolino A, Kassim AA, Giralt SA, Landau H, Schouten HC, Maziarz RT, Michael J, Kindwall-Keller T, Stiff PJ, Gibson J, Lonial S, Krishnan A, Dispenzieri A, Hari P; Plasma Cell Disorders Working Committee of the Center for International Blood and Marrow Transplant Research.
This study reports the outcomes of 187 patients who underwent a second autologous stem cell transplant for relapsed/refractory myeloma. Patients previously treated with tandem transplants were excluded from the analysis. Median interval between the first SCT and relapse/progression of myeloma was 18 months, and median interval between the first transplant and the second one was 32 months. At 3 years, progression-free survival was 13%, and overall survival was 46%. As expected, the benefit of the second SCT done as salvage therapy was greater in those patients who experienced a longer (>36 months) period of disease remission after the first SCT.

Autologous retransplantation for patients with recurrent multiple myeloma: a single-center experience with 200 patients.
Cancer. 2013 Jul 1;119(13):2438-46.
Sellner L, Heiss C, Benner A, Raab MS, Hillengass J, Hose D, Lehners N, Egerer G, Ho AD, Goldschmidt H, Neben K.
In this study of 200 patients with myeloma previously treated with an upfront autologous stem cell transplantation, and subsequently treated with a second autologous transplant as salvage therapy, the median  progression-free survival was 15 months. Median overall survival was 42 months.

High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial.
Lancet Oncol. 2014 Jul;15(8):874-85.
Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group.
This study, done in 51 institutions in the UK, randomized 174 patients with multiple myeloma who relapsed after the first transplant: one group (89 patients) was treated with conventional chemotherapy (cyclophosphamide 400 mg/m2 PO once a week for 12 weeks), and the other group (85 patients) with a "salvage" autologous stem cell transplantation (using melphalan 200 mg/m2 IV, and no maintenance), i.e., as a second transplant done late in the course of the disease. Median follow-up was 31 months. Results were better in the transplant group: median time to progression was 19 months in the transplant group, and 11 months in the non-transplant group. Median overall survival was similar in the two groups, but median follow-up was relatively short to formally assess impact of therapy on overall survival. Moreover, 20% of patients in the cyclophosphamide group eventually received a salvage autologous transplant.

Autologous stem cell transplantation versus novel drugs or conventional chemotherapy for patients with relapsed multiple myeloma after previous ASCT.
Bone Marrow Transplant. 2015 Jun;50(6):808-12.
Grövdal M, Nahi H, Gahrton G, Liwing J, Waage A, Abildgaard N, Pedersen PT, Hammerstrøm J, Laaksonen A, Bazia P, Terava V, Ollikainen H, Silvennoinen R, Putkonen M, Anttila P, Porkka K, Remes K.
This is a retrospective analysis of outcomes between salvage therapies in patiuents with multiple myeloma in relapse after they already received a first autologous stem cell transplant. A second autologous transplant was performed in 111 patients, whereas other patients were treated with novel agents, including proteasome inhibitors and IMiDs (362 patients), or traditional chemotherapy (91 patients). The results favored the second autologous transplant, because the median survival was 4 years with the second autologous transplant, 3.3 years with the novel agents, and 2.5 years with the conventional chemotherapy drugs.



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.