Molecular and clinical remissions in multiple myeloma: role of autologous and allogeneic transplantation of hematopoietic cells.
J Clin Oncol. 1999 Jan;17(1):208-15.
Corradini P, Voena C, Tarella C, Astolfi M, Ladetto M, Palumbo A, Van Lint MT, Bacigalupo A, Santoro A, Musso M, Majolino I, Boccadoro M, Pileri A.
29 myeloma patients treated with stem cell transplantation (15 patients with autologous transplant and 14 with allogeneic transplant) were monitored for minimal residual disease with PCR. Molecular complete remission was observed in:
  - 50% of patients treated with allogeneic transplantation
  - Only 7% of patients treated with single or tandem autologous transplantation

Outcome after autologous and allogeneic stem cell transplantation for patients with multiple myeloma: impact of graft-versus-myeloma effect.
Bone Marrow Transplant. 2003 Dec;32(12):1145-51.
Alyea E, Weller E, Schlossman R, Canning C, Mauch P, Ng A, Fisher D, Gribben J, Freeman A, Parikh B, Richardson P, Soiffer R, Ritz J, Anderson KC.
Among 228 myeloma patients, 166 patients received autologous transplant (124 from peripheral blood and 38 from bone marrow), and 66 patients receiving allogeneic transplant (T-cell depleted). Results at 2 years:
  - OS:   74% after autologous SCT and 51% after allogeneic SCT (p= 0.006)
  - PFS: 48% after autologous SCT and 28% after allogeneci SCT (p= 0.002)
However, 4 years after transplantation, outcome was similar:
  - OS:   41% after autologous SCT and 39% after allogeneic SCT
  - PFS: 23% after autologous SCT and 18% after allogeneic SCT
Risk of relapse at 4 years was 46% after allogeneic SCT vs 56% after autologous SCT (p= 0.02).

Results of autologous and allogeneic hematopoietic cell transplant therapy for multiple myeloma.
Bone Marrow Transplant. 2005 Jun;35(12):1133-40.
Arora M, McGlave PB, Burns LJ, Miller JS, Barke JN, Defor TE, Weisdorf DJ.
This study compared outcomes of autologous (70 patients) and myeloablative allogeneic stem cell transplant (17 patients) in multiple myeloma. Results:
  - Transplant-related mortality was lower with autologous transplant (4% vs 18%)
  - Complete responses were higher with allogeneic transplant (64% vs 34%)
  - After autologous transplant, survival at 1 year was 86%, but it fell to 50% at 4 years, mainly because of disease relapse
  - After allogeneic transplant, survival at 1 year was 64%, and it remained the same at 4 years
Therefore, although autologous transplant was associated with a lower mortality and superior short-term outcomes, allogeneic transplant produced superior long-term responses.

Long-term outcome of myeloablative allogeneic stem cell transplantation for multiple myeloma.
Biol Blood Marrow Transplant. 2007 Aug;13(8):925-31.
Kuruvilla J, Shepherd JD, Sutherland HJ, Nevill TJ, Nitta J, Le A, Forrest DL, Hogge DE, Lavoie JC, Nantel SH, Toze CL, Smith CA, Barnett MJ, Song KW.
This study retrospective compares outcomes of myeloma treated with myeloablative allogeneic SCT (72 patients) vs autologous SCT (86 patients).58 patients had related allogeneic SCT, and 14 unrelated allogeneic SCT. Results (median follow-up 7.4 years):
  - Treatment-related mortality at 1 year: 22% in the allogeneic group and 14% in the autologous group (p= 0.21)
  - Acute GVHD, grade II-IV: 72%. Chronic GVHD: 68%
  - 5-year survival: 48% in the allogeneic group and 46% in the autologous group
  - 10-year survival: 40% in the allogeneic group and 31% in the autologous group (p= 0.94)
  - EFS survival at 10 years: 31% in the allogeneic group and 32% in the autologous group (p= 0.64)

Long-term outcomes following myeloablative allogeneic transplantation for multiple myeloma compared to autologous transplantation and the impact of graft-versus-myeloma effect.
Bone Marrow Transplant. 2009 Sep;44(5):325-6.
Khaled Y, Mellacheruvu S, Reddy P, Peres E, Mineishi S.
In this retrospective study, 28 patients with multiple myeloma underwent myeloablative allogeneic stem cell transplantation using TBI, busulfan PO, and cyclophosphamide IV. The transplant-related mortality at day 100 was 22%. Acute GVHD (grade II-IV) was seen in 46% of patients, and chronic GVHD was seen in 73% of patients. With a median follow-up of 10 years, the median progression-free survival was 3.8 years, which compared favorably with that of a control group of 46 patients treated with an autologous stem cell transplant (1.7 years). Overall survival was similar (5.8 years in the autologous group and 5.7 years in the allogeneic group).




