AllogenEic stem cell transplantation

 

 

In allogeneic transplant, the stem cells are obtained from a donor, which may be “related” (brothers and sisters) or ”unrelated” (from a donor in the world data bank). Each sibling has a 25% chance to be a match. Related donors are preferred over unrelated ones, since they give an inferior risk of Graft-versus-Host-Disease (GVHD).

GVHD is a complication of allogeneic transplant in which the donor cells “reject” the host tissues, and it is associated with several important complications and possibly death.

Allogeneic transplantation for myeloma can result in long-term disease-free survival in a minority of patients. Most myeloma experts recommend an autologous transplant over an allogeneic transplant, mainly because of risk of complications: in fact, the mortality of an autologous transplant is relatively low, approximately 1% if age <70, while the mortality of an allogeneic transplant is much higher, in the order of 30% with myeloablative allogeneic transplants, and 10-15% with so-called “mini-allogeneic” transplant, with remission results that are not clearly superior to those obtained with an autologous transplant.

Molecular remissions are more frequent after allogeneic than after autologous transplantation, and this indicates the presence of a graft-versus-myeloma effect.

Allogeneic transplants may be indicated when patients can tolerate it, have a matched related donor, and have chemosensitive disease. For a minority of patients, allogeneic stem cell transplantation results in long-term disease-free survival; a few patients remain free of disease more than 10 years after transplantation. The fact that only allogeneic transplantation is associated with very long survival may be due to the graft-versus-myeloma effect.

Outcomes of allogeneic transplant are better when the procedure is done early during the course of the disease, and in patients in remission. As of 2014, since no survival benefit has been observed (with the exception of the study by Bruno et al. in 2007), allogeneic transplant are considered only in patients with high-risk cytogenetics, and usually within the context of clinical trials.

 

Allogeneic transplantation in multiple myeloma.
Haematologica. 2008 Sep;93(9):1295-300.
Gahrton G, Björkstrand B.
[Review]

The impact of donor gender on outcome of allogeneic hematopoietic stem cell transplantation for multiple myeloma: reduced relapse risk in female to male transplants.
Bone Marrow Transplant. 2005 Mar;35(6):609-17.
Gahrton G, Iacobelli S, Apperley J, Bandini G, Björkstrand B, Bladé J, Boiron JM, Cavo M, Cornelissen J, Corradini P, Kröger N, Ljungman P, Michallet M, Russell NH, Samson D, Schattenberg A, Sirohi B, Verdonck LF, Volin L, Zander A, Niederwieser D.
This is a retrospective study of 1312 myeloma patients who underwent allogeneic stem cell transplant from HLA-identical siblings. It suggested that the donor gender influences the outcome: for female patients, the use of a male donor was a negative factor for outcome.
  - Male to male (476): median OS 25 months
  - Female to male (334): median OS 18 months
  - Male to female (258): median OS 19 months
  - Female to female (244): median OS 41 months

Peripheral blood or bone marrow cells in reduced-intensity or myeloablative conditioning allogeneic HLA identical sibling donor transplantation for multiple myeloma.
Haematologica. 2007 Nov;92(11):1513-8.
Gahrton G, Iacobelli S, Bandini G, Björkstrand B, Corradini P, Crawley C, Hegenbart U, Morgan G, Kröger N, Schattenberg A, Schönland SO, Verdonck LF, Volin L, de Witte T, Niederwieser D; Myeloma Subcommittee of the EBMT.
This study compared the use of peripheral blood stem cells (PBSC) vs bone marrow (BM) in 1,667 myeloma patients treated with allogeneic transplant from identical sibling, either myeloablative or RIC. Results:
  - The median engraftment was faster with PBSC (14 days for neutrophils and 15 days for platelets) than with BM (18 days for neutrophils and 25 days for platelets)
  - The incidence of acute GVHD was similar between the two groups, whereas chronic GVHD was more frequent with PBSC
  - Progression/relapse rate and non-relapse mortality were similar between the two groups
  - Overall survival and progression-free survival were similar between the two groups

Extramedullary relapses after allogeneic non-myeloablative stem cell transplantation in multiple myeloma patients do not negatively affect treatment outcome.
Bone Marrow Transplant. 2008 May;41(9):779-84.
Minnema MC, van de Donk NW, Zweegman S, Hegenbart U, Schonland S, Raymakers R, Zijlmans JM, Kersten MJ, Bos GM, Lokhorst HM.
In this study of 54 patients with myeloma relapsed after mini-allogeneic SCT, the incidence of extramedullary relapse was 20%. Interestingly, response rate, overall survival, and progression-free survival were similar those observed in patients without extramedullary disease.

