Pomalidomide and Dexamethasone in Patients with Relapsed AL (Light Chain) Amyloidosis: Results of a Phase 1 Study

Background: Immunomodulatory agent, lenalidomide, has shown to induce hematologic response and improve survival in patients with relapsed AL amyloidosis. Pomalidomide, a third generation immunomodulatory agent, was studied in combination with low dose dexamethasone in a prospective phase I/II study of patients with relapsed AL amyloidosis (NCT01570387).

Methods: Patients were aged ≥18 years with relapsed AL amyloidosis after ≥1 prior therapy, and measurable plasma cell dyscrasia with dFLC of > 50 mg/L (difference between involved and uninvolved free light chain levels), at least one major vital organ involvement and serum creatinine of < 3.0 mg/dL, received pomalidomide in a standard 3+3 dose escalation design on days 1-28 of 28 day cycles for cohort 1 (2 mg) and 2 (3 mg), and days 1-21 of the cycle for cohort 3 (4 mg). Low dose dexamethasone was administered at 20 mg orally once a week. All patients received prophylaxis with daily aspirin and proton pump inhibitor. MTD was defined as the highest dose resulting in DLT during cycle 1 in < 1 of 6 patients. Hematologic and organ responses were measured at 3 cycles after treatment. Treatment was continued till progression or toxicity or achievement of a hematologic complete response. An expansion cohort of 12 patients is to be enrolled at the MTD. The objectives were to determine the safety, tolerability, MTD, recommend phase 2 dose and hematologic and clinical response.

Results: At data cut-off (July 31, 2014) 16 patients have been enrolled and 15 patients have been enrolled in phase I part of the study. The median age was 69 years (range, 44-78), and median number of prior therapies was 2 (range, 1-6): 10 (63%) had received HDM/SCT, 10 (63%) had received lenalidomide, and 13 (81%) bortezomib. The median time from diagnosis to enrollment on this trial was 30 months. The median number of organ system involvement was 2 (range, 1-5). Eleven patients (68%) had >2 organ system involvement, 9 patients with renal and 11 patients with cardiac involvement. Thirteen (81%) patients had cardiac biomarker stage II or III disease. Six patients were treated in the 2 mg cohort (this cohort expanded due to grade 3 renal failure in cycle 3 in one of first 3 patients) and 3 were treated in the 3 mg and 6 in the 4 mg cohort (this cohort expanded due to grade 3 pneumonia with neutropenia in cycle 1 considered as DLT). There were two on-study death due to GI bleeding/sepsis and Legionella pneumonia/sepsis, respectively. Twelve patients have discontinued study treatment due to disease progression (n=5), withdrawal by patient (n=2), hematologic CR (n=3) or death (n=2). Median number of cycles administered is 5 and 4 patients continue on therapy. There was one DLT in cohort 3 of grade 3 pneumonia with neutropenia, establishing 4 mg/day of pomalidomide Days 1-21 of 28 days cycle as MTD. Twelve patients (75%) experienced at least one grade ≥3 AE (any cause). The most common drug-related AEs included fatigue (69%) and anemia (87). There was paradoxical increase of BNP by 30% in 11 patients (69%) after 1 cycle and in 13 patients (81%) after first 3 cycles of therapy. In phase I part of the study, hematologic complete response was observed in 3 of 14 evaluable (completing at least 3 cycles) patients at 3 months (n=2) and 9 months (n=1) of treatment respectively. Hematologic partial response was observed in 3 additional patients.

Conclusions: Pomalidomide and dexamethasone treatment is feasible in patients with relapsed AL amyloidosis, with MTD defined as 4 mg/day Days 1-21 of 28 day cycle. Phase II expansion cohort accrual is ongoing at MTD of 4 mg/day of Pomalidomide D1-21 and Dexamethasone 20 mg weekly every 28 days. Preliminary data suggests a hematologic response of > PR in 43% of patients.

This clinical trial was partly supported by Celgene Corporation.