Bortezomib after dose-reduced allogeneic stem cell transplantation for multiple myeloma to enhance or maintain remission status.
Exp Hematol. 2006 Jun;34(6):770-5.
Kröger N, Zabelina T, Ayuk F, Atanackovic D, Schieder H, Renges H, Zander A.
18 myeloma patients treated with mini-allogeneic stem cell transplantation received at least two cycles of bortezomib. Treatment with bortezomib was effective (CR was seen in 30% of patients with measurable disease), but it was followed by several complications, including:
  - development or worsening of GVHD (4 patients)
  - neurotoxicity requiring discontinuation of the drug (3 patients)
  - complicated by infections (herpes zoster in 3 patients)

Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial.
Blood. 2011 Sep 1;118(9):2413-9.
Kneppers E, van der Holt B, Kersten MJ, Zweegman S, Meijer E, Huls G, Cornelissen JJ, Janssen JJ, Huisman C, Cornelisse PB, Bruijnen CP, Emmelot M, Sonneveld P, Lokhorst HM, Mutis T, Minnema MC.
30 patients treated with mini-allogeneic stem cell transplantation started post-transplant maintenance with low-dose lenalidomide (10 mg on days 1-21 every 28 days x 24 cycles). 87% of patients had to stop lenalidomide early, because of development of acute GVHD (43%), toxicities (17%), or disease progression (17%). Acute GVHD occurred at a median of 18 days after the start of lenalidomide. Lenalidomide induced acute GVHD, likely due to early activation of T cells. 1-year PFS from start of lenalidomide was 69%.




See specific section (tandem SCT).




Allogeneic hematopoietic cell transplantation from unrelated donors in multiple myeloma: study from the Italian Bone Marrow Donor Registry.
Biol Blood Marrow Transplant. 2013 Jun;19(6):940-8.
Passera R, Pollichieni S, Brunello L, Patriarca F, Bonifazi F, Montefusco V, Falda M, Montanari M, Guidi S, Giaccone L, Mordini N, Carella AM, Bavaro P, Milone G, Benedetti F, Ciceri F, Scimè R, Benedetti E, Castagna L, Festuccia M, Rambaldi A, Bacigalupo A, Corradini P, Bosi A, Boccadoro M, Bandini G, Fanin R, Bruno B.
This is a study of 196 consecutive myeloma patients treated with a stem cell transplant from unrelated donors, between 2000 and 2009. The long-term results were disappointing, because the median event-free survival was:
  - 10 months with myeloablative regimens (OS 29 months)
  -   6 months with reduced-intensity regimens (OS 11 months)
  - 13 months with nonmyeloablative regimens (OS 32 months)



In haploidentical allogeneic trabnsplant, the donor of stem cells is a first-degree relative, usually a child (but also a parent or sibling). In this type of transplant, the HLA match is not complete or near-complete, but is only 50%. This poses problems of graft-vs-host disease (GVHD), which can be helped by the use of post-transplant cyclophosphamide.

Haploidentical Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Post-Transplantation Cyclophosphamide Graft-versus-Host Disease Prophylaxis.
Biol Blood Marrow Transplant. 2017 Sep;23(9):1549-1554.
Castagna L, Mussetti A, Devillier R, Dominietto A, Marcatti M, Milone G, Maura F, de Philippis C, Bruno B, Furst S, Blaise D, Corradini P, Montefusco V.
In this study, 30 patients with heavily pretreated myeloma underwent haploidentical SCT. Results, after a median follow-up of 25 months:
  - Grade II-IV aGVHD at day +100: 39%
  - cGVHD at 18 months: 7%
  - Non-relapse mortality at 18 months: 10% (95% CI, 2-24%)
  - Progression-free survival at 18 months: 33% (95% CI, 17-50%)
  - Overall survival at 18 months: 63% (95% CI, 44-78%)