International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma.
J Clin Oncol. 2010 Oct 10;28(29):4521-30.
Lokhorst H, Einsele H, Vesole D, Bruno B, San Miguel J, Pérez-Simon JA, Kröger N, Moreau P, Gahrton G, Gasparetto C, Giralt S, Bensinger W.
[Review]

Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis.
Blood. 2011 Aug 18;118(7):1979-88.
Kumar S, Zhang MJ, Li P, Dispenzieri A, Milone GA, Lonial S, Krishnan A, Maiolino A, Wirk B, Weiss B, Freytes CO, Vogl DT, Vesole DH, Lazarus HM, Meehan KR, Hamadani M, Lill M, Callander NS, Majhail NS, Wiernik PH, Nath R, Kamble RT, Vij R, Kyle RA, Gale RP, Hari PN.
The authors reviewed data from the Center for International Blood and Marrow Transplantation Research (CIBMTR). Outcomes of 1207 myeloma patients treated with allogeneic stem cell transplant were reviewed. Results in 488 patients transplanted in the period 2001-2005:
  - Relapse rate at 5 years: 58%
  - Progression-free survival at 5 years: 14%
  - Overall survival at 5 years: 29%
Survival was negatively affected by:
  - Older age
  - Unrelated donor
  - Longer interval between diagnosis and transplant

Allo-SCT for multiple myeloma: a review of outcomes at a single transplant center.
Bone Marrow Transplant. 2012 Oct;47(10):1312-7.
Bensinger W, Rotta M, Storer B, Chauncey T, Holmberg L, Becker P, Sandmaier BM, Storb R, Maloney D.
This is a retrospective study of myeloma patients who underwent allogeneic stem cell transplant at the prestigious Fred Hutchinson Cancer Cancer Research Center in Seattle, WA. They included 278 patients transplanted in a period of 34 years (1975-2008): 144 myeloablative allo-SCT, done between 1975 and 2000, and 134 non-myeloablative allo-SCT, done between 1998 and 2008. Results:
  - With myeloablative all-SCT: at 15 years, overall survival was 11%, and progression-free survival 8%
  - With non-myeloablative all-SCT: at 10 years, overall survival was 39%, and progression-free survival 16%
  - The best outcomes were observed with tandem auto-allo SCT (88 patients): at 10 years, OS was 49%, and PFS 27%

Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long-term follow-up study.
Br J Haematol. 2013 Jan;160(2):199-206.
Sahebi F, Shen Y, Thomas SH, Rincon A, Murata-Collins J, Palmer J, Krishnan AY, Karanes C, Htut M, Somlo G, Forman SJ.
In this study, 60 patients with multiple myeloma received a RIC allogeneic SCT, either alone or after an autologous transplant. After a median follow-up of 9.8 years, OS at 7 years was 60%, and EFS 31%. Interestingly, the authors noted that 10% patients experienced very late relapses, between 6 and 12 years post-transplant. This observation argues against the achievement of definitive cure, even in patients who seem to be long-term survivors.

 

 


MYELOABLATIVE ALLOGENEIC stem cell transplantation

Myeloablative allogeneic stem cell transplantation is almost never performed in multiple myeloma, because of unacceptably high transplant-related mortality.

 

Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome.
Blood. 1996 Oct 1;88(7):2787-93.
Bensinger WI, Buckner CD, Anasetti C, Clift R, Storb R, Barnett T, Chauncey T, Shulman H, Appelbaum FR.
This study evaluated outcomes of 80 myeloma patients who underwent myeloablative allogeneic transplantation, using busulfan + cyclophosphamide, with or without TBI. Results:
  - Transplant-related mortality: 35 of 80 patients (44%)
  - CR: 36%
  - Overall survival at 4.5 years: 24%
  - Progression-free survival at 4.5 years: 20%

Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation.
Blood. 1996 Dec 15;88(12):4711-8.
Björkstrand BB, Ljungman P, Svensson H, Hermans J, Alegre A, Apperley J, Bladé J, Carlson K, Cavo M, Ferrant A, Goldstone AH, de Laurenzi A, Majolino I, Marcus R, Prentice HG, Remes K, Samson D, Sureda A, Verdonck LF, Volin L, Gahrton G.
This study reviewed outcomes of 189 myeloma patients treated with allogeneic bone marrow transplants. Median post-transplant follow-up was 46 months. The median overall survival was 18 months, worse than in the control group treated with autologous SCT (18 months). The main reason for the worse outcome in allogeneic SCT was the higher transplant-related mortality (41%). However, those patients who were alive at 1 year post-transplant had a lower relapse rate (p= 0.02), and they seemed to have a better long-term survival (p= 0.09).

Partially T-cell-depleted allogeneic stem-cell transplantation for first-line treatment of multiple myeloma: a prospective evaluation of patients treated in the phase III study HOVON 24 MM.
J Clin Oncol. 2003 May 1;21(9):1728-33.
Lokhorst HM, Segeren CM, Verdonck LF, van der Holt B, Raymakers R, van Oers MH, Barge RM, Schouten HC, Westveer PH, Steijaert MM, Cornelissen JJ, Sonneveld P; Dutch-Belgian Hemato-Oncology Cooperative Group.
This is a prospective phase III study of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). 53 patients with MM were treated with up-front myeloablative allogeneic stem cell transplant, from HLA-identical sibling. Results: RR 89%. After a median follow-up of 38 months: 20 patients were alive, and 33 dead, because of transplant-related mortality (18 pts), progressive disease (14 pts), or other causes (1 pt). Median progression-free survival was 17 months, and median overall survival was 25 months. The results were overall disappointing, even because only 3 patients were alive and in CR, indicating that with an upfront myeloablative allogeneic SCT, the chance of presumed cure was only 6%.

Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning--evidence for a superior outcome using melphalan combined with total body irradiation.
Br J Haematol. 2005 Feb;128(4):496-502.
Hunter HM, Peggs K, Powles R, Rahemtulla A, Mahendra P, Cavenagh J, Littlewood T, Potter M, Hunter A, Pagliuca A, Williams CD, Cook G, Towlson K, Marks David I, Russell NH; Clinical Trials Committee of the British Society of Blood and Marrow Transplantation (BSBMT).
This is a retrospective analysis of 139 myeloma patients treated with myeloablative sibling allogeneic stem cell transplant, using either cyclophosphamide/TBI or melphalan/TBI. Results:
  - Transplant-related mortality at 1 year was 38% (no difference between cyclophosphamide/TBI and melphalan/TBI)
  - CR was 47% with cyclophosphamide/TBI and 65% with melphalan/TBI (p= 0.085)
  - Risk of relapse/progression at 5 years was 81% with cyclophosphamide/TBI and 37% with cyclophosphamide/TBI (p < 0.0001)
  - Overall survival at 5 years was 28% with cyclophosphamide/TBI and of 44% with melphalan/TBI (p= 0.059)
Therefore, melphalan/TBI was a better regimen than cyclophosphamide/TBI.

Outcome of unrelated transplants in patients with multiple myeloma.
Bone Marrow Transplant. 2005 Apr;35(7):675-81.
Ballen KK, King R, Carston M, Kollman C, Nelson G, Lim S, Reece D, Giralt S, Vesole DH.
This study analyzed outcomes of unrelated allogeneic stem cell transplant in 71 patients with multiple myeloma. The results were disappointing:
  - Transplant-related mortality at day 100 was 42%
  - The 3-year risk of relapse was 34%
  - Overall survival at 5 years was 9%

Myeloablative allogeneic stem cell transplantation for advanced stage multiple myeloma: very long-term follow up of a single center experience.
Clin Lab Haematol. 2006 Jun;28(3):189-97.
Kennedy GA, Butler J, Morton J, Hill G, Western R, Cummings J, Allison R, Durrant S.
This is a retrospective study of 37 patients with heavily pretreated myeloma who underwent myeloablative allogeneic SCT. After a median follow-up of 108 months (range: 33-148):
  - TRM at day 100: 32%
  - Median OS: 28 months
  - Median EFS: 13 months
  - Median PFS: 66 months
The authors conclude that allogeneic SCT can result in long-term survival in a minority of patients with heavily pretreated myeloma.

