Patients eligible for transplant

EBMT 2019 | Outcome of second allogeneic stem cell transplant in patients with multiple myeloma

In patients with multiple myeloma (MM) it is generally very difficult to treat disease relapse following allogeneic hematopoietic stem cell transplant (allo-HSCT), with most chemotherapy being palliative. Treatment options include the use of donor lymphocyte infusions (DLIs) or second allo-HSCTs, though few data are available on patient outcomes in these scenarios.

On Wednesday 27 March 2019, during the 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE, Patrick Hayden, St James’s Hospital, Trinity College Dublin, Dublin, IR, presented the results from an EBMT chronic malignancies working party (CMWP) study which analyzed the outcomes of patients with MM who received a second allo-HSCT for graft failure or relapse.1

Background2

In a prior study, by Tapani Ruutu et al., overall survival (OS) rates of 40% at one year and 20% at five years were observed in 2,632 patients with malignant disease who underwent second allo-HSCT. In patients with MM (n = 80), the one year survival was 49% and was 24% at five years.

A multivariate analysis identified several factors associated with an improved OS after second allo-HSCT which included; a lower disease burden and age at transplant, a longer remission period after first allo-HSCT, an extended time between transplants, a more recent transplant, receiving a transplant from a sibling donor, and a lack of acute graft-versus­-host disease (GvHD) grade II–IV after first allo-HSCT. Notably, there was no difference in OS when considering the source of the second transplant (i.e. from the same or a new donor as the first). Although this study investigated patient outcomes after a second allo-HSCT, only a small sample of patients with MM were recruited. The study by the EBMT CMWP therefore aimed to build upon this by investigating the outcomes of patients with MM who received a second allo-HSCT by indication, including a subgroup analysis of those transplanted within 4-months for primary graft failure.

EBMT CMWP study1

In 273 patients with MM who had a second allo-HSCT between 1994 and 2017, data regarding the indication of the second allo-HSCT was missing in 58. In the remaining 215 patients, the indication for second transplant was:

  • Relapsed myeloma; n = 159 (74%)
  • Graft failure; n = 56 (26%)
    • Within 4 months; n = 32

Table 1: Key patient characteristics based on indication for second transplant

 

Transplanted for relapsed disease (n = 159)

Transplanted for primary graft failure within 4 months (n = 32)

Median age at second transplant

51 (29–69)

51.3 (25.3–68)

Median interval between transplants

40.5 months (1.5–170.4)

1.9 months (0.7–3.9)

Human leukocyte antigen (HLA)-identical sibling donor (first vs second transplant)

68.8% vs 60.9%

38.7% vs 40.6%

Same donor for both transplants

43.1%

71.4%

Advanced disease status (first vs second transplant)

22.1% vs 58.6%

15.6% vs 32%

Karnofsky status 80–100 (first vs second transplant):

94.1% vs 80.2%

96% vs 48%

 

Patient outcomes

Table 2 below shows 2-year and 5-year OS and progression-free survival (PFS) rates for both groups.

Table 2: Patient outcomes based on indication for transplant

 

Relapsed disease (n = 159)

Graft failure within 4 months (n = 32)

OS at 2 years

38%

31%

OS at 5 years

25%

Not reported (NR)

PFS at 2 years

17%

NR

PFS at 5 years

6%

NR

Neutrophil engraftment at day +28

94%

75%

Death prior to engraftment

5%

4%

The authors then conducted an analysis of factors associated with OS, PFS and relapse rates in the group who received their transplant for relapsed disease (n = 159). This analysis found:

  • Transplants from HLA-matched donors conferred an OS advantage (P < 0.001, HLA-matched vs other):
    • Two-year OS: 48% vs 23%
    • Five-year OS: 34% vs 8%
  • Second transplants from the same donor as the first provided a superior OS (P = 0.042, same donor vs other):
    • Two-year OS: 43% vs 27%
    • Five-year OS: 37% vs 16%
  • Patients receiving transplants <24 months from the first had a poorer OS (P = 0.01, second transplant <24 months vs >24 months from first transplant):
    • Two-year OS: 26% vs 43%
    • Five-year OS: 10% vs 31%
  • These results were similarly significant when looking at PFS
  • Additionally, age and disease status were found to be associated with relapse rates:
    • Disease status (low vs advanced disease): 67% vs 85% (P = 0.01)
    • Age (<50 vs 50–70): 67% vs 88% (P = 0.02)
GvHD rates

Table 3: GvHD rates based on indication for transplant

 

Relapsed disease (n = 159)

Graft failure within 4 months (n = 32)

Rates of acute GvHD (aGvHD) grade II–IV at day + 100

14%

25%

Death without aGvHD

12%

18%

Chronic GvHD (cGvHD)

40%

43%

Death without cGvHD

45%

43%

In patients experiencing aGvHD after their first transplant who then had a second allo-HSCT from the same donor, there was a significantly higher incidence of aGvHD.

Causes of death

The authors analyzed the causes of death between the groups transplanted for relapse or graft failure. The most common cause of death was disease relapse/progression (55.1%) in the relapse group and infection in the graft failure group (40.9%). The full breakdown is shown in Table 4.

Table 4: Causes of death by indication for second allo-HSCT

Cause of death

Relapse group; n = 110 (n, %)

Graft failure group; n = 22 (n, %)

Relapse/progression

59 (55.1)

5 (22.7)

Secondary malignancy

2 (1.9)

0

GvHD

12 (11.2)

2 (9.1)

Infection

21 (19.6)

9 (40.9)

Organ damage

2 (1.9)

2 (9.7)

Toxicity

1 (0.9)

2 (9.7)

HSCT-related death

5 (4.7)

0

Other

5 (4.7)

2 (9.7)

Missing

3

0

Conclusion

In patients who received a second allo-HSCT due to relapse, factors that conferred a superior OS were receiving donor cells from a HLA-identical sibling and using the same donor as the first transplant. A poorer OS was seen in patients who received their second transplant within two years.

In the 32 patients in this retrospective study who were transplanted for primary graft failure, the OS was 31% at 2-years, but then this plateaued.

The authors concluded that second allo-HSCT may have a role for specific patients in late relapse with myeloma and those with graft failure.

 

References
  1. Hayden P. et al. Outcomes after second allogeneic haematopoietic cell transplantation (HCT) for multiple myeloma – an EBMT CMWP analysis. Abstract OS12-5. 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE
  2. Ruutu T. et al. Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT. Bone Marrow Transp. 2015 Sep 14. DOI: 10.1038/bmt.2015.186
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