A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis

A rapid and profound reduction of amyloid-forming circulating free light chains (FLCs) is the key to improving the outcome of patients with light-chain (AL) amyloidosis.¹  Thalidomide and lenalidomide are effective, particularly in relapsed/refractory patients.^2-5  The immunomodulatory agent pomalidomide is active in patients with relapsed/refractory multiple myeloma, including those who failed to respond to prior treatment with lenalidomide and bortezomib.⁶  Most patients with AL amyloidosis are currently treated upfront with combinations of alkylating agents and bortezomib.¹  Although these regimens are highly effective, there is a need for active rescue options in patients who fail to respond.^7,8  Two independent trials showed efficacy of pomalidomide in AL amyloidosis; hematologic response occurred in 48% to 50% of patients.^9,10  However, these studies could not show an impact of response on survival. We designed the present phase 2 trial to assess the efficacy, safety, and impact on survival of the combination of pomalidomide and dexamethasone (PDex) in patients with AL amyloidosis treated upfront with bortezomib and an alkylating agent.

Key eligibility criteria included the following: prior treatment with alkylating agents (melphalan or cyclophosphamide) and bortezomib (relapsed/refractory patients who could not be treated with alkylators and/or bortezomib due to contraindications were also eligible); difference between amyloidogenic (involved) and uninvolved FLCs (dFLC) > 50 mg/L; and adequate renal (estimated glomerular filtration rate ≥ 30 mL/min) and cardiac (New York Heart Association Class < IV) function. The primary end point was hematologic response at 3 months by intent-to-treat according to current criteria.¹¹  Secondary end points were rate and severity of adverse events, quality of hematologic response, organ response according to validated criteria,^11,12  and survival. A 3 + 3 dose-escalation design was used (detailed in the supplemental Material, available on the Blood Web site). Pomalidomide was administered continuously in 28-day cycles, and dexamethasone was given once per week at a dose of 40 mg (20 mg in cases of severe fluid retention and/or repetitive ventricular arrhythmia) until disease progression or unacceptable toxicity. Prophylactic cotrimoxazole, omeprazole, and aspirin were administered. Criteria for disease progression and statistical methods are reported in the supplemental Material. The study was approved by the Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Review Board, and all patients gave written informed consent.

Between June 2012 and November 2013, 28 patients were enrolled. Their clinical characteristics are reported in Table 1. Median time from diagnosis was 16 months. In the dose-escalation phase, 3 patients received pomalidomide 2 mg/d, and the following 3 patients received 4 mg/d. No dose-limiting toxicity was observed. The maximum tolerated dose was 4 mg/d, and was administered to the subsequent 22 patients. A total of 227 cycles were delivered. The median number of cycles per patient was 6 (range, 1-30). Dexamethasone was started at 20 mg/wk in 12 patients (43%).

Thirty-one grade 3 to 4 adverse events were recorded (supplemental Table 1) in 15 patients (54%); the most common were fluid retention (25%), infection (25%), atrial fibrillation (7%), and deep vein thrombosis (7%). The most common grade 1 to 2 adverse events were fever (15 patients; 54%), neutropenia (12 patients; 43%), skin rash (4 patients; 14%), and worsening peripheral neuropathy (2 patients; 7%). The pomalidomide dose was reduced in 9 patients (32%), and dexamethasone was reduced in 10 patients (36%). Dose reductions were not associated with clinical, biochemical, and echographic markers of heart involvement. Treatment was discontinued as a result of disease progression in 14 patients (50%), adverse events in 8 patients (29%), patient choice in 3 patients (11%), and achievement of durable complete response in 1 patient (4%). Two patients are receiving treatment after 28 and 30 cycles, having achieved a very good partial response (VGPR) and partial response (PR), respectively.

After cycle 3, 17 patients (61%) achieved hematologic responses; PR was achieved in 10 patients (36%) and VGPR in 7 patients (25%). Hematologic response rate and quality improved during treatment (Figure 1A). The best responses were achieved by cycle 7 in 19 subjects (68%; 95% confidence interval, 49% to 83%), and included complete response in 1 patient (4%), VGPR in 7 patients (25%), and PR in 11 patients (39%). With a single exception, treatment resulted in a dFLC decrease in patients who did not meet response criteria (Figure 1B). Hematologic responses were seen in 6 of 7 patients (86%) who received prior lenalidomide, and in 3 of 4 subjects (75%) who were exposed to ixazomib. Treatment was associated with a median 116% increase of N-terminal pronatriuretic peptide type B, and this prevented the assessment of cardiac response. A renal response was observed in 2 of 12 evaluable patients (17%), one who achieved VGPR and one who achieved PR.

