Anthracyclines, such as doxorubicin, are effective and generally well tolerated when used in combination with bortezomib, thalidomide or lenalidomide (LEN) in multiple myeloma (MM). However, dose dependent cardiac toxicity is a limitation of anthracycline treatment. Amrubicin is a third generation anthracycline that is not associated with cardiac toxicity. No anthracyline-class related maximum cumulative dose of amrubicin has been established. Here we report the findings from the dose escalation portion of a phase I/II trial of amrubicin with LEN and dexamethsone (DEX) in patients with relapsed and/or refractory MM.
The primary objectives were to establish the maximum tolerated dose (MTD) and toxicity profile for the combination of amrubicin with LEN and DEX. Secondary objectives were to determine the overall response rate, progression free survival (PFS), and time to tumor progression. Patients with MM who had received ≥1 prior therapy, which may have included lenalidomide and/or an anthracycline, were eligible. Patients received amrubicin beginning with 40 mg/m2 intravenously on Day 1, LEN 15 mg orally daily on Days 1 to 14, and DEX 40 mg orally on Days 1, 8 and 15 of each 21 day cycle. Dose escalation of amrubicin proceeded using a standard 3+3 schema based on dose limiting toxicities (DLTs) occurring in cycle 1. There were 3 planned dose cohorts: 40 mg/m2, 60 mg/m2, and 80 mg/m2. Pegfilgrastim 6 mg was administered subcutaneously on Day 2. Prophylactic anticoagulation with aspirin or low molecular weight heparin was mandatory. Maximum treatment period was 4 cycles in the absence of unacceptable toxicity or disease progression as assessed after a minimum of 2 cycles. Patients who achieved a response or stable disease after 4 cycles continued on maintenance with LEN with or without DEX until disease progression or until toxicity occurred. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by current IMWG criteria.
Ten patients have been enrolled to date (cutoff: August 10, 2012). The MTD has not been reached. Currently patients are enrolling in the third and final dose cohort, which is receiving amrubicin 80 mg/m2. Patients had a median age of 62.5 years (range 51–77), and median ECOG performance status of 1. Nine patients had refractory disease at the time of enrollment, including 7 refractory to LEN. Nine patients were previously treated with a proteasome inhibitor, and 9 patients with an immunomodulator. Three patients had undergone autologous hematopoietic stem cell transplant (HSCT); 1 of these patients also underwent allogeneic HSCT. All patients had lytic bone lesions, and 7 patients had 4 or more lesions. One patient had high risk cytogenetics with a p53 mutation. Median cardiac ejection fraction was 59% at baseline. Patients received a median of 2 treatment cycles (range 1–4). Median follow up time was 3.25 months (range 0.25–11.75). Most commonly reported treatment related AEs included grade 1 GI symptoms such as dysguesia, anorexia, nausea, emesis, diarrhea, and constipation. One patient experienced grade 3 neutropenia, and 2 patients experienced grade 3 anemia. One patient was taken off study during cycle 1 due to reactivation of oral GVHD. One patient in the 3rd cohort was taken off study during cycle 1 due to DLTs, including grade 3 dizziness and diarrhea for 7 days. Cardiac ejection fractions were unchanged in all patients after completing treatment. No cardiac or thromboembolic events occurred. Five patients were evaluable for treatment response. Three patients completed 4 cycles of treatment; 1 patient had a partial response to treatment and went on to maintenance with LEN and DEX; 2 patients had stable disease on treatment, and elected not to continue maintenance. The remaining two patients had stable disease; one discontinued treatment after 2 cycles to pursue other treatment, the other discontinued treatment after 3 cycles in order to receive radiation therapy for pain management of lytic bone lesions. Median PFS for all patients was 4.25 months (range 0.75-NR). Median time to next treatment after discontinuing study drug was 1 month (range 0.25–5).
These data suggest that amrubicin in combination with lenalidomide and dexamethasone is overall well tolerated in this heavily pre-treated population. To date, toxicity has been manageable, and no cardiac toxicity has been observed.
Liedtke:Celgene: Research Funding.