Lenalidomide Maintenance Improves PFS, OS in Patients With Transplant-Eligible Multiple Myeloma

Maintenance therapy with lenalidomide (Revlimid) significantly improved progression-free survival (PFS) compared with observation alone in patients with newly diagnosed multiple myeloma and the benefit was seen in both transplant-eligible and -ineligible groups.

Median PFS, defined as the time from maintenance therapy randomization to progressive disease or death, was 39 months (95% CI, 36-42) with lenalidomide and 20 months (95% CI, 18-22) with observation (HR, 0.46; 95% CI, 0.41-0.53;P<.0001).

Maintenance therapy in multiple myeloma is undertaken to control or eliminate residual disease clones that often lead to disease relapse in patients with a high-cytogenetic risk. Good markers of early relapse are cytogenetic lesions t(4;14), t(14;16), t(14;20), del(17p), and gain(1q). Finding strategies that overcome the biological features that impair the activity of disease therapy could improve outcomes and prevent relapse in patients who harbor these markers.

&ldquo;An adverse cytogenetic profile is a major risk factor for relapse, and outcomes for patients with high-risk cytogenetics are poor,&rdquo; trial investigators, led by Graham H. Jackson, MD, said. &ldquo;Data supporting the use of lenalidomide maintenance in patients with adverse cytogenetics are scarce and results thus far have been inconclusive.&rdquo;

The phase III, open-label, randomized Myeloma XI trial on which the data are based involved 3 potential randomizations: once at trial entry to allocate induction therapy; once following induction to assign dose intensification in patients who had a suboptimal response, defined as either a minimal or partial response; and once at the completion of induction and intensification or autologous stem cell transplantation (ASCT) to assign maintenance therapy. For this study, investigators were concerned with the results of the randomization to maintenance treatment.

The study protocol inclusion criteria comprised patients &ge;18 years with multiple myeloma or nonsecretory multiple myeloma. Patients could not enroll if they had previous or concurrent malignancies, previous treatment for myeloma, grade &ge;2 peripheral neuropathy or acute renal failure, and active or previous hepatitis C infection.

Patients were initially divided into 2 groups. Those who were transplant ineligible, older, and less fit entered the nonintensive treatment pathway. Patients that were transplant eligible, young, and fit entered the intensive treatment pathway. Strict age limits were avoided, but generally, patients &le;60 years entered the intensive group and patients &ge;70 years entered the nonintensive group and those aged 61 to 69 years were eligible to enter either group.

At trial entry, patients who were considered transplant eligible were randomized 1:1 to either cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD) induction. After the accrual of 1512 patients, a protocol amendment began randomizing patients 1:1:2 to CTD; CRD; or carfilzomib (Kyprolis), cyclophosphamide, lenalidomide, and dexamethasone (KCRD). Those who were in the nonintensive treatment group were randomly assigned to attenuated CTD or attenuated CRD induction. Attenuated versions of therapy included lower doses of dexamethasone and a lower starting dose of thalidomide.

Patients receiving immunomodulatory triplets who achieved a complete response or very good partial response proceeded to ASCT and transplant-ineligible patients went directly onto maintenance therapy.

Patients eligible for maintenance therapy randomization (n = 1971) must have completed &ge;4 cycles of CTD, CRD, or KCRD in the intensive therapy group or &ge;6 cycles of attenuated CTD or attenuated CRD in the nonintensive group and intensification treatment, where applicable. These patients were treated 1:1 with lenalidomide or observation. Following a protocol amendment and after the accrual of 442 patients, patients were newly randomized 1:1:1 to lenalidomide, lenalidomide plus vorinostat (Zolinza), or observation. A further randomization occurred after the accrual of another 615 patients that assigned participants 2:1 to lenalidomide or observation.

These changes were made to add and remove research questions in the adaptive design study. In total, 1137 patients were assigned to lenalidomide alone and 834 patients to observation.

The coprimary endpoints of the maintenance analysis were PFS and overall survival (OS), or the time from randomization to death of any cause or last follow-up. Secondary endpoints included PFS2, defined as the time from maintenance randomization to the date of second progressive disease, start of third antimyeloma treatment, or death; time to improved response; and toxicity.

