Patients eligible for transplant

Allogeneic stem cell transplantation in multiple myeloma 

In April, two review articles were published in peer-reviewed journals, reflecting on the role of stem cell transplantation (SCT) in multiple myeloma (MM). The first review, published in Cancer and authored by Roberto Mina and our co-chair Sagar Lonial, questioned the role of SCT in MM.1 The second review, in Blood Cancer Journal, by Rama Al Hamed, Adbul Hamid Bazarbachi and colleagues, including our Steering Committee member, Mohamad Mohty, reflected on the current status of autologous-SCT (ASCT) in MM.2

Here, the MM Hub present a series of three articles on the current status of SCT in MM and discuss its role in treatment both now, and in the future. This article focuses on allogeneic SCT (allo-SCT) and its role in the treatment of MM. The following articles will focus on ASCT in MM - the optimal regimens and the big questions

Background: allo-SCT1

Allo-SCT, whereby a patient receives stem cells from a healthy donor, is postulated as being potentially curative in MM based on the graft-versus-myeloma effect. A study by Michele L Donato and colleagues showed allo-SCT could provide sustained remissions in a small cohort of 57 patients who had received one prior ASCT. In this study, chronic graft-versus-host disease (GvHD) had a favorable impact on OS and PFS indicating a graft-versus-myeloma effect.3

Allo-SCT in newly diagnosed MM (NDMM)1

Metaanalysis data has failed to show a benefit of allo-SCT + ASCT to tandem ASCT in patients with NDMM:4,5

  • Patients treated with ASCT + allo-SCT reduced intensity conditioning (RIC) had higher complete response (CR) rates but also more frequent treatment-related mortality (TRM)
  • Relapse remained an issue
  • Tandem ASCT alone was superior in relation to PFS and OS

To maximize the graft-versus­-myeloma effect, trials comparing tandem ASCT/allo-SCT with RIC to tandem ASCT were designed. Only two of these showed a benefit in PFS and OS of tandem ASCT/allo-SCT with RIC, and these were limited by a lack of randomization and pre-dated the era of novel agent use. Subsequent trials have failed to replicate this benefit.

Table 1: Outcomes from trials comparing tandem ASCT to tandem ASCT/allo-SCT in patients with NDMM (tandem ASCT vs tandem ASCT/allo-SCT)6-10

 

Median follow-up (months)

N (enrolled)

Median PFS or event-free survival (EFS)

Median OS

TRM

Moreau et al.6

56

284

22 vs 19 months

P = 0.58

48 vs 34 months

P = 0.07

Not available (NA) vs 11%

Gharton et al.7

96

357

8 year: 12% vs 22%

P = 0.027

8 year: 36% vs 49%

P = 0.03

3 year: 3% vs 13%

P = 0.0004

Rosinol et al.8

62

110

31 vs not reached (NR)

P = 0.08

58 vs NR

P = 0.9

5% vs 16%

Krishnan et al.9

36

710

3 year PFS: 46% vs 43%

P = 0.7

3 year: 80% vs 71%

P = 0.2

4% vs 11%

P < 0.001

Conclusion: allo-SCT is not recommended as a standard of care for patients with NDMM. Young, fit patients with NDMM however may be considered for allo-SCT in the clinical trial setting.1

Salvage allo-SCT in relapsed/refractory MM (RRMM)1

 Limited data exists for allo-SCT in RRMM

  • The European Society for Blood and Marrow Transplantation (EBMT) registry shows the use of allo-SCT has increased, and is becoming more common in later treatment lines10

Table 2: Outcomes of patients with RRMM undergoing allo-SCT11-12

Study

N

Patient cohort

Treatment

PFS

NRM

OS

Patriarca et al.11

 

169

Patients who relapsed after ASCT who were treated with salvage therapy containing a novel agent.

Allo-SCT + RIC (available donor vs no donor)

2 years: 42% vs 18%

P < 0.0001

22% vs 1%

P < 0.0001

54% vs 53%

P = 0.33

Freytes et al.12

 

289

Patients who relapsed after prior ASCT

Second ASCT or allo-SCT with RIC (Second ASCT vs allo-SCT + RIC)

3 year: 12% vs 6%

1 year: 2% vs 13%

P < 0.001

3 year: 46% vs 20%

Conclusion: The advantage of allo-SCT over ASCT has not been proven so far and allo-SCT for RRMM is currently limited to a trial setting.

