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

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^st American Society of Hematology Meeting & Exposition, Orlando, US, by Stefan Schönland from 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 design²

• 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 analysis²

• 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

 Table 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)	p value
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 1st transplant	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 1st transplant	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.