Lenalidomide Combined With Cyclophosphamide and Dexamethasone Is Effective and Well Tolerated Induction Treatment For Newly Diagnosed Myeloma Patients Of All Ages
Authors: Pawlyn Charlotte , Brioli Annamaria , Gregory Walter , Hinsley Samantha , Lindsay Jindriska , Cook Gordon , Milligan Donald , Chapman Claire , Owen Roger G , Drayson Mark T , Russell Nigel , Jackson Graham H , Davies Faith E , Morgan Gareth J 
Published: October 2019

Abstract
Lenalidomide is an excellent option for induction therapy for myeloma due to its oral administration and lack of significant peripheral neuropathy when compared with bortezomib and thalidomide. Triplet combinations containing novel agents have been shown to be more effective than doublets or single agents, whilst there is little additive benefit from quadruplets without increasing toxicity. Lenalidomide has been combined in the older population with melphalan and prednisolone but this has raised concerns due to the rates of cytopenias and the possibility of increasing second primary malignancies (SPMs).
We have studied the combination cyclophosphamide, lenalidomide and dexamethasone (CRD) in relapsed patients (Morgan et al, BJH, 2007; Schey et al BJH, 2010) and found it well tolerated and highly effective (ORR 65-81%), giving better responses than would be expected with RD alone.
We therefore designed a trial, Myeloma XI, which compared responses to cyclophosphamide, lenalidomide and dexamethasone (CRD) with cyclophosphamide, thalidomide and dexamethasone (CTD) given to maximum response or intolerance. Younger/fitter patients received cyclophosphamide 500mg (p.o. D 1,8), lenalidomide 25mg (p.o. D1-21) and dexamethasone 40mg (p.o. D1-4, D12-15) as part of a 28 day regimen on the intensive pathway whilst older/less fit patients received attenuated doses of dexamethasone, 20mg (p.o. D1-4, D15-18) on the non-intensive pathway (CRDa). Patients achieving no response (NC or PD) after a minimum of 4 cycles received further therapy with a triplet composed of cyclophosphamide, bortezomib and dexamethasone (CVD), those with a suboptimal response (MR or PR) were randomised to either no further therapy or to CVD and those achieving ≥ VGPR received no further induction. Younger/fitter patients went on to receive high dose melphalan (HDM) plus ASCT whereas older/less fit patients did not. The trial is ongoing and to date has recruited 1310 patients to the intensive pathway (650 CRD vs 660 CTD, median age 61 years, range 28-75) and 1058 to the non-intensive (531 CRDa vs 527 CTDa, median age 74 years, range 51-89).
The overall response rate (≥PR) at the end of lenalidomide induction for those currently evaluable in the intensive pathway is 83% (CR 16%, VGPR 42%, PR 24%, n=389) and in the non-intensive pathway 73% (CR 17%, VGPR 34%, PR 21%, n=289). Given that those patients with <VGPR undergo a further randomisation to possible further induction therapy with bortezomib we anticipate, based on previous analysis, that this will translate into rates of ≥VGPR at the end of induction of 64% and 57% respectively which compares very favourably to response rates seen when immunomodulatory drugs and proteasome inhibitors are given in combination.
CRD was well tolerated with patients receiving a median of 5 cycles in the intensive pathway and 6 cycles in the non-intensive pathway. 61% (236/389, intensive) and 74% (206/279, non-intensive) of patients required a dose reduction of at least one drug but this did not affect their ability to remain on treatment with only 5% (18/389) and 11% (30/279) respectively failing to complete the minimum number of cycles stipulated in the protocol due to toxicities. Dose density was maintained with 62% of patients receiving all doses with no delay. Overall 12% of treatment cycles given had a delay either between or within cycles but of these 93% were delays of less than 3 days.
In the lenalidomide treated population available for safety analysis (n=907) the most common grade 3/4 toxicities were cytopenias with slightly higher rates seen in the older/less fit population (neutropenia 20% vs 33%, thrombocytopenia 5% vs 10% and anaemia 10% vs 17%). Only 1.1% of patients developed grade 3/4 peripheral motor or sensory neuropathy and there were a total of 22 PEs reported (2%) with no difference between the pathways. In the randomised population treated with lenalidomide, (n=1181) treatment related mortality was 0.4% and the incidence of SPMs was low at 0.7% with a median follow up of 1.36 years which may reflect the significantly lower mutagenicity of cyclophosphamide than melphalan.
These preliminary results suggest that the combination of lenalidomide, cyclophosphamide and dexamethasone is effective as induction treatment and has a good safety profile in myeloma patients of all ages.
On behalf of the NCRI Haemato-oncology subgroup

Disclosures:
Pawlyn: Celgene: travel support, unrestricted educational grant Other. Off Label Use: Lenalidomide and vorinostat as maintenance treatment for myeloma. Brioli:Celgene: Honoraria, unrestricted educational grant Other. Gregory:Celgene: unrestricted educational grant Other. Hinsley:Celgene: unrestricted educational grant Other. Lindsay:Celgene: unrestricted educational grant Other. Cook:Celgene: unrestricted educational grant Other. Milligan:Celgene: unrestricted educational grant Other. Chapman:Celgene: unrestricted educational grant Other. Owen:Celgene: unrestricted educational grant Other. Drayson:Celgene: unrestricted educational grant Other. Russell:Celgene: unrestricted educational grant Other. Jackson:Celgene: Honoraria, unrestricted educational grant Other. Davies:Celgene: Honoraria, Speakers Bureau, unrestricted educational grant Other; Jansen: Honoraria, Speakers Bureau. Morgan:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, unrestricted educational grant Other; Merck: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.