Outcomes of unrelated cord blood transplantation in patients with multiple myeloma: a survey on behalf of Eurocord, the Cord Blood Committee of Cellular Therapy and Immunobiology Working Party, and the Chronic Leukemia Working Party of the EBMT.
Haematologica. 2016 Sep;101(9):1120-7.
Paviglianiti A, Xavier E, Ruggeri A, Ceballos P, Deconinck E, Cornelissen JJ, Nguyen-Quoc S, Maillard N, Sanz G, Rohrlich PS, Garderet L, Volt F, Rocha V, Kroeger N, Gluckman E, Fegueux N, Mohty M.
This is a retrospective study of 95 patients with multiple myeloma treated in several institutions with a single or double umbilical cord transplant, over a period of 12 years. Plasma cell leukemia was present in 10 patients. Median follow-up was 41 months. Results:
  - Acute GVHD at day 100: 41%. Chronic GVHD at 2 years: 22%.
  - Non-relapse mortality at 3 years: 29%. Relapse mortality at 3 years: 47%.
  - Progression-free survival at 3 years: 24%. Overall survival at 3 years: 40%. 



SyngenEic stem cell transplantation

Syngeneic transplantation is feasible if an identical twin donor is available.


Syngeneic transplantation in multiple myeloma - a case-matched comparison with autologous and allogeneic transplantation. European Group for Blood and Marrow Transplantation.
Bone Marrow Transplant. 1999 Oct;24(7):741-5.
Gahrton G, Svensson H, Björkstrand B, Apperley J, Carlson K, Cavo M, Ferrant A, Fouillard L, Gratecos N, Gratwohl A, Guilhot F, Lambertenghi Deliliers G, Ljungman P, Masszi T, Milligan DW, Powles RL, Reiffers J, Samson JD, Stoppa AM, Vernant JP, Volin L, Wallvik J.
25 patients with myeloma underwent syngeneic stem cell transplantation, with cells obtained from the bone marrow (24 patients) or peripheral blood (1 patient). Compared with a control group treated with autologous transplant, these patients had:
  - Better median overall survival: 73 months (44 months in the control group)
  - Better median progression-free survival: 72 months (25 months in the control group)
  - Lower relapse rate
  - Transplant-related mortality: 2 of 25 patients
The authors concluded that syngeneic transplantation is the transplant modality of choice in multiple myeloma if a twin donor is available. The improved results compared with those seen with autologous transplant could be due to either the reinfusion of malignant plasma cells in patients treated with autologous transplants, or the presence of graft-versus-myeloma effect in patients treated with syngeneic transplants.

Comparison of twin and autologous transplants for multiple myeloma.
Bashey A, Pérez WS, Zhang MJ, Anderson KC, Ballen K, Berenson JR, To LB, Fonseca R, Freytes CO, Gale RP, Gibson J, Giralt SA, Kyle RA, Lazarus HM, Maharaj D, McCarthy PL, Milone GA, Nimer S, Pavlovsky S, Reece DE, Schiller G, Vesole DH, Hari P; Plasma Cell Disorders Working Committee.
Biol Blood Marrow Transplant. 2008 Oct;14(10):1118-24.
This is a study of 43 patients treated with syngeneic transplant. When compared with a matched group of patients treated with autologous transplant, these patients had a lower relapse/progression rate, and longer progression-free survival.

A case control study of syngeneic transplantation versus autologous transplantation for multiple myeloma: two decades of experiences from a single center.
Leuk Lymphoma. 2018 Feb;59(2):515-518.
Mohyuddin GR, Faisal MS, Badar T, Shah N, Bashir Q, Patel KK, Hosing C, Popat UR, Rondon G, Delgado R, Shah JJ, Weber DM, Thomas SK, Manasanch EE, Orlowski RZ, Champlin RE, Qazilbash MH.
This is a retrospective study comparing outcomes of 10 patients with myeloma who underwent a syngeneic stem cell transplant, vs 48 matched control represented by 48 patients who underwent an autologous transplant. The outcomes were superior with the syngeneic transplant. The authors believe that one of the reason for the difference may be the contamination of the graft by malignant plasma cells with the autologous transplant. In laternative, there may be a subclinical GVHD with the syngeneic transplant.



PSEUDO-AUTOLOGOUS stem cell transplantation

Pseudo-autologous hematopoietic SCT as treatment for a patient with multiple myeloma who relapsed following an allogeneic hematopoietic SCT.
Bone Marrow Transplant. 2013 Aug;48(8):1138.
Palfreyman E, Song K, Nantel S.
The authors described the case of a myeloma patient previously treated with an allogeneic stem cell transplant. At disease relapse, they decided to collect her stem cells, and use them after high-dose melphalan. The term pseudo-autologous refers to the original allogeneic source of patient's stem cells: while the "usual" sequence of transplant in myeloma is autologous, possibly followed by an allogeneic transplant, in this case the sequence is reversed, and it involved an allogeneic followed by an autologous transplant.




