Long-term outcomes of lenalidomide maintenance after the STaMINA trial

The initial STaMINA trial (BMT CTN 0702, NCT01109004) aimed to demonstrate an association between additional progression-free survival (PFS) and overall survival (OS) benefit, and further interventions following autologous hematopoietic cell transplant (AHCT) in the treatment of multiple myeloma (MM). After the initial analysis, the study protocol was amended to evaluate long-term results and additional benefits of lenalidomide (Len) maintenance until disease progression in the BMT CTN 07LT follow-up trial (NCT02322320). Hari and colleagues presented, at the American Society of Clinical Oncology (ASCO) 2020 Virtual Annual Meeting, a detailed discussion on STaMINA 6-year results, as well as the results of lenalidomide continuation vs discontinuation after 3 years of treatment.¹

Background

The phase III STaMINA trial included randomized patients who underwent a first AHCT and were to receive

1. a second AHCT with 200 mg/m² melphalan (MEL) then lenalidomide maintenance as below (Auto/Auto arm, N = 247)
2. bortezomib/lenalidomide/dexamethasone (VRD) for four cycles then lenalidomide maintenance as below (Auto/VRD arm, N = 254)
3. Lenalidomide maintenance alone for 3 years (initially): 10 mg/day for 3 cycles, 15 mg/day as tolerated thereafter (Auto/Main arm, N = 257)

The first report of the study did not show any additional benefit in terms of PFS and OS when more intensive treatment approaches, such as a second AHCT or VRD consolidation, were used after the first transplant.²

Patients who were progression-free at the 38-month time point (N = 431) were included in the long-term BMT CTN 07LT follow-up trial and here, we summarize its results.

BMT CTN 07LT trial¹

Study design

The objectives were to study long-term outcomes from all STaMINA trial arms, and to investigate the benefit of lenalidomide maintenance until progression in a landmark analysis. The selection criteria included: be progression-free at 38 months, have completed the planned lenalidomide maintenance phase, and being within 4 years of the initial study.

Endpoints included PFS, OS, secondary primary malignancies (SPM), event-free survival, and quality of life.

The patient distribution among ‘continuous’ (those who continued lenalidomide maintenance until progression) and ‘fixed-duration’ (those who discontinued lenalidomide maintenance) arms are summarized in Table 1.

Table 1. Patients who continued and discontinued lenalidomide maintenance among STaMINA groups¹

VRD, bortezomib/lenalidomide/dexamethasone
Patient distribution	Continuous arm N = 215	Fixed-duration arm N = 207
Auto/Auto, n	63	80
Auto/VRD, n	79	66
Auto/Main, n	71	67
High-risk disease, n	57	60
Standard risk disease, n	149	154

Results

Long-term analysis

Intention-to-treat analysis at median follow-up of 76 months showed that

• there were no differences in PFS, OS or the incidence of SPM between the three STaMINA treatment arms
• the number of patients with malignancies, hematologic or solid, was also similar (see Table 2 below)
• incidence of SPM was found to be associated with age (Hazard Ratio [HR], 1.07; p < 0.0001)

 Table 2. Intention-to-treat analysis results¹

OS, overall survival; PFS, progression-free survival; SPM, secondary primary malignancies; VRD, bortezomib/lenalidomide/dexamethasone
Outcome	Auto/Auto	Auto/VRD	Auto/Main	p-value
PFS, % (95% CI)
5-year	47.4 (41–53)	44.1 (38–50)	45 (38–51)	0.685
6-year	43.9 (37–50)	39.7 (33–45)	40.9 (34–47)
OS, % (95% CI)
5-year	74.7 (69–80)	75.4 (70–80)	76.4 (71–81)	0.797
6-year	73.1 (67–78)	74.9 (69–80)	76.4 (71–81)
Incidence of SPM, % (95% CI)
5-year	10.8 (6.5–16)	7.9 (4.3–12)	7.2 (3.8–11)	0.745
Histology, n
Hematologic	16	15	14	—
Solid	14	11	14

 In the as-treated analysis (see Table 3)

• The probability of PFS at 5- and 6-year time points was higher in the Auto/Auto arm compared with other arms (53.6% and 49.4%, respectively, p = 0.015)
• PFS benefit was significant for patients with high-risk disease in the Auto/Auto arm (43.7%, p = 0.03) compared with the Auto/Main arm (32%)

 Table 3. As-treated analysis results¹

PFS, progression-free survival; VRD, bortezomib/lenalidomide/dexamethasone
Outcome	Auto/Auto	Auto/VRD	Auto/Main	p-value
PFS, % (95% CI)
High-risk	43.7 (33–58)	37.3 (26–48)	32 (24–40)	0.03
Standard risk	58.1 (48–67)	48.2 (40–56)	47.7 (41–54)	0.196

High-risk disease and age were defined as adverse risks for PFS in the study protocol, and multivariate analysis results were consistent (HR, 1.53; p < 0.0001, for high-risk disease, and p < 0.03, for age). Discontinuation of lenalidomide maintenance due to reasons other than disease progression resulted in a HR of 3.8 (p < 0.0001) for PFS, but the result was not statistically significant for SPM incidence.

Landmark analysis

The probability of PFS was estimated to be higher with lenalidomide maintenance in all timepoints studied (p = 0.0004), but to date, there was no difference in OS between both groups. The results of landmark analysis are summarized in Table 4. Lenalidomide maintenance continuation beyond 3 years of treatment was associated with a statistically significant higher probability of PFS in patients with standard risk (86.3% vs 66.7%, p < 0.001).

Table 4. Results among continuous and fixed-duration arms¹

PFS, progression-free survival
Outcome	Continuous arm (N = 215)	Fixed-duration arm (N = 207)
PFS, % (95% CI)
4-year	95.8 (92–98)	80.1 (74–85)
5-year	86.5 (81–90)	67.2 (60–73)
6-year	79.5 (73–84)	61 (54–67)
5-year PFS according to cytogenetic risk, % (95% CI)
High-risk (n = 117)	86.7 (77–94)	67.8 (52–79)
Standard risk (n = 303)	86.3 (80–91)	66.7 (58–74)

Conclusion

These results are from the largest randomized comparison of further interventions following frontline transplantation in MM. All three treatment approaches did not differ in PFS or OS, both in the short-term and long-term.

Auto/Auto approach resulted in superior PFS, particularly in those with high-risk disease in the long-term, therefore, this approach would be relevant in patients with high-risk MM. Discontinuation of lenalidomide maintenance beyond 38 months put patients at higher risk of disease progression, but there were no differences in OS and SPM incidence at 6 years.

The study results suggest that lenalidomide maintenance beyond 3 years may be a feasible approach in MM based on the higher probability of PFS observed at the 6-year time point. As highlighted by María-Victoria Mateos in a recent interview (see below), minimal residual disease (MRD)-driven studies will further elucidate how to guide maintenance therapy after transplantation according to patient’s disease characteristics and response.

Expert opinion