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.
28 myeloma patients underwent myeloablative related allogeneic SCT with Bu/Cy + TBI:
  - TBI 3 Gy/day days -10 to -8
  - Busulfan 2.4 mg/Kg/day PO days -7 to -4
  - Cyclophosphamide 60 mg/Kg/day IV days -3 and -2
After a median follow-up of 10 years:
  - TRM at day 100: 22%
  - Median PFS: 3.8 years
  - Median OS: 5.7 years

 

MYELOABLATIVE VS RIC ALLOGENEIC SCT

Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning.
Blood. 2007 Apr 15;109(8):3588-94.
Crawley C, Iacobelli S, Björkstrand B, Apperley JF, Niederwieser D, Gahrton G.
This study compares outcomes of 196 patients treated with myeloablative allogeneic SCT vs 320 patients treated with RIC allogeneic SCT. The 2 groups had some imbalance: median age was 45 years in the myeloablative group and 51 in the RIC group, and patients who received a prior transplant were 11% in the myeloablative group and 76% in the RIC group. Results:
  - Nonrelapse mortality at 2 years: 37% in the myeloablative group and 24% in the RIC group (p= 0.002)
  - CR: 53% in the myeloablative group and 34% in the RIC group
  - Relapse at 3 years: 27% in the myeloablative group and 54% in the RIC group
  - Median PFS: 34.5% in the myeloablative group and 19% in the RIC group (p= 0.001)
  - Median OS: 51% in the myeloablative group and 38% in the RIC group (NS)

 

 

 

REDUCED INTENSITY CONDITIONING (RIC) ALLOGENEIC Stem cell transplantation

When compared to myeloablative allogeneic SCT, RIC allogeneic SCT are associated with a lower transplant-related mortality.

 

Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning.
J Clin Oncol. 2002 Mar 1;20(5):1295-303.
Badros A, Barlogie B, Siegel E, Cottler-Fox M, Zangari M, Fassas A, Morris C, Anaissie E, Van Rhee F, Tricot G.
In this study, 31 patients with relapsed multiple myeloma received a nonmyeloablative allogeneic stem cell transplantation, using a melphalan-based conditioning regimen. 25 patients had HLA-matched siblings, and 6 patients had unrelated donors. Results:
  - At day 100, 89% of patients were full donor chimeras, 1 patient was a mixed chimera, and 2 had autologous reconstitution
  - CR/near CR was 61%
  - Transplant-related mortality: 9 patients (29%)
  - Median overall survival: 15 months
These results should be interpreted in the context of high-risk disease, often leading to death in the order of months instead of years.

Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation.
Bone Marrow Transplant. 2004 Jul;34(1):77-84.
Mohty M, Boiron JM, Damaj G, Michallet AS, Bay JO, Faucher C, Perreau V, Bilger K, Coso D, Stoppa AM, Tabrizi R, Gastaut JA, Michallet M, Maraninchi D, Blaise D.
In this study, 41 patients with myeloma received a RIC allogeneic stem cell transplant  from HLA-identical siblings, using ATG, fludarabine, and busulfan. Transplant-related mortality was 17%. At 2 years, OS was 62% and PFS was 41%.

Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose-reduced allogeneic stem cell transplantation in patients with multiple myeloma.
Biol Blood Marrow Transplant. 2004 Oct;10(10):698-708.
Kröger N, Perez-Simon JA, Myint H, Klingemann H, Shimoni A, Nagler A, Martino R, Alegre A, Tomas JF, Schwerdtfeger R, Kiehl M, Fauser A, Sayer HG, Leon A, Beyer J, Zabelina T, Ayuk F, San Miguel JF, Brand R, Zander AR.
This study evaluated outcomes of 120 myeloma patients treated with melphalan/fludarabine-based allogeneic SCT. Results:
  - Treatment-related mortality at 1 year: 18%
  - CR 49%, PR 38%
  - With related donors (34 patients): 2-year EFS 60%, 2-year OS 75%
  - With MUD (12 patients): 2-year EFS 81%, 2-year OS 92%

Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT.
Blood. 2005 Jun 1;105(11):4532-9.
Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S, Juliusson G, Ahlberg L, Nagler A, Shimoni A, Sureda A, Boiron JM, Einsele H, Chopra R, Carella A, Cavenagh J, Gratwohl A, Garban F, Zander A, Björkstrand B, Niederwieser D, Gahrton G, Apperley JF; Chromic Leukaemia Working Party of the EBMT.

