High-Dose Pomalidomide and Dexamethasone Induce Rapid Responses In Patients With AL Amyloidosis Exposed To Alkylators, Immune Modulatory Drugs, and Proteasome Inhibitors
Authors: Palladini Giovanni , Milani Paolo , Rosin Marta Vidus , Foli Andrea , Merlini Giampaolo 
Published: October 2019

Abstract
In the present trial (NCT01510613) we treated with the combination of pomalidomide and dexamethasone (PDex) 27 patients previously exposed to alkylators and bortezomib. All the patients were refractory to the last line of therapy performed. The median number of prior treatments was 2 (range: 1-7). Seven patients (26%) also received lenalidomide, 4 (15%) thalidomide, 3 (11%) ixazomib, 2 (7%) bendamustine, and six (22%) underwent autologous stem cell transplant. Pomalidomide was administered continuously in 28-day cycles. A standard 3 + 3 dose escalation scheme was adopted: since no dose limiting toxicity was observed in the first 3 patients treated with pomalidomide 2 mg/day, the remaining received 4 mg/day. Dexamethasone was administered at 40 mg weekly, and at 20 mg in 13 subjects who had baseline fluid retention >3% of body weight and / or repetitive ventricular arrhythmias at Holter electrocardiography. Prophylactic aspirin was also administered. Nineteen (68%) patients had heart involvement and 8 (29%) were stage 3. The kidney was involved in 11 patients (39%), the soft tissues in 5 (18%), and 4 subjects (14%) had peripheral neuropathy. The median number of PDex cycles performed was 3 (range: 1-9), and treatment is ongoing in 20 patients. Overall 18 patients (67%) experienced severe (grade 3-4) adverse events: neutropenia (8, 30%), fluid retention (7, 26%, all with heart involvement), infection (3, 11%), worsening neuropathy (2, 7%, all with peripheral nervous system involvement), and rash (2, 7%). Five patients (18%) discontinued treatment due to adverse events. Overall, 18 patients (67%) achieved a hematological response, with 5 (18%) very good partial responses. Importantly, the median times to first response and to best response were 1.1 and 3.0 months, respectively. Moreover, of the 7 patients previously exposed to lenalidomide 5 responded to pomalidomide, and the 3 patients who were refractory to ixazomib responded, indicating that pomalidomide can overcome resistance to other immune modulatory drugs and a second-generation proteasome inhibitor. As previously reported with other immune modulatory drugs, pomalidomide was associated with a median 116% increase in NT-proBNP during cycle 1, preventing the assessment of cardiac response according to current criteria. A renal response was achieved in 3 of the 11 patients (27%) with kidney involvement. With a median follow-up of 6 months, 1 patient died 5 months after enrollment due to heart failure.
“High-dose” (4 mg/day) pomalidomide combined with dexamethasone induces a high rate of rapid responses in patients previously exposed to alkylators, other immune modulatory drugs, and proteasome inhibitors, representing a powerful and rapid rescue treatment in AL amyloidosis. Further studies are warranted to elucidate whether different dosing schedules based on high-dose induction followed by low-dose (2 mg/day) maintenance might retain the high response rates and rapid action, while improving tolerability.

Disclosures:
Off Label Use: Pomalidomide in AL amyloidosis. Merlini:Millennium-Takeda: Honoraria; Pfizer: Honoraria.