Background: Two pivotal phase 3 trials (MM-009 and MM-010) randomized 704 pts to assess Len+Dex vs placebo plus dexamethasone (Dex) in RRMM. The results demonstrated the significant overall survival (OS) benefit of Len+Dex vs Dex (38.0 vs 31.6 mos; p = .045) despite crossover of 48% of Dex pts to the Len+Dex arm at unblinding or progression (Dimopoulos MA et al. Leukemia 2009;23:2147-52). This is an analysis of the long-term outcomes and safety of continuous Len+Dex treatment.
Methods: This retrospective analysis pooled pts treated with Len+Dex in MM-009 and MM-010, with a median follow-up of 48 mos for surviving pts. A subset of pts with progression-free survival (PFS) of ≥ 2 yrs was selected. Prognostic factors for PFS within this subgroup of pts were identified by incorporating all baseline covariates with a univariate p < .15 into multivariate Cox regression analyses, and all possible models were fitted using SAS 9.2. Adverse event (AE) management and dosing for pts with PFS ≥ 2 yrs was compared with that for all pts treated with Len+Dex in order to evaluate if differences in pt management could contribute to better clinical outcomes. Incidence rates for AEs were calculated using person-yrs of follow-up. Data from pts who received Len+Dex in MM-009 (up to July 23, 2008) and MM-010 (up to March 2, 2008) were included in this analysis.
Results: Among all pts treated with Len+Dex (N = 353), a total of 64 pts (18%) achieved PFS ≥ 2 yrs. For these 64 pts, median age was 61 yrs (range 33–81 yrs), 48% received > 1 prior therapy, and 57% had β2-microglobulin levels of ≥ 2.5mg/L. All these pts achieved a ≥ partial response (PR), including 67% with a ≥ very good PR and 50% with a complete response. Median time to first response was 2.8 mos (range 1.9–18.2 mos) which is comparable to that of all pts treated with Len+Dex. Median duration of response was not reached vs 15.5 mos, respectively. With median follow-up of 49 mos, the 3-yr OS is 94% (95% confidence interval [CI] 88.06–99.94). In a multivariate Cox regression analysis, shorter PFS was predicted with higher baseline β2-microglobulin level (hazard ratio [HR] 1.07; 95% CI 1.02–1.12) and lower hemoglobin (HR 0.91; 95% CI 0.84–0.99), as well as a higher number of prior therapies (HR 1.18; 95% CI 1.02–1.37).
The median duration of treatment was longer among pts with PFS ≥ 2 yrs vs all pts treated with Len+Dex (46.2 mos [range 11.3–58.3] vs 9.8 mos [range 3.8–24], respectively). A higher proportion of these pts had a dose reduction within 12 mos after start of therapy vs all pts treated with Len+Dex (57% vs 24%, respectively). Dex dose was reduced in 27% of pts with PFS ≥ 2 yrs. Among pts without Len dose reduction, 31% had Dex dose reduction within the first 4 cycles. Granulocyte colony-stimulating factor was administered for the management of neutropenia in 39% of pts with PFS ≥ 2 yrs vs 25% of all pts treated with Len+Dex. Low discontinuation rates due to AEs were observed in both groups (12.5% vs 18.7%, respectively).
The incidence rates per 100 person-yrs for grade 3–4 AEs among pts with PFS ≥ 2 yrs vs all pts treated with Len+Dex (N = 353) were, respectively: neutropenia (14.9 vs 29), febrile neutropenia (0.9 vs 2.3), thrombocytopenia (2.6 vs 10.2), anemia (4.4 vs 9.5), infection (11.8 vs 20.9), deep vein thrombosis/pulmonary embolism (2.2 vs 8.9), fatigue (2.2 vs 5.5), neuropathy (1.8 vs 3.4), and gastrointestinal disorders (5.3 vs 9.7).
The incidence rates per 100 person-yrs for second primary malignancies (SPMs) were similar to that of all pts treated with Len+Dex, respectively: myelodysplastic syndromes (0 vs 0.4), solid tumor (1.8 vs 1.3), and non-melanoma skin cancer (2.3 vs 2.4). These rates are comparable to those expected in people aged > 50 yrs generally (1.4 per 100 person-yrs) (Altekruse SF et al. SEER Cancer Statistics Review, 1975–2007).
Conclusions: Long-term continuous therapy with Len+Dex has demonstrated efficacy and is generally well tolerated in pts with RRMM. Overall, 18% of patients treated with Len+Dex achieve a PFS of > 2 yrs. No increase in SPMs was observed with long term Len+Dex therapy. With appropriate AE management, the incidence rates of grade 3–4 AEs remain low. This analysis demonstrates the value of AE management and the need for appropriate dose-adjustment to maintain tolerability, allowing pts to remain on therapy for maximal benefit.