The median follow-up of living patients is 44 months. Overall, 19 patients (68%) died and 23 (82%) experienced hematologic progression according to the protocol criteria. There were no deaths in the first 100 days. Median overall and progression-free survival were 26 and 16 months, respectively (Figure 1C). Hematologic response significantly improved overall survival (Figure 1D; median 36 vs 19 months in a 6-month landmark analysis; P = .001). Patients with high concentrations of cardiac troponin I (best cutoff > 0.04 ng/mL) and N-terminal pronatriuretic peptide type B (best cutoff > 1300 ng/L) at the time of treatment initiation had shorter overall survival (median 20 months vs not reached with both biomarkers; P = .016 and P < .001, respectively). Hematologic progression predicted overall survival (median of 25 months in patients who progressed, no deaths observed in nonprogressing patients; P = .013).

The PDex combination was highly effective, with a 68% response rate, in patients who had been extensively exposed to currently available chemotherapy agents, including alkylators, first- and second-generation proteasome inhibitors, and other immunomodulatory drugs. The hematologic response rate observed in the present study (68%) compares favorably with that reported by the Mayo Clinic (48%)⁹  and Boston University (50%)¹⁰  groups, although with an overlap in confidence intervals due to small numbers. This might be a result of the greater proportion of patients initially exposed to full doses of pomalidomide and dexamethasone. However, dose reductions were frequent in our study, and lower pomalidomide doses could be better tolerated in fragile patients with AL amyloidosis. Moreover, the proportion of patients in the Mayo Clinic, Boston University, and present studies who had undergone previous transplantation (48%, 59%, and 21%, respectively) and patients exposed to proteasome inhibitors (42%, 78%, and 100%, respectively) also differed, and these differences may have affected responses to pomalidomide. Importantly, responses were rapid and were achieved after a single cycle in 53% of responders. Unlike in previous studies, the longer follow-up of the present trial, and possibly differences in prior treatment exposure and in the availability of newer rescue agents, allowed demonstration of a survival benefit for responders even in heavily pretreated patients, indicating the need to actively pursue hematologic responses in this setting.

Toxicity was manageable and the maximum tolerated dose was 4 mg/d, in agreement with the Boston University data.¹⁰  The rate of thromboembolic events (2 of 28 patients; 7%), although comparable with Mayo Clinic data,⁹  was higher than that reported in multiple myeloma (1% to 3%)¹³  and in the Boston University study (among 27 patients, no thromboembolic events were reported).¹⁰ 

In our study, the severity of cardiac dysfunction remained a powerful prognostic determinant, indicating the need to improve on the problem of organ damage that persists after chemotherapy.¹⁴  Importantly, hematologic progression, defined with criteria (reported in the supplemental Material) compatible with the current revised response categories, predicts overall survival in AL amyloidosis. This observation and the availability of newer effective drugs such as daratumumab¹⁵  support early treatment of hematologic relapses in patients who have been exposed to several lines of therapy. The validation of hematologic progression criteria in larger studies is warranted.

The present study shows that PDex is an effective treatment in relapsed/refractory AL amyloidosis. The high rate of rapid responses suggests that pomalidomide can have a role in combination with other agents in upfront treatment.

The authors acknowledge the study coordinators Anna Carnevale Baraglia and Claudia Sforzini.

This work was supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro Molecular Clinical Oncology Special Program 5 per mille (9965), and by grants from the Fondazione Cariplo (2013-0964 and 2015-0591). Celgene provided the study drug.

Contribution: G.P. designed the study, evaluated patients, collected data, analyzed data, wrote the manuscript, and gave final approval; G.M. designed the study, evaluated patients, critically reviewed the manuscript, and gave final approval; P.M. evaluated patients, collected data, analyzed data, critically reviewed the manuscript, and gave final approval; M.B., F.R., A.F., and S.P. evaluated patients, collected data, critically reviewed the manuscript, and gave final approval.

Conflict-of-interest disclosure: G.P. received honoraria from Jannsen-Cilag, honoraria and travel support from Prothena, and travel support from Celgene. G.M. is a consultant for Millennium Pharmaceuticals, Pfizer, Janssen, Prothena, and ISIS Pharmaceuticals. The remaining authors declare no competing financial interests.

Corresponding author: Giovanni Palladini, Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Viale Golgi, 19, 27100 Pavia, Italy; e-mail: giovanni.palladini@unipv.it.