Use of Lenalidomide May Surmount the Adverse Prognosis Induced by Renal Impairment In Patients (pts) with Relapsed/Refractory Multiple Myeloma (MM)

Current goals in MM treatment are to achieve prolonged remission- and treatment-free-intervals and to transform the disease into an indolent course. Renal impairment is a dreaded complication in MM and has formerly been associated with decreased progression free- (PFS) and overall-survival (OS) - at least with standard-MM-agents. Lenalidomide is an effective novel substance, recently suggested to overcome the adverse prognostic impact of renal impairment in MM to a similar extent as other agents, therefore the current study was undertaken to further evaluate the impact of lenalidomide treatment on PFS and OS of MM pts with varying degrees of renal impairment.

Forty-five consecutive MM pts received lenalidomide with dose modification according to current guidelines in G1-4 treatment groups (G1: lenalidomide 25mg+dexamethasone (dex) 40mg [n=19]; G2: lenalidomide 25mg+low-dose dex [n=10]; G3: lenalidomide 10mg [n=11]; G4: lenalidomide 10–15mg plus chemotherapy [n=5]) in our department between 2006 and 2010. Serum creatinine and eGFR were determined before lenalidomide treatment and after 1, 3 and 6 months. Renal function was defined via NKDOQI guidelines and response according to EBMT.

The median pt age was 66 years (range: 44–78), with predominantly stage II/III disease according to Durie-Salmon (97%) and ISS (71%). Pretreatment before lenalidomide initiation was substantial: ≥2 previous therapy lines had been performed in 71% and autologous or allogeneic SCT in 49% and 11% of pts, respectively. Lenalidomide induced an overall response rate (ORR: CR+PR) in 27% (n=12) and clinical benefit rate (CBR=CR+PR+MR) in 37% (n=14). Median PFS and OS for all pts were 13 and 25 months, respectively, which is consistent with the results of both lenalidomide/dex-FDA-approved studies, albeit our pt cohort was older and more pretreated. Lenalidomide was well tolerated as previously reported. Although baseline renal function appeared normal with a median creatinine of 1.0mg/dl (range: 0.6–2.7), mild renal impairment was readily detectable via eGFR measurement (median 80ml/min/1.73m²; range: 25–119). Of note, eGFR <90 and <60ml/min/1.73m² before lenalidomide-initiation was prominent, with 64% and 29%, respectively. Within various eGFR groups of ≥ vs. <90, 80, 70, 60 and 50ml/min/1.73m², and creatinine groups of ≥ vs. < 0.9, 1.0, 1.1, 1.3 and 1.4mg/dl median PFS as well as 1- and 2-year PFS rates were similar in pts without or with renal impairment. With eGFR-changes of 10ml/min/1.73m² and serum creatinine-changes of 0.1mg/dl, hazard ratios (HR) were 0.973 (95% CI: 0.849–1.115, p=0.6927) and 0.989 (95% CI: 0.923–1.059, p=0.7538) for PFS, respectively. For OS, HR were 0.839 (95% CI: 0.708–0.994, p=0.0421) and 1.047 (95% CI: 0.972–1.128, p=0.2253), respectively. This data and our HR suggest that large PFS and OS differences under lenalidomide treatment were unlikely existing between pts with vs. without renal impairment, albeit this does not exclude smaller differences detectable with larger pt scrutiny. In order to also determine reasons for and the implications of initial eGFR declines as compared to pts with improved renal function under lenalidomide, we compared pts who displayed decreasing vs. increasing eGFR. After 1 month of treatment, we observed no differences in specific pt characteristics, but notably more pts staying longer on lenalidomide-therapy and showing an ORR of 42% vs. 20% with decreasing vs. increasing eGFR, respectively. After 6 months, ORR in pts with decreased vs. increased eGFR was 8% vs. 47%, respectively, suggesting that an initial eGFR decline does not impair therapy efficacy, whereas after 6 months the group comparison suggested that pts with persistent renal impairment constitute a pt group with a more unfavourable prognosis.

Our results underline that treatment with lenalidomide is feasible and well tolerated in elderly and intensively pretreated MM pts, including pts with renal impairment. We suggest that consequent measurement of eGFR - rather than solely via traditional serum creatinine - may predict therapy response. Group comparison of different eGFR and creatinine subgroups indicated that lenalidomide can reverse the adverse prognosis of renal impairment in MM pts with hematological and renal treatment response.

Kleber:Celgene: educational grant. Engelhardt:celgene: educational grant.