This is a retrospective study of 229 myeloma patients who underwent a RIC allogeneic stem cell transplant in 33 European centers. Results:
  - Transplant-related mortality at 1 year: 22%
  - Progression-free survival at 3 years: 21%
  - Overall survival at 3 years: 41%
  - No significant benefit was observed in heavily pretreated patients and patients with progressive disease

Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma.
Bone Marrow Transplant. 2005 Dec;36(11):963-9.
Gerull S, Goerner M, Benner A, Hegenbart U, Klein U, Schaefer H, Goldschmidt H, Ho AD.
This is a retrospective study of 52 patients with high-risk myeloma, treated with nonmyeloablative allogeneic stem cell transplant. The conditioning regimen was TBI + fludarabine (49 patients) or TBI alone (2 patients). Patient were heavily pretreated and with relapsed disease after a median of 8 cycles of conventional chemotherapy and autologous transplant. Median follow-up was about 19 months. Results:
  - Transplant-related mortality: 17%
  - Acute GVHD, grade II-IV: 37%
  - Chronic GVHD: 70%
  - Overall survival at 18 months: 41%
  - Progression-free survival at 18 months: 29%

Clonal cytogenetic changes and myeloma relapse after reduced intensity conditioning allogeneic transplantation.
Bone Marrow Transplant. 2006 Mar;37(5):511-5.
Lee CK, Zangari M, Fassas A, Thertulien R, Talamo G, Badros A, Cottler-Fox M, van Rhee F, Barlogie B, Tricot G.

Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma.
Bone Marrow Transplant. 2008 Jun;41(11):953-60.
de Lavallade H, El-Cheikh J, Faucher C, Fürst S, Stoppa AM, Coso D, Bouabdallah R, Chabannon C, Gastaut JA, Blaise D, Mohty M.
This is a retrospective analysis of 32 patients with relapsed myeloma, treated with RIC allogeneic SCT. PFS at 3 years was 46%.
Conditioning regimens:
  - FBA: Fludarabine 30 mg/m2 x 5 days + Busulfan 4 mg/Kg PO x 2 days + ATG 2.5 mg/Kg x 1 day
  - FT: Fludarabine 30 mg/m2 x 3 days + low-dose TBI (2 Gy)

Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation.
Br J Haematol. 2010 Jan;148(2):323-31.
Kröger N, Shimoni A, Schilling G, Schwerdtfeger R, Bornhäuser M, Nagler A, Zander AR, Heinzelmann M, Brand R, Gahrton G, Morris C, Niederwieser D, de Witte T.
49 patients with myeloma in relapse after autologous SCT were treated with:
  - Fludarabine 30 mg/m2 IV day -6, -5, -4
  - Melphalan 140 mg/m2 IV day -3
Results:
  - Acute GVHD, grade II-IV: 25%
  - Chronic GVHD: 35%
  - RR at day 100: 95%, including 46% CR
  - Non-relapse mortality at 1 year: 25%
  - 5-year progression-free survival: 20%
  - 5-year overall survival: 26%

Reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed multiple myeloma.
Biol Blood Marrow Transplant. 2010 Aug;16(8):1122-9.
Efebera YA, Qureshi SR, Cole SM, Saliba R, Pelosini M, Patel RM, Koca E, Mendoza FL, Wang M, Shah J, Alousi A, Hosing C, Popat U, Kebriaei P, Anderlini P, Khouri IF, Champlin R, Giralt S, Qazilbash MH.
51 patients with relapsed myeloma underwent a RIC allogeneic SCT, using fludarabine 90-120 mg/m2 + melphalan 90-140 mg/m2. Results:
  - Transplant-related mortality at 100 days: 12%
  - Transplant-related mortality at 1 year: 25%
  - Grade II/IV acute GVHD: 27%
  - Grade II/IV chronic GVHD: 47%
  - Progression-free survival at 2 years: 19%
  - Overall survival at 2 years: 32%
  - Long-term survivors in remission (presumed cure): 14%
N.B.: These patients were heavily pretreated, with a predicted life expectancy of only 8-12 months.

