Maintenance therapy following second auto-HSCT: A CIBMTR analysis

Maintenance therapy after chemotherapy and first autologous hematopoietic stem cell transplantation (auto-HSCT1) in patients with multiple myeloma (MM) helps sustain the depth of responses achieved. The efficacy of maintenance therapy after auto-HSCT1 is well established and is a widely used strategy in the treatment of patients with MM. However, there is a dearth of evidence supporting maintenance therapy after a second auto-HSCT (auto-HSCT2), and the available evidence is mostly from single-center retrospective studies.

Pasvolsky and colleagues,¹ including two members of the Multiple Myeloma Hub Steering Committee, Nina Shah and Shaji Kumar, recently published in Bone Marrow Transplantation a study exploring the efficacy of maintenance therapy after auto-HSCT2 in patients with MM.¹ The key findings are summarized here.

Study design

This was a retrospective study exploring the efficacy of maintenance therapy after auto-HSCT2 using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. The study population comprised adult patients with MM reported to the CIBMTR who had undergone auto-HSCT2 with melphalan-based regimens without total body irradiation (TBI) between 2010–2018.

The outcomes of interest included:

• nonrelapse mortality (NRM): Death without preceding disease
• relapse/progression (REL)
• progression-free survival (PFS): Time from auto-HSCT2 to relapse, progression, or death from any cause
• overall survival (OS): Time from auto-HSCT2 to death from any cause.

Results

Baseline characteristics

A total of 522 patients were eligible for the analysis, and the disease characteristics were well balanced between patients receiving and not receiving maintenance therapy (Table 1). The median age was 61 and 62 years, and the median follow-up duration was 58 and 62 months in the maintenance and non-maintenance groups, respectively.

Table 1. Baseline characteristics for patients, disease, and treatments*

Efficacy

• Patients receiving maintenance therapy after auto-HSCT2 demonstrated better response rates, with 56% of patients achieving at least a very good partial response (VGPR) at Day 100.
• The maintenance group demonstrated superior outcomes (NRM, REL, PFS, and OS) at 5 years compared with the non-maintenance group (Table 2).
• Maintenance therapy containing immunomodulatory drugs (IMiD) showed an improved 5-year PFS and OS at 36.4% vs 10.5% or 26.2%, and 62.5% vs 34.8% or 51.6%, respectively, compared with other or double (protease inhibitor [PI] + IMiD) maintenance therapy.
  • Patients who received IMiD-only were more likely to have >5 years from auto-HSCT1 to auto-HSCT2 (68% vs 32%; p = 0.03, respectively) than those who received double maintenance therapy.
  • However, high-risk cytogenetics (54% vs 46%; p = 0.14), Stage III disease (50% vs 50%; p = 0.40), and the receipt of 200 mg/m² melphalan (60% vs 40%; p = 0.5) were similar in both subgrups, receiving IMiD-only or double maintenance therapy, respectively.
• NRM, REL, PFS, and OS consistently showed improved outcomes in multivariable analysis (MVA) (Table 2).
  • Patients who received melphalan-only or other melphalan-based conditioning regimen showed improved NRM.
  • Statistical significance for an increased rate of relapse in patients with a time interval of <60 months between auto-HSCT1 and auto-HSCT2 was retained for an age above 60 years, a Karnofsky performance status (KPS) <90, and high-risk cytogenetics (p < 0.01 each).
  • Age (p = 0.01), KPS, lactose dehydrogenase (LDH) levels, high-risk cytogenetics, and time interval between auto-HSCT1 and auto-HSCT2 remained statistically significant for PFS (p < 0.01 each, respectively).
  • A statistically significant impact on OS was retained for KPS (p <0.01), LDH levels (p = 0.02), response at auto-HSCT2 (p = 0.02), and time interval between auto-HSCT1 and auto-HSCT2 (p <0.01).
• More patients died in the non-maintenance group (n = 110) compared with the maintenance group (n = 131) (61% vs 38%; p < 0.01) during follow-up, with primary disease as the most common cause of death in both groups.
• Additional analyses, including a 100-day and a 6-month post-auto-HSCT2, and subgroup analysis of patients who received 200 mg/m² melphalan, all demonstrated improved outcomes in the maintenance group.
• Secondary malignancies were reported in 5% (n = 17) and 3% (n = 6) of patients in the maintenance and non-maintenance group, respectively.
  • However, there was no difference in the risk of developing secondary malignancies between the various maintenance regimens.

Table 2. Outcomes using univariate and multivariate analysis*

CI, confidence interval; HR, hazard ratio; NRM, nonrelapse mortality; OS, overall survival; PFS, progression-free survival. *Adapted from Pasvolsky et al.1 †Values in bold are statistically significant.
Outcomes at 5 years	Maintenance (n = 342)	No maintenance (n = 180)	p value†
Univariate analysis	Probability, % (95% CI)	% (95% CI)
NRM	2 (0.7–3.9)	9.9 (5.9–14.9)	<0.01
Relapse	70.2 (64.4–75.8)	80.3 (73.6–86.3)	<0.01
PFS	27.8 (22.4–33.5)	9.8 (5.5–15.2)	<0.01
OS	54 (47.5–60.5)	30.9 (23.2–39.2)	<0.01
Multivariate analysis	HR (95% CI)	HR (95% CI)
NRM	0.19 (0.08–0.44)	Reference	<0.01
Relapse	0.58 (0.47–0.72)	Reference	<0.01
PFS	0.52 (0.43–0.64)	Reference	<0.01
OS	0.46 (0.36–0.60)	Reference	<0.01

Conclusion

This study analyzed data from the largest dataset of CIBMTR to investigate the role of maintenance therapy after auto-HSCT2 for patients with MM. The study demonstrated that maintenance therapy after auto-HSCT2 improved the 5-year NRM, relapse incidence, PFS, and OS. IMiD-containing maintenance regimens were also associated with superior outcomes compared with other maintenance regimens. However, the study is limited by its retrospective nature and, therefore, the risk of inherent selection bias. Future prospective randomized controlled trials exploring the role of maintenance therapy after auto-HSCT2 are therefore warranted.