Lenalidomide is an immunomodulatory drug with significant efficacy in relapsed and refractory multiple myeloma (MM) in combination with high or intermediate dose dexamethasone (RD). Previous studies in newly diagnosed patients (pts) showed that the combination of lenalidomide plus low dose dexamethasone (Rd) is associated with better overall survival (OS) and lower toxicity. However, there are no data comparing different dose of dexamethasone with lenalidomide in pts with relapsed or refractory myeloma.
To address this issue we analyzed, retrospectively, 102 consecutive pts with relapsed or refractory MM, treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece), who received lenalidomide with dexamethasone: 70 patients received lenalidomide and dexamethasone at a dose 40 mg PO, on days 1–4 and 15–18 for the first 4 cycles and only on days 1–4 thereafter (intermediate dose; group RD) and 32 pts who received lenalidomide and low dose dexamethasone (40 mg PO weekly; group Rd). Lenalidomide was administered on days 1–21 according to creatinine clearance (CrCl): 25mg/day for CrCl >50 ml/min, 10 mg/day for CrCl 30–50 ml/min, 15 mg every other day for CrCl 15–29 ml/min and for pts on dialysis 5 mg, once daily. RD and Rd were repeated every 28 days till disease progression or unacceptable toxicity. All pts received DVT prophylaxis with aspirin 100 mg/day except 18 pts (18%) who were already on coumadin or LMWH for other indications (atrial fibrillation, previous DVT, etc).
The median age of the pts was 67 years for RD and 69 years for Rd (p=0.36). There were no significant differences regarding the presence of specific cytogenetic abnormalities or high risk cytogenetics (p>0.3 for all comparisons). Patients in group RD were more heavily pretreated and had more often exposed to thalidomide (69% vs. 43%, p=0.013) or bortezomib (76% vs. 63%, p=0.1) and had more often thalidomide resistance (43% vs. 10%, p=0.001) or bortezomib resistance (46% vs. 20%, p=0.014). The number of prior therapies in group RD was 2 (range: 1–6) vs. 1 (range: 1–3) in group Rd (p=0.007), while 60% in RD vs. 30% in Rd were refractory to last line of therapy (p=0.006).
Pts in RD have received a median of 10 cycles (range: 1–44 cycles) and only 2 pts are still receiving therapy, while pts in Rd have received a median of 5 (range: 1–17) cycles but 21 (70%) continue to receive treatment. The median follow-up was 18 months (range: 1–58 months) for RD and 7.6 months (range: 1.9–23.6 months) for Rd. Responses, according to IMWG criteria, were not different among the two groups: in RD, CR (26%), PR (36%), SD (26%), PD (12%) and in Rd, CR (13%), PR (53%), SD (27%) and PD (7%). At least PR was observed in 32% of pts in RD and in 66% in Rd (p=0.45) of thalidomide-refractory pts, and in 45% in RD and 33% in group Rd (p=0.72) of bortezomib-refractory pts. The median progression-free survival (PFS) was 10 months (range: 1–55 months) for RD and has not been reached for Rd, but the 6-month PFS rate was 84% (p=0.003). The median time to next treatment was 11 months (range: 0.9–53 months) for RD and has not been reached for Rd. The OS was 18 months (range: 0.9–58 months) for RD and has not been reached for Rd, but the 1-year probability for OS was 81% (p=0.27). After adjustment for prior thalidomide and/or bortezomib resistance, disease refractory to last line of therapy and number of prior therapies, there was no difference for RD vs. Rd for OS (HR: 1.7, 95% CI 0.572–5, p=0.338) but Rd was associated with better PFS than RD (HR: 0.36, 95% CI 0.14–0.95, p=0.038).
We also evaluated the effect of treatment on renal impairment reversal. Twenty nine pts (40%) in group RD and 7 pts (23%) in group Rd had an eGFR, calculated by the MDRD formula, of <60 ml/min. Seven patients (25%) from group RD and none from group Rd achieved renal response (p=0.199), according to the IMWG criteria.
More patients treated with RD developed grade ≥3 neutropenia (23% vs. 3%) and fatigue ≥grade 3 (15% vs. 3%); 3 pts from group RD developed thrombosis (2 patients DVT and one pulmonary embolism) vs. none with Rd. Other toxicities occurred with similar frequency between RD and Rd.
This is the first analysis, which compared the role of intermediate and low dose dexamethasone with lenalidomide in pts with relapsed or refractory myeloma. Our data indicate that Rd is probably as effective as RD, while it may be better tolerated. Updated results regarding OS and PFS as well as renal recovery will be presented at the meeting.
Dimopoulos:Celgene: Honoraria. Terpos:Celgene: Honoraria.
Asterisk with author names denotes non-ASH members.