Allogenic hematopoietic stem-cell transplantation with reduced-intensity conditioning in patients with refractory and recurrent multiple myeloma: long-term follow-up.
Cancer. 2010 Aug 1;116(15):3621-30.
Shimoni A, Hardan I, Ayuk F, Schilling G, Atanackovic D, Zeller W, Yerushalmi R, Zander AR, Kroger N, Nagler A.
This is a retrospective study of 50 patients with relapsed/refractory myeloma treated with RIC allogeneic SCT. Stem cells were taken from a sibling (27 patients) or matched unrelated donors (23 patients). At a median follow-up of 6.4 years, progression-free survival was 26%, and overall survival 34%. Non-relapse mortality was 26%.

Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma.
Bone Marrow Transplant. 2012 Jun;47(6):831-7.
Ringdén O, Shrestha S, da Silva GT, Zhang MJ, Dispenzieri A, Remberger M, Kamble R, Freytes CO, Gale RP, Gibson J, Gupta V, Holmberg L, Lazarus H, McCarthy P, Meehan K, Schouten H, Milone GA, Lonial S, Hari PN.
This study analyses outcomes of 177 myeloma patients treated with non-myeloablative allogeneic stem cell transplant. The authors found that chronic GVHD was associated with improved progression-free survival, but this advantage did not translate into an overall survival advantage.

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.

 

RIC-ALLO-SCT FOR RELAPSE AFTER AUTOLOGOUS SCT

Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation.
Bone Marrow Transplant. 2013 Nov;48(11):1395-400.
Auner HW, Szydlo R, van Biezen A, Iacobelli S, Gahrton G, Milpied N, Volin L, Janssen J, Nguyen Quoc S, Michallet M, Schoemans H, El Cheikh J, Petersen E, Guilhot F, Schönland S, Ahlberg L, Morris C, Garderet L, de Witte T, Kröger N.
Reduced-intensity conditioned allogeneic stem cell transplant was performed in 413 patients with myeloma. All patient had disease relapse after 1 or more autologous transplants. Results:
  - Non-relapse mortality at 1 year: 21%.
  - Median progression-free survival: 10 months. PFS was better with CMV seronegativity of both patient and donor, and with patient-donor gender mismatch.
  - Median overall survival: 25 months.

 

MRD-RIC vs MUD-RIC

Comparable outcomes between unrelated and related donors after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in patients with high-risk multiple myeloma.
Eur J Haematol. 2012 Jun;88(6):497-503.
El-Cheikh J, Crocchiolo R, Boher JM, Furst S, Stoppa AM, Ladaique P, Faucher C, Calmels B, Castagna L, Lemarie C, De Colella JM, Coso D, Bouabdallah R, Chabannon C, Blaise D.
These authors compared results of mini-allogeneic stem cell transplant from MRD (matched related donor) (17 patients) vs MUD (matched unrelated donor) (23 patients) in multiple myeloma. Results:
  - Acute GVHD, grade II-IV: 17% with MRD and 47% with MUD
  - Chronic GVHD: 30% with MRD and 24% with MUD
  - Treatment-related mortality at 2 years: 22% with MRD and 12% with MUD
  - Progression-free survival at 2 years: 44% with MRD and 42% with MUD
  - Overall survival at 2 years: 66% with MRD and 59% with MUD

 

CONDITIONING REGIMEN

Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma.
Bone Marrow Transplant. 2002 Sep;30(6):367-73.
Giralt S, Aleman A, Anagnostopoulos A, Weber D, Khouri I, Anderlini P, Molldrem J, Ueno NT, Donato M, Korbling M, Gajewski J, Alexanian R, Champlin R.
In this study, 22 myeloma patients underwent a mini-allogeneic stem cell transplant using fludarabine + melphalan:
  - Fludarabine 30 mg/m2 for 4 days + melphalan 140 mg/m2 (18 pts)
  - Fludarabine 25 mg/m2 for 5 days + melphalan 90 mg/m2 for 2 days (4 pts)
After a median follow-up of 15 months (range, 10-47 months), 6 patients were alive. Transplant-related mortality at day 100 was 19%.