The response rate of DLIs in MM is about 40%, and the CR rate is about 20%. The response lasts >1 year in only about 20% of patients.
Usually, DLIs are not given earlier than 3 weeks after discontinuation of immunosuppressive therapy without any sign of acute GVHD.
The most important toxicity of DLI is the occurrence of GVHD.


Donor leukocyte infusions for multiple myeloma.
Bone Marrow Transplant. 2000 Dec;26(11):1179-84.
Salama M, Nevill T, Marcellus D, Parker P, Johnson M, Kirk A, Porter D, Giralt S, Levine JE, Drobyski W, Barrett AJ, Horowitz M, Collins RH.
In this study, 25 MM patients were treated with DLI. Response to DLI alone was observed in 2 of 22 patients, and response to DLI + chemotherapy was observed in 3 patients. Additional DLIs produced CR or PR in 5 of 9 patients. 4 patients had responses which lasted >1 year after DLI. Many patients had either no response or short duration of response.

Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome.
J Clin Oncol. 2000 Aug;18(16):3031-7.
Lokhorst HM, Schattenberg A, Cornelissen JJ, van Oers MH, Fibbe W, Russell I, Donk NW, Verdonck LF.
27 MM patients received 52 DLI courses, with or without reinduction therapy. RR was 52%, and CR was 22%. Remission lasted >30 months in 5 patients. Median overall survival of all patients was 18 months.

The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma.
Blood. 2004 Jun 1;103(11):4362-4.
Lokhorst HM, Wu K, Verdonck LF, Laterveer LL, van de Donk NW, van Oers MH, Cornelissen JJ, Schattenberg AV.
In this study, 54 patients with myeloma in relapse after allogeneic SCT received DLI. Results:
  - Response rate was 52%: PR 35%, CR 17%
  - Progression-free survival: 19 months
  - Overall survival: 23 months
The strongest predictors of response were acute GVHD (57%) and chronic GVHD (47%).

Prognostic factors for donor lymphocyte infusions following non-myeloablative allogeneic stem cell transplantation in multiple myeloma.
Bone Marrow Transplant. 2006 Jun;37(12):1135-41.
van de Donk NW, Kröger N, Hegenbart U, Corradini P, San Miguel JF, Goldschmidt H, Perez-Simon JA, Zijlmans M, Raymakers RA, Montefusco V, Ayuk FA, van Oers MH, Nagler A, Verdonck LF, Lokhorst HM.
At the time of its publication, this was the largest study of DLI in myeloma. Among 63 patients who relapsed after allogeneic transplant , 48 patients had relapsed disease, and 15 patients persistent disease. Results after DLI:
  - Response rate: 38% (CR 19%)
  - Treatment-related mortality: 11%
  - Median OS: 24 months
  - In non-responders: median OS 24 months
  - In responders: median OS not reached, median PFS 28 months
  - Prognostic factors for response were acute and chronic GVHD
  - Efficacy of DLI decreased in patients who received DLI after 12 months post transplant

Multiple myeloma patients receiving pre-emptive donor lymphocyte infusion after partial T-cell-depleted allogeneic stem cell transplantation show a long progression-free survival.
Bone Marrow Transplant. 2007 Aug;40(4):355-9.
Levenga H, Levison-Keating S, Schattenberg AV, Dolstra H, Schaap N, Raymakers RA.
In this study, 24 MM patients received partial T-cell-depleted myeloablative SCT, followed by pre-emptive DLI. Transplant-related mortality within 1 year was 29%. With a median follow-up of 67 months, 7 patients (29%) were in persistent CR.

Post-transplant immunotherapy with donor-lymphocyte infusion and novel agents to upgrade partial into complete and molecular remission in allografted patients with multiple myeloma.
Exp Hematol. 2009 Jul;37(7):791-8.
Kröger N, Badbaran A, Lioznov M, Schwarz S, Zeschke S, Hildebrand Y, Ayuk F, Atanackovic D, Schilling G, Zabelina T, Bacher U, Klyuchnikov E, Shimoni A, Nagler A, Corradini P, Fehse B, Zander A.
This study investigates the use of DLIs in combination with novel agents (thalidomide, bortezomib, and lenalidomide) in 32 patients with myeloma in partial remission after allogeneic stem cell transplant, aiming at CR. If no CR was achieved with DLIs, one of the novel agents was added. CR was obtained in 50-63% of patients, depending on the criteria used to define CR. Achievement of CR resulted in improved 5-year progressive-free survival and overall survival.



Giampaolo Talamo, M.D.