Efficacy of Lenalidomide As Salvage Therapy for Patients with AL Amyloidosis

Current treatment approach to AL amyloidosis aims at the elimination of the plasma cell clone that produces the amyloidogenic light chains. Bortezomib-based regimens are used in most centers as primary treatment; however, there are limited data on the outcomes of patients with AL who fail bortezomib. Lenalidomide is a standard treatment for patients with myeloma who fail bortezomib. In patients with AL amyloidosis there data from mixed cohorts of previously untreated and pretreated patients, indicating that lenalidomide with dexamethasone with or without a third agent (cyclophosphamide or melphalan) is active but is not well tolerated at standard doses; however, data regarding the efficacy of lenalidomide specifically in patients with relapsing or refractory AL, especially after bortezomib, are limited. The aim of the current study was to evaluate lenalidomide as salvage therapy in consecutive patients with pretreated AL amyloidosis, in order to assess its efficacy and toxicity in this setting.

This analysis included 50 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis; all were diagnosed, treated and followed in the Department of Clinical Therapeutics, Athens, Greece. Definition of hematologic and organ response and progression was based on consensus criteria.

The median age was 63 years (range 42-82) and 67% were males. Heart was involved in 72%, kidneys in 75%, peripheral nerve in 33% and liver in 24%. At the time of initiation of lenalidomide, median eGFR was 53 ml/min/1.73 m2 and 12% were on dialysis; median NTproBNP was 2369 pg/ml and 21% were Mayo stage -1, 41% stage -2 and 38% stage -3. Median time from the start of primary therapy to lenalidomide was 14 months (range 1 to 108) and the median number of prior therapies was 1 (range 1-4), while, 72% of the patients had prior bortezomib: 42% were bortezomib refractory and 30% were potentially bortezomib sensitive (i.e. had responded to bortezomib and relapsed > 6 months after last bortezomib dose).

On intention to treat, hematologic response rate was 57% (5% CRs, 24% VGPRs and 28% PRs); was similar for patients with and without prior bortezomib (56% vs 58%) and was 38% vs 62% for bortezomib refractory vs non-refractory patients (p=0.084).

Organ responses were recorded in 10% of evaluable patients and included 11% renal responses and 8% liver responses; however, no cardiac responses were recorded based on NTproBNP criteria, probably due to increase of NTproBNP in most patients after start of lenalidomide therapy. Among patients not in dialysis, 10 (20%) eventually progressed to end stage renal disease requiring dialysis.

Median overall survival post lenalidomide initiation was 29 months. There was no difference in the survival of patients who were potentially bortezomib sensitive vs refractory (p=0.395); however, bortezomib naive patients had better survival, even after adjustment for Mayo stage (p=0.028).

Median dose of lenalidomide was 10 mg (range 5 to 15); no patient received the 25 mg dose. Median duration of lenalidomide therapy was 7.2 months (7 cycles) and 46% of the patients discontinued lenalidomide before completion of planned therapy. Main reasons to discontinue lenalidomide were disease progression/no response in 10%, toxicity in 26%, patient's or physician's decision in 10%, while 17% died while on therapy with lenalidomide due to AL-related complications. Common hematologic toxicities (≥Gr3) included thrombocytopenia in 6%, anemia in 15%, neutropenia in 6%. Most common non hematologic toxicities (≥Gr3) that led to dose reduction or early discontinuation of therapy were diarrhea in 9%, fatigue in 15%, skin rash in 15%, pneumonitis in 4%. Transient increases in serum creatinine (up to Gr1) were common; however, in 8% this was associated with acute renal failure.

We conclude that lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, with hematologic responses in 57% of patients, including patients who are refractory to bortezomib. However, organ responses were poor, probably because of the prolonged disease course which may have affected the ability of organ function recovery, at the time of initiation of lenalidomide, while NTproBNP based cardiac response criteria are challenging to use with IMiDs-based therapies. The toxicity of lenalidomide in patients with AL amyloidosis is significant and dose adjustments are commonly required.