Reduced intensity conditioning with thiotepa, fludarabine, and melphalan is effective in advanced multiple myeloma.
Leuk Lymphoma. 2007 Apr;48(4):759-66.
Majolino I, Davoli M, Carnevalli E, Locasciulli A, Di Bartolomeo P, Scimè R, Corradini P, Selleri C, Narni F, Musso M, Bregni M, Olivieri A, De Fabritiis P, Pogliani L, Arbelaez JE, Ruscio C, Bacigalupo A; Gitmo Institutions.
In this study, 53 patients with multiple myeloma underwent a RIC allogeneic stem cell transplant from HLA identical siblings using thiotepa 5 mg/kg + fludarabine 90 mg/m2 + melphalan 80 mg/m2. Results:
  - Transplant-related mortality: 13%
  - Acute GVHD of grade II-IV 45%, chronic GVHD 64%
  - Disease relapse: 32%
  - 3-year overall survival: 45%
  - 3-year progression free survival: 37%

A Randomized Phase II Trial of Fludarabine/Melphalan 100 versus Fludarabine/Melphalan 140 Followed by Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Multiple Myeloma.
Biol Blood Marrow Transplant. 2013 Oct;19(10):1453-8.
Bashir Q, Khan H, Thall PF, Liu P, Shah N, Kebriaei P, Parmar S, Oran B, Ciurea S, Nieto Y, Jones R, Hosing CM, Popat UR, Dinh YT, Rondon G, Orlowski RZ, Shah JJ, De Lima M, Shpall E, Champlin R, Giralt S, Qazilbash MH.
This is a study of 50 patients with newly diagnosed or relapsed myeloma, who were randomized between two different "Flu/Cy" conditioning regimens for an allogeneic stem cell transplant: FM100 (fludarabine 120 mg/m2 + melphalan 100 mg/m2) vs FM140 (fludarabine 120 mg/m2 + melphalan 140 mg/m2). There was no significant difference in terms of toxicities and clinical outcomes. Median progression-free survival was 11.7 vs 8.4 months (p= 0.12).

 

 


KIR HAPLOTYPE AND KIR LIGANDS

 

KIR (killer cell immunoglobulin-like receptors) genes are located on chromosome 19, and they produce proteins expressed in NK cells, with activating or inhibitory functions.

In allogeneic stem cell transplantation, inhibitory KIRs of the NK cells from the donor interact with the HLA class I molecules of the healthy and malignant cells of the recipient.

There are 2 biologically distinct groups of KIR haplotypes, group A and B. Group B produces more activating receptor genes than group A.

 

Donor KIR haplotype B improves progression-free and overall survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma.
Leukemia. 2011 Oct;25(10):1657-61.
Kröger N, Zabelina T, Berger J, Duske H, Klyuchnikov E, Binder T, Stübig T, Hilde-brandt Y, Atanackovic D, Alchalby H, Ayuk F, Zander AR, Bacher U, Eiermann T.
This study showed that allogeneic transplants from a donor carrying the B haplotype (BB or B/X), regardless of patient haplotype, had better clinical outcomes that transplant from donors with KIR haplotype AA. These findings are similar to those observed in patients with acute myeloblastic leukemia. KIR haplotype did not affect rates of acute and chronic GVHD. A sex-specific graft-vs-myeloma effect was observed with female donors, but allogeneic transplants with female donors was associated with a higher non-relapse mortality. The authors concluded that the donor of choice for myeloma patients undergoing an allogeneic stem cell transplantation should be a male carrying the KIR haplotype B. The use of female donors with the KIR haplotype AA was associated with impaired survival.

A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma.
Blood. 2012 Nov 22;120(22):4324-33.
Benson DM Jr, Hofmeister CC, Padmanabhan S, Suvannasankha A, Jagannath S, Abonour R, Bakan C, Andre P, Efebera Y, Tiollier J, Caligiuri MA, Farag SS.
Myeloma cells express HLA class I molecules that acts as KIR ligands to NK cells with inhibitory KIRs. In this phase I trial, 32 patients with relapsed/refractory myeloma received IPH2101, an anti-KIR antibody. Although IPH2101 enhanced NK cell cytotoxicity against myeloma in vitro, no objective responses were seen.

 

 


Giampaolo Talamo, M.D.