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Comparison of transplant strategies in multiple myeloma: lessons from a large EBMT registry study

Dec 17, 2019

Although many different drugs are available to treat multiple myeloma (MM), high-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) remains the gold standard, and use of this treatment approach has increased in Europe, especially as a second- and later-line option. 1

Studies assessing various transplant intensification strategies to improve disease control have been conducted, however, no clear consensus on their use has emerged. To help guide clinicians in choosing between different upfront transplant strategies in MM (e.g. single auto-HSCT, tandem auto-HSCT, and auto-allogeneic HSCT [auto-allo HSCT]), the Chronic Malignancies Working Party (CMWP)of the European Society for Blood and Bone Marrow Transplantation (EBMT)has evaluated the outcomes from a large cohort of almost 25,000 patients with MM enrolled into the EBMT Registry who received their first auto-HSCT in EBMT centers. The study results were presented at the 61 stAmerican Society of Hematology Meeting & Exposition, Orlando, US, by Stefan Schönlandfrom the University Clinic Heidelberg, Heidelberg, DE. 2

To watch a recent interview with Mohamad Mohty from Saint-Antoine Hospital and Sorbonne University, Paris, FR, on the future role of autologous transplant in the treatment of MM, scroll to the end of this article, or click here.

Study design 2

  • Retrospective analysis of EBMT Registry
  • Patient eligibility:
    • Patients with MM
    • Aged 20–65 years
    • Auto-HSCT as a first transplant between 2002 and 2015
  • Primary endpoints: progression-free survival (PFS) and overall survival (OS)
  • Different upfront strategies (single auto-HSCT, auto-auto-HSCT, auto-allo-HSCT) were analyzed in addition to the effects of age, disease status, and calendar year at first auto-HSCT

Statistical analysis 2

  • Three different statistical methods were applied to avoid time bias and to account for time-dependent effects:
    • Model one: Single and tandem transplant groups were compared by landmark analysis
    • Models two and three: Two different dynamic prediction models were applied to predict long-term outcomes in all patients according to the treatment received and to avoid the loss of information that occurs in landmark analyses:
      • Models incorporated a horizon time of five years for PFS and OS during the first three years following the first auto-HSCT
      • Effects of tandem transplants were split into “recent” (first 100 days following the second transplant) and “past” for the longer term
      • The third model incorporated the long-term time-varying effect of tandem transplants and possible associated interactions with patient characteristics

Patient characteristics

  • 24,936 patients who received an auto-HSCT as their first transplant were evaluated ( Table 1)
    • 3,683 patients proceeded to receive a tandem auto-auto-HSCT
    • 878 patients proceeded to receive a tandem auto-allo-HSCT
      • 72% of patients had HLA identical sibling donors and 25% had matched unrelated donors
      • Reduced intensity conditioning was performed in 85% of patients who received allogeneic transplants
    • Median follow-up: 66.3 months

 T able 1.Patient characteristics

Allo, allogeneic; Auto, autologous; CR, complete response; HSCT, hematopoietic stem cell transplantation; PR, partial response

 

Total group

(N= 24,936)

Auto-auto-HSCT

(n= 3,683)

Auto-allo-HSCT

(n= 878)

Age at first auto-HSCT, years, median (range)

57(18.1–65)

56.7 (23.4­­–65)

51.7 (18.9–65)

18–50 years

20%

21%

42%

50–60 years

48%

49%

47%

60–65 years

32%

30%

11%

Male

58%

60%

63%

Time from diagnosis to first auto-HSCT <12 months

78%

81%

86%

Status at first auto-HSCT: CR/PR

18%/69%

9%/72%

8%/67%

Year of first auto-HSCT

 

 

 

2002–2006

33%

50%

56%

2007–2011

45%

35%

34%

2012–2015

22%

15%

10%

Median time from first auto-HSCT to second transplant, months

3.6 (0.5–9)

3.9 (1.1–9)

Status at second transplant: CR/PR

18%/69%

19%/66%

  • Allo-auto-HSCT patients were younger, and fewer patients had a complete response (CR) at first auto-HSCT in both tandem groups
  • There was no difference in CR rates at second transplant

Results

  • At 60 months following the first auto-HSCT, PFS was 24.8% and OS was 63.1%
  • All three statistical methods found that a younger age and having a CR at first transplant were associated with superior PFS and OS

Table 2.Predictors of PFS and OS after first auto-HSCT

CR, complete response; HR, hazard ratio

 

HR (95% CI)

pvalue

OS dynamic prediction

Age (+ 1 year)

1.02 (1.02–1.03)

< 0.001

Calendar year (+ 1 year)

0.98 (0.97–0.98)

< 0.001

No CR status at 1 sttransplant

1.08 (1.01–1.16)

0.021

PFS dynamic prediction

Age (+ 1 year)

1.01 (1.01–1.01)

< 0.001

Calendar year (+ 1 year)

1 (0.99–1.00)

0.683

No CR status at 1 sttransplant

1.29 (1.22–1.36)

< 0.001

  • A landmark analysis at four months found that allo-auto-HSCT had an advantage in terms of very long-term PFS but not for OS
  • Dynamic prediction found that the tandem groups were superior in terms of PFS compared with single auto-HSCT
    • Auto-allo-HSCT: HR= 0.56, corresponding to a 21% gain in PFS probability
    • Auto-auto-HSCT: HR= 0.85, corresponding to a 6% gain in PFS probability
  • Dynamic prediction found that the tandem groups were only slightly superior in terms of OS compared with single auto-HSCT
    • Auto-allo-HSCT: HR= 0.78, corresponding to a 7% gain in OS probability
    • Auto-auto-HSCT: HR= 0.87, corresponding to a 4% gain in OS probability
  • Dynamic prediction with time-varying effect and interactions found that auto-auto-HSCT was superior, especially for patients that had a CR at first auto-HSCT

Conclusions

This study demonstrated, in a large cohort of patients who had undergone auto- and allo-HSCT as first-line treatment for MM, that a younger age and having a CR at first transplant were positive prognostic factors for PFS and OS. The study also demonstrated that tandem auto-allo-HSCT was associated with the best long-term disease control, however, the PFS benefits observed only translated into a small OS benefit, even when the analysis was restricted to patients who did not have a CR at the time of their first auto-HSCT.

The authors cautioned that, although early mortality after allogeneic transplantation has decreased in the last decade, current mortality risk and late morbidity such as chronic graft- versus-host disease should be balanced against any improved long-term survival.

Expert Opinion

  1. 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 Oct;30(10):2047–2054. DOI: 10.1038/leu.2016.101
  2. Schönland S.O. et al., Comparison of different upfront transplant strategies in multiple myeloma: a large registry study from Chronic Malignancies Working Party of EMBT; 2019. Oral Abstract #324: 61st American Society of Hematology (ASH) Meeting & Exposition, Orlando, US