GvHD Prophylaxis,   cGvHD

MRD-negativity after tandem autologous-allogeneic HSCT with bortezomib maintenance

During the 17th International Myeloma Workshop (IMW), in Boston, MA, US, a ‘Myeloma Transplant and Maintenance Strategies’ session was held on Saturday 14th September 2019. In this session, Richard LeBlanc from the Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, CA presented results of a phase II clinical trial using bortezomib in the post allo-SCT maintenance regimen.1

As part of the phase II clinical trial (NCT02308280) LeBlanc and the team aimed to determine whether the addition of maintenance bortezomib (V) to tandem autologous- and allogeneic- (allo-) stem cell transplantation (SCT) would reduce relapse rates and chronic graft-versus-host disease (cGvHD) in patients with high-risk (HR) newly diagnosed multiple myeloma (NDMM). They also aimed to determine the value of bone marrow measurable residual disease (MRD) assessment to determine the progression of the disease.

Study design and results:
  • Inclusion criteria:
    • NDMM with measurable disease
    • Aged < 65 with ISS of III, a diagnosis of plasma cell leukemia, and/or cytogenetics associated with poor outcome
    • Aged ≤ 50 regardless of other risk factors
    • Matched related (MRD) or unrelated donor (URD)
  • Participant treatment regimen:
    • V induction
    • Autologous SCT, high dose melphalan 200 mg/m2
    • Non-myeloablative allo-SCT
    • V 1.3 mg/m2 subcutaneously every two weeks for twelve months
  • Patient characteristics (Table 1)
Table 1: Patient characteristics

Patient characteristics

%

Age, median years (range)

54 (35—64)

≤ 50

41

Sex

Male

Female

54

46

ISS

I

II

III

Unknown

15

36

41

8

Cytogenetics (n= 34)

t(4:14)

t(14:16)

t (14:20)

del 17p

Gain 1q

del 1p

≥ 2 adverse cytogenetics

Any high-risk adverse cytogenetics

15

0

0

6

24

3

18

65

Induction

CyBorD

VTdD

82

18

Number of induction cycles

Median four

Range 4 — 7

 

Maintenance

Lenalidomide

13

Comorbidity index (HCT-CI)

0

1

2

3

49

15

21

15

Donors

Sibling

MUD

41

59

Abbreviations: ISS; international staging system, CyBorD; cyclophosphamide/bortezomib/dexamethasone, VTdD; Bortezomib/thalidomide/dexamethasone, MUD; matched unrelated donor, HCT-CI; Hematopoietic cell transplantation - specific comorbidity index

  • Responses were determined according to the International Myeloma Working Group (IMWG) guidelines2 (Table 2)

Table 2: Response rates after treatment phases
 

Induction (n= 39)

After ASCT (n= 39)

After allo-SCT (n= 39)

During V(n= 38)

After V(n= 31)

%

≥ CR

NE

56

64

77

61

VGPR

72

36

23

8

3

PR

28

8

5

0

0

SD

0

0

0

0

0

PD

0

0

8

16

35

Abbreviations: CR; complete response, VGPR; very good partial response, PR; partial response, SD; stable disease, PD; progressive disease

  • Overall survival (OS) at two years was 92% (95%CI 77 — 97)

  • Progression-free survival (PFS) at two years was 67% (95%CI 49 — 80)

  • Three patients died (one from the progression of myeloma, and two from GvHD/infection)

  • Myeloma progression was noted in 14 patients

  • On MRD assessment, < 50 cells were associated with a cumulative incidence of progression at two years of 27%, and ≥ 50 cells, an 82% cumulative incidence of progression at two years

  • In terms of V safety, side-effects included diarrhea (n= 1), hemorrhagic cystitis (n= 3) and brain infection (n= 2)

  • Grade II—IV acute GvHD (aGvHD) was observed in 26% at 12 months (95% CI 13 — 40) and moderate/severe cGvHD was observed in 46% at 24 months (95% CI 29—61)

    • When compared with a historical control, there was a significant reduction in all grades (85 vs 56%, p= 0.0002) and of moderate/severe (69 vs 46%, p= 0.008) cGvHD, and a non-significant reduction in severe cGvHD (26 vs 11%, p= 0.065) with the addition of V

LeBlanc concluded that adding V into the post allo-SCT maintenance regimen is safe and may reduce cGvHD development and severity. They also found that low MRD six months after V is related to improved outcomes. He added that longer-term follow-up was needed to evaluate the curative ability of this regimen.

References
  1. LeBlanc, R. et al., Profound MRD negativity rates after frontline tandem autologous-allogeneic stem cell transplantation followed by bortezomib maintenance in high-risk or young myeloma patients; 2019 September 14. Oral Abstract #AB285: 17th International Myeloma Workshop, Boston, MA.
  2. Kumar S. et al., International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016 Aug;17(8):e328-e346. DOI: 10.1016/S1470-2045(16)30206-6
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