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Pooled analysis of long-term data from studies of tandem autologous versus autologous-allogeneic HSCT for newly diagnosed multiple myeloma

Dec 19, 2019

Tandem autologous hematopoietic stem cell transplantation (HSCT) (auto-HSCT) has been studied as a method of increasing remission rates and reducing relapse in the upfront treatment of multiple myeloma (MM). 1,2Autologous HSCT followed by reduced intensity conditioning allogeneic HSCT (auto-allo-HSCT) offers the potential for a long-term graft- versus-myeloma (GVM) effect, but carries a risk of graft- versus-host disease (GvHD) and potentially higher non-relapse mortality (NRM).

Tandem auto-allo-HSCT has been compared with tandem auto-HSCT in multiple prospective studies with conflicting results, leaving clinicians unclear which strategy is preferred for newly diagnosed patients with MM. In 2013, a meta-analysis of published results was performed, which suggested that auto-allo-HSCT was associated with a better chance of a complete response, but with higher NRM and no improvement in PFS or OS compared with tandem auto-HSCT. 3

With the passage of time, many of these studies now have long-term follow-up data available, enabling a fresh analysis of pooled individual patient data from these studies. The latest analysis, which included long-term follow-up data from four of the original meta-analyses, was presented in December 2019 at the 61 stAmerican Society of Hematology Meeting & Exposition, Orlando, US, by Luciano Costafrom the O’Neal Comprehensive Cancer Center at the University of Alabama, Birmingham, US. 4

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Study design

  • Studies were selected for inclusion that fulfilled the following criteria:
    • Newly diagnosed patients with MM who had received brief induction therapy
    • Allocation to auto-auto-HSCT or auto-allo-HSCT arms based exclusively on the availability of HLA-matched sibling donors (“biologic randomization”)
    • Conditioning regimen for allo-HSCT met Center for International Blood and Marrow Transplant Research ®(CIBMTR)criteria for reduced intensity
  • Investigators from all trials meeting eligibility criteria were invited to submit a limited dataset (age, gender, risk profile, treatment arm, relapse, NRM, PFS, OS)
  • Patients were designated high-risk if they had a β2 microglobulin level at diagnosis of ≥ 4 mg/L and/or a deletion of chromosome 13 by metaphase karyotyping
  • Outcomes analyzed: PFS, OS, NRM, risk of relapse
  • All analyses were by intention-to-treat (ITT) analysis
  • NRM and relapse/progression were analyzed as competing risks
  • Post-relapse survival (PRS) was defined as the time from relapse/progression until death, censored at last follow-up if alive

Patient characteristics

  • Data from four studies were included: BMT CTN 0102, NMAM2000, PETHEMA/GEM2000, and NCT00415987
  • 1,338 patients were included in the analysis ( Table 1)
    • 899 patients underwent auto-auto-HSCT
    • 439 patients underwent auto-allo-HSCT
  • Median follow-up of survivors: 118.5 months
  • Patients receiving auto-allo-HSCT were slightly younger than patients receiving auto-auto-HSCT
  • The median follow-up of survivors was longer in the auto-allo-HSCT group than in the auto-auto-HSCT group

  Table 1.Patient characteristics

Allo, allogeneic; Auto, autologous; HSCT, hematopoietic stem cell transplantation

 

Auto-auto-HSCT

(n= 899)

Auto-allo-HSCT

(n= 439)

Median follow-up of survivors,months

112.2

122.3

Median age,years

56

53.4

Age < 50 years

238 (26.4%)

150 (34.2%)

Male

527 (58.6%)

249 (56.7%)

High-risk

125 (13.9%)

89 (20.3%)

Results

  • PFS and OS were significantly improved after auto-allo-HSCT compared with auto-auto-HSCT ( Table 2)

Table 2.OS, PFS, and NRM in newly diagnosed patients with MM receiving either auto-auto-HSCT or auto-allo-HSCT in four studies

Allo, allogeneic; Auto, autologous; CI, confidence interval; HSCT, hematopoietic stem cell transplantation; NRM, non-relapse survival; PFS, progression-free survival; OS, overall survival

 

Auto-auto-HSCT

(n= 899)

Auto-allo-HSCT

(n= 439)

HR (95% CI)

p value

OS

Median OS, months (95% CI)

78 (71.5–84.5)

98.3 (81.8–114.7)

HR= 0.84 (0.73–0.97) p= 0.02

5-year OS, % (95% CI)

59.8 (56.6–63)

62.3 (57.8–66.8)

p= 0.37

10-year OS, % (95% CI)

36.4 (32.9–40)

44.1 (39.2–49)

p= 0.01

PFS

Median PFS, months (95% CI)

26.4 (23.8–28.9)

24.4 (18.8–30)

HR= 0.85 (0.75–0.95) p= 0.004

5-year PFS, % (95% CI)

23.4 (20.7–26.1)

30.1 (25.8–34.4)

p= 0.01

10-year PFS, % (95% CI)

14.4 (11.8–16.9)

18.7 (15.0–22.4)

p= 0.06

Relapse

5-year relapse, % (95% CI)

69.7 (66.8–72.6)

52.4 (47.9–56.9)

 

10-year relapse, % (95% CI)

77.2 (74.5–79.9)

61.6 (56.9–66.3)

 

NRM

5-year NRM, % (95% CI)

6.9 (5.3–8.5)

17.4 (13.9–20.9)

 

10-year NRM, % (95% CI)

8.3 (6.5–10)

19.7 (16—23.4)

 

  • For the 214 high-risk patients (125 auto-auto-HSCT, 89 auto-allo-HSCT), 5-year and 10-year PFS rates were significantly higher with auto-allo-HSCT than with auto-auto-HSCT, but there was no difference in OS
  • Median PRS was 41.5 months (95% CI, 36.5–46.4) in the auto-auto-HSCT arm and 62.3 months (95% CI, 47.7–76.9) in the auto-allo-HSCT arm (HR= 0.70; 95% CI, 0.58–0.84; p< 0.001)

Conclusions

The authors of this study have concluded that, compared with auto-auto-HSCT, auto-allo-HSCT is associated with the best long-term outcomes, although the benefits are only evident with long-term follow-up. Auto-allo-HSCT was associated with a lower risk of relapse, longer OS and PFS, and a higher risk of NRM compared with auto-auto-HSCT. Robust improvements in post-relapse survival were attributed to potential cooperation between GVM and novel MM agents. Nevertheless, despite the advantages of auto-allo-HSCT over auto-auto-HSCT demonstrated in this study, the authors suggest that the improved long-term survival benefit should be balanced against the late morbidity such as chronic GvHD.

Expert Opinion

  1. Kröger N. et al., Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood. 2002 Aug 1;100(3):755–760. DOI: 10.1182/blood-2002-01-0131
  2. Maloney D.G.  et al.,Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood. 2003 Nov 1;102(9):3447–3454. DOI: 10.1182/blood-2002-09-2955
  3. 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 Transplant. 2013 Apr;48(4):562–567. DOI: 10.1038/bmt.2012.173
  4. Costa L.J.  et al.,Tandem autologous–autologous vs. autologous–allogeneic transplantation for newly diagnosed multiple myeloma: pooled analysis of 1,338 patients from four trials with long-term follow-up; 2019. Oral Abstract #259: 61st American Society of Hematology (ASH)Meeting & Exposition, Orlando, FL