A Systematic Review on Efficacy and Safety of Lenalidomide Based Regimens for Treatment of Newly Diagnosed Amyloidosis
Authors: Ahmad Muhaddis Ejaz , Yousaf Muhammad Abdullah , Malik Mustafa Nadeem , Rafae Abdul , Syed Tariq Iqtidar Sadiq , Abdullah Syed Maaz , Shah Zunairah , Qamar Fazeel , Ibrahim Ahmed , Anwer Faiz 
Published: November 2019

Introduction:
Lenalidomide (L), a commonly used drug for the treatment of Multiple Myeloma, but currently it is not being not used as front line agent for the treatment of AL amyloidosis. It works through various mechanism, can cause direct toxicity to plasma cells, inhibits angiogenesis, and promotes tumor apoptosis. Cyclophosphamide (Cy), causes cross links between DNA which leads to cell apoptosis. For last decade, Cy is being used in combination with agents like Velcade for more than and decade, there is paucity of literature about its use in combination with L. L based regimen may be necessary in patients who have contraindications to bortezomib use, additionally targeted immunotherapy based combinations with daratumumab, through NK cell mediated cytotoxicity, may be more effective in the presence of immunomodulatory drugs. Our main objective is to analyze the published literature for the efficacy and toxicity of L based regimens for the treatment of newly diagnosed Amyloidosis (ND-AL).
Methods:
A systematic search of databases using (per PRISMA guidelines) PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed from January 2012 onward, with no restrictions of publication language. A total of 649 articles were identified initially and after a detailed screening, we finalized 9 studies involving 223 ND-AL patients.
Results:
Lenalidomide, dexamethasone, Cyclophosphamide (LCyD):
In a phase II trial by Ciberia et al, (n=28) ND-AL patients (pts) were treated with LCyD. Overall hematological response (OHR) was 46% with complete response (CR) in 25%, very good partial response (VGPR) in 18% and partial response (PR) in 3% pts. Organ response (OR) was 46% with maximum pts. showing response in kidney (43%) and heart (26%). In a study by Kastritis et al., involving 24 pts, LCyD induced, OHR was observed in 55% pts with CR in 8 % (Table 1). For comparison with regimens like Cy, Bortezomib and Dexamethasone (CyBorD), in a retrospective study by Hong et al., 24 pts were given CyBorD. OHR was 89% with CR, VGPR and PR demonstrated in 55%, 33% and 10% pts respectively. 5-yr OS was 80% and 5-yr PFS was 69% (Table 1). Mikhael et al., reported 17 pts given CyBorD. OHR was 94% with CR in 71% and PR in 24% pts. Venner et al., et al. (n=43) reported 20 patients of ND-AL treated with CyBorD showed OHR of 81.4%, with CR in 41.9% and PR in 39.5%. 46% pts showed OR. Chari et al. reported 9 pts. who were given extensive combinations of Cyc and L. OHR was 88%, with CR in 22% and PR in 66% pts. 77% pts showed an OR (Table 1).
Induction with L prior to High dose Melphalan (HDM) and stem cell transplant (SCT) vs front line HDM/SCT:
In a study by Cowan et al., (n=45) pts in group A (n=21) received induction therapy using novel agent induction using agents like Bortezomib and Lenalidomide prior to HDM/SCT. CR was observed in 50%, VGPR in 7% and PR in 7% pts. Group B (n=24) pts were given HDM/SCT upfront. CR was observed in 28%, VGPR in 14% and PR in 14% pts. Similarly study by Scott et. al., 31 pts who received HDM consolidation were categorized in 3 groups i.e no induction, induction with V-based regimen and induction with other regimens including L. In pts with len/dex (n=2) OHR was 100%, with CR observed in 100% pts (Table 1).
Melphalan (M), Lenalidomide (L) and Dexamethasone (d):
In a clinical trial (NCT00890552), 25 pts who were given L, M and d, showed a CR of 8%, VGPR of 16% and PR of 33% pts. mOS was 12 mo (Table 1).
Conclusion:
There is paucity of literature about the use of Lenalidomide for the treatment of newly diagnosed AL patients. In ND-AL pts, CyBorD and as well as Lenalidomide/dexamethasone-based regimens has shown excellent overall hematological responses (up to 100%). Major adverse effects were anemia, thrombocytopenia, neutropenia and rash. We recommend, with adequate sample size, prospective studies need to be conducted for better understanding of efficacy and safety of L based therapies in newer combinations for the treatment of AL Amyloidosis. With good efficacy and tolerance data to support its use, Lenalidomide may have a potential role for its use as an induction agent, salvage therapy as well as post induction long term term maintenance therapy for select AL amyloidosis cases who cant achieve complete remission with induction and / or consolidation regimens.

Disclosures
Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.