Allo-SCT in high-risk MM1

Trials have been designed, retrospectively, to analyze the impact of allo-SCT on patient outcomes in the high-risk subgroup. However, these too have failed to show a benefit of allo-SCT over.

Table 3: Analyses of allo-SCT in high-risk MM13-14

Study

N

Patient cohort

PFS

TRM

OS

Safety

Roos-Weil et al.13

143

High-risk patients undergoing allo-SCT as initial treatment or salvage

3 year (high-risk, n=53 vs standard risk, n=32): 30% vs 17%

P = 0.9 

2 year: 25%

45% vs 39%

P = 0.8

(high-risk, n=53 vs standard risk, n=32)

Acute GvHD: 47% (66/143)

Chronic GvHD: 43% (53/123)

Kroger et al.14

73

High-risk patients received tandem ASCT/allo-SCT

5 year (high-risk, n=16 vs standard risk, n=57): 24% vs 30%

P = 0.7

1-year all patients : 23%

5-year all patients: 54%

aGvHD all patients: 57%

Conclusion: In a clinical trial setting, allo-SCT may be considered for young, fit patients with high risk NDMM, in-line with International Myeloma Working group recommendations, but is not routinely recommended.

Summary

The authors did not recommend allo-SCT as a standard of care in the NDMM setting, aside from in clinical trials, and it has no proven benefit over ASCT.

 

References
  1. Mina R. and Lonial S. Is there still a role for stem cell transplantation in multiple myeloma? Cancer. 2019 Apr 15. DOI: 10.1002/cncr.32060
  2. Al Hamed R., Bazarbachi A.H. et al. Current status of autologous stem cell transplantation for multiple myeloma. Blood Cancer J. 2019 Apr 08. DOI: 10.1038/s41408-019-0205-9
  3. Donato M.L. et al. The Graft-Versus-Myeloma Effect: Chronic Graft-Versus-Host Disease but Not Acute Graft-Versus-Host Disease Prolongs Survival in Patients with Multiple Myeloma Receiving Allogeneic Transplantation. Bone Marrow Transpl. 2014 Aug. DOI: 10.1016/j.bbmt.2014.04.027
  4. Armeson K.E. et al. Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transpl. 2012 Sep 10. DOI: 10.1038/bmt.2012.173
  5. Kharfan-Dabaja M.A. et al. Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. J Hem. & Onc. 2013 Jan 04. DOI: 10.1186/1756-8722-6-2
  6. Moreau P. et al. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Oct 23. DOI: 10.1182/blood-2008-07-168823
  7. Gahrton G. et al. Autologous/reduced intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMTNMAM2000 study. Blood. 2013 Jun 20. DOI: 10.1182/blood-2012-11-469452
  8. Rosinol L. et al. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood. 2008 Oct 23. DOI: 10.1182/blood-2008-02-141598
  9. Krishnan A. et al. 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 DOI: 10.1016/S1470-2045(11)70243-1
  10. Sobh M. et al. Allogeneic hematopoietic cell transplantation for multiple myeloma in Europe: trends and outcomes over 25 years. A study by the EBMT Chronic Malignancies Working Party. Leukemia. 2016 Apr 27. DOI: 10.1038/leu.2016.101
  11. Patriarca F. et al. Allogeneic Stem Cell Transplantation in Multiple Myeloma Relapsed after Autograft: A Multicenter Retrospective Study Based on Donor Availability. Biol Blood & Marrow Transp. 2012 Apr. DOI: 10.1016/j.bbmt.2011.07.026
  12. Freytes C.O. et al. SECOND TRANSPLANTS FOR MULTIPLE MYELOMA RELAPSING AFTER A PRIOR AUTOTRANSPLANT – REDUCED INTENSITY ALLOGENEIC VERSUS AUTOLOGOUS TRANSPLANTATION. Bone Marrow Transp. 2013 Nov 25. DOI: 10.1038/bmt.2013.187
  13. Roos-Weil D. et al. Impact of genetic abnormalities after allogeneic stem cell transplantation in multiple myeloma: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire. Haematologica. 2011 Oct. DOI: 10.3324/haematol.2011.042713
  14. Kroger N. et al. Impact of high-risk cytogenetics and achievement of molecular remission on long-term freedom from disease after autologous-allogeneic tandem transplantation in patients with multiple myeloma. Biol Blood Marrow Transpl. 2012 Oct 16. DOI: 10.1016/j.bbmt.2012.10.008.
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