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Median follow-up after randomization was 31 months (range, 18-50) for this analysis. In total, 234 patients (21%) taking lenalidomide versus 226 (27%) in the observation group had died and the median OS had not been reached in either group.

No differences in OS were observed between the 2 groups; the 3-year OS rate was 78.6% (95% CI, 75.6%-81.6%) versus 75.8% (95% CI, 72.4%-79.2%) in the lenalidomide and observation groups, respectively. Rates of OS at 5 years were similar between the groups, with 61.3% (95% CI, 56.6%-66.1%) of patients in the lenalidomide arm and 56.6% (95% CI, 51.5%-61.7%) in the observation arm reaching this endpoint.

The trial met its secondary endpoint with a median PFS2 of 64 months (95% CI, 57-not reached) in patients treated with lenalidomide versus 45 months (95% CI, 41-50) with observation (HR, 0.65; 95% CI, 0.56-0.77;P<.0001) and this benefit was observed in both transplant-eligible and -ineligible patients. These data suggest that lenalidomide maintenance does not negatively impact the activity of subsequent treatment by selecting for more aggressive or drug-resistant myeloma clones and is supported by previous analyses indicating lenalidomide maintenance does not increase genomic change or mutational load.

Median duration of lenalidomide treatment was 18 cycles and dose modifications occurred in 781 patients (69%). A total of 564 patients discontinued lenalidomide treatment, including 320 (54%) who experienced disease progression or death, 167 (28%) who experienced adverse events (AEs), and 45 (8%) who preferred to stop treatment.

There were 1097 patients in the lenalidomide arm evaluated for AEs. Of that group, 494 (45%) experienced serious AEs compared with 150 (17%) in the observation group (n = 874); however, no deaths in the lenalidomide group were reported as treatment-related. The most common grade 3/4 hematologic AEs in the lenalidomide group were neutropenia in 362 (33%), thrombocytopenia in 72 (7%), and anemia in 42 (4%). The most common serious AEs in both groups were infections.

The 3-year cumulative incidence of second primary malignancies was higher with lenalidomide (5.3%; 95% CI, 3.6%-7.1%) compared with observation (3.1%; 95% CI, 1.8%-4.5%) and led to a higher 3-year cumulative incidence of deaths related to second primary malignancies in the lenalidomide arm (2.0% vs 0.9%).

PFS benefit was observed when patients were stratified by transplant eligibility status. In the transplant-eligible group, the median PFS was 57 months with lenalidomide versus 30 months in the observation group (HR, 0.48; 95% CI, 0.40-0.58;P<.0001). The median PFS was 26 months versus 11 months in patients who were transplant ineligible and receiving lenalidomide or observation therapy, respectively (HR, 0.44; 95% CI, 0.37-0.53;P<.0001).

A prespecified subgroup analysis by cytogenetic risk group found that lenalidomide improved PFS across all groups (standard-, high-, and ultra-high—risk cytogenetic groups). That benefit was seen when patients were further divided into transplant-eligible and -ineligible groups.

An improvement in 3-year OS was observed in patients who were transplant eligible and taking lenalidomide (87.5%) versus those on observation (80.2%; HR, 0.69; 95% CI, 0.52-0.93;P= .014). However, this benefit did not extend to those patients who were transplant-ineligible (66.8% vs 69.8% with lenalidomide and observation, respectively [HR, 1.02; 95% CI, 0.8-1.29;P= .88]).

By cytogenetic risk group, patients who were transplant eligible and considered ultra-high risk had the most benefit with lenalidomide with a 3-year OS rate of 43.5% compared with 62.9% in the observation group. No cytogenetic subgroup appeared to have improvements in OS with lenalidomide therapy if they were transplant ineligible.

&ldquo;Prespecified subgroups analyses by cytogenetic risk and transplantation status suggest a PFS benefit across all cytogenetic risk groups, and an OS benefit in transplantation-eligible patients,&rdquo; the investigators concluded.

Reference:

Jackson GH, Davies FE, Pawlyn C, et al; UK NCRI Haemato-oncology Clinical Studies Group. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol. 2019;20(1):57-73. doi: 10.1016/S1470-2045(18)30687-9.