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Tandem stem cell transplantation for newly diagnosed high-risk multiple myeloma

Aug 24, 2020

As part of this month’s editorial theme, the Multiple Myeloma Hub is focusing on the clinical outlook of high-risk multiple myeloma (MM), and how patient prognosis can be improved in this setting. Despite significant advances in treatment options for patients with MM in recent decades, certain cytogenic aberrations are still associated with inferior outcomes in MM.

Currently employed standard-of-care regimens for patients with newly diagnosed MM (NDMM) have improved survival outcomes, but patients harboring del(17p) and/or t(4;14) genetic alterations have been identified as particularly high risk, and benefit least from emerging treatments. Among efforts to improve patient outlook, tandem transplantation has been employed in certain settings. However, the benefit of a tandem transplant remains ill-defined and, until now, no studies have reported alternative transplant approaches in distinct cytogenetic groups in the real-world setting.

In an endeavor to provide answers, Nico Gagelmann et al. 1evaluated patients with high-risk NDMM with del(17p) and/or t(4;14) undergoing frontline treatment with single autologous (auto), tandem autologous (auto-auto), or tandem autologous/reduced-intensity allogeneic (auto-allo) stem cell transplantation (SCT). Data were obtained from the European Society for Blood and Marrow Transplantation (EBMT) registry, and the results were published in Bone Marrow Transplant—below is a summary.

Study design

  • Patients receiving SCT for the treatment of NDMM between 2000–2015, and with cytogenetic data available, were reported to the EBMT registry (N = 623)
  • SCT approaches included
    • single auto (n = 446)
    • auto-auto (n = 105)
    • auto-allo (n = 72)
  • Primary endpoints: Overall survival (OS) and progression-free survival (PFS) within the first 5 years following initial auto-SCT
  • Using single auto-SCT as a reference, multivariable analyses were carried out to evaluate the impact of tandem SCT approaches and cytogenetics on OS, PFS, and relapse

Results

Patient characteristics

  • Baseline patient characteristics and demographics are presented in Table 1

Table 1.Baseline patient characteristics 1

Auto, single autologous; auto-allo, tandem autologous/reduced-intensity allogeneic; auto-auto, tandem autologous; CA, cytogenetic aberration

Characteristic

Total patient population (N = 623)

Median age, years (range)

59 (25.6–76.7)

Male, %

55.5

Transplant, %

 

Auto (n = 446)

71.6

Auto-auto (n = 105)

16.9

Auto-allo (n = 72)

11.6

ISS, %

 

I

20.9

II

57.5

III

21.7

Cytogenetics, %

 

del(17p)

44.8

t(4;14) 

46.5

Both

8.7

Number of high-risk CAs, %

 

1

77.0

≥ 2

23.0

Bortezomib-based induction regimen, %

69.2

Months from diagnosis to first transplant, median (range)

5.6 (2.2–11.7)

Patient outcome

  • Patient outcomes across the entire cohort are presented in Table 2
  • 5-year PFS and relapse rates were significantly improved in the tandem transplant cohorts (auto-auto and auto-allo) vssingle auto cohort ( Table 3)
  • 5-year OS, PFS, and relapse rates, as well as NRM were not significantly different between high-risk cytogenetic subgroups ( Table 3)

Table 2.Patient outcomes to frontline transplant across the study cohort 1

NRM, non-relapse mortality rate; OS, overall survival; PFS, progression-free survival

Outcome, % (range) unless otherwise stated

Entire cohort (N = 623)

Median follow-up, months (range)

58 (53–63)

5-year OS

49 (44–54)

5-year PFS

20 (16–24)

5-year relapse rate

77 (73–81)

NRM

3 (2–5)


Table 3.Patient outcomes to frontline transplant with respect to transplant approach and cytogenetic abnormalities

NRM, non-relapse mortality rate; OS, overall survival; PFS, progression-free survival

Transplant approach

Outcome, % (range) unless otherwise stated

Single auto

(N = 446)

Auto-auto

(N = 105)

Auto-allo

(N = 72)

p

Median follow-up, months

56

52

63

5-year OS

51 (45–58)

60 (49–72)

67 (53–80)

0.187

5-year PFS

17 (12–22)

33 (22–43)

34 (21–38)

0.048

5-year relapse rate

82 (77–87)

63 (52–74)

56 (42–70)

0.001

NRM, %

1

4

10

Cytogenetics

Outcome, % (range)

t(4;14)

del(17p)

t(4;14) + del(17p)

p

5-year OS

53 (46–60)

44 (37–51)

52 (37–67)

0.463

5-year PFS

20 (15–26)

20 (14–26)

16 (5–28)

0.179

5-year relapse rate

76 (70–82)

77 (71–83)

78 (66–91)

0.311

NRM

3 (1–6)

3 (1–5)

6 (0–12)

0.531

Multivariate analysis

When adjusted for patient baseline characteristics, the outcomes of the different transplant strategies depended on the type of cytogenetic aberration present:

  • In patients harbouring del(17p)
    • outcomes following tandem auto-auto were comparable to those following single auto
    • patients who underwent a tandem auto-allo improved their survival outcomes versussingle-auto, although these differences were not statistically significant
  • In patients harbouring t(4;14), PFS following tandem auto-auto was significantly superior to PFS following single auto (HR, 0.44; 95% CI, 0.24–0.8; p 0.007), that translated into apparent improvement of the OS

PFS rates following tandem auto-allo were superior to single auto (HR, 0.54; 95% CI, 0.23–0.87; p 0.018), but OS was comparable

Conclusion

Nico Gagelmann and colleagues established that frontline treatment with tandem autologous transplant was associated with superior PFS and relapse rates compared with single auto-SCT in patients with NDMM and t(4;14). In addition to the positive results from the EMN02/HO95 trial in patients with del(17p) and the STAMINA study , these data support the benefit of a tandem auto-SCT in patients with high-risk cytogenetics.

On the other hand, the higher NRM rates, together with the limited number of patients, impedes to make a clear recommendation on the use of tandem auto-allo based only on this real-world study.

At the 45th Annual Meeting of the EBMT in 2019, Nico Gagelmann summarized for the Multiple Myeloma Hub the reported outcomes of this study :

Expert Opinion

  1. Gagelmann N, Eikema D-J, de Wreede LC, et al. Upfront stem cell transplantation for newly diagnosed multiple myeloma with del(17p) and t(4;14): a study from the CMWP-EBMT. Bone Marrow Transpl.DOI:  10.1038/s41409-020-01007-w