Sequential Immunomodulatory Drug (IMiD) and Proteosome Inhibitor Therapy Improves Response Rates in Newly Diagnosed Multiple Myeloma: Preliminary Results From the Myeloma XI Trial
Authors: Pawlyn Charlotte , Davies Faith E. , Gregory Walter M , Szubert Alex J , Bell Sue E , Ouzman Jacqueline , Drayson Mark T , Owen Roger G , Jackson Graham H , Russell Nigel H , Morgan Gareth J. 
Published: October 2019

Abstract
Abstract 335

Background
Induction treatment for myeloma has focused on improving response rates and many centres have evaluated and used triplets of therapy based on either IMiD or proteosome inhibitor drugs. Other strategies rely on combining the two classes of novel agents and excellent response rates have been obtained. An alternative approach to this, which moves some way towards personalised therapy, is to use sequential combinations of the two classes of novel agents dependent on the response achieved. The aim of this approach is to maximise responses and, by so doing, improve survival.

Methods
In order to test this concept, we have carried out a trial, Myeloma XI, which compared responses to cyclophosphamide, thalidomide and dexamethasone (CTD) with cyclophosphamide, lenalidomide and dexamethasone (CRD). Following the randomised use of either of these triplets, given to maximum response, patients achieving no response (NC or PD) received further therapy with a triplet composed of cyclophosphamide, bortezomib and dexamethasone (CVD). In order to test if a bortezomib combination could improve the response of maximally treated patients, those with a suboptimal response (MR or PR) were randomised to either no further therapy or to CVD. For patients achieving ≥ VGPR no further induction was given. Younger fitter patients went on to receive HDM plus ASCT whereas older less fit patients did not. All patients were eligible for a maintenance randomisation to no maintenance, lenalidomide or lenalidomide/vorinostat maintenance. For patients receiving CVD, treatment was continued to a maximum of 8 cycles, with response being assessed using IMWG criteria after each cycle and therapy continued to maximum response or intolerance. Here we present the response rates for patients who have received CVD.

Results
At the time of this initial analysis 1424 patients have been randomised overall; 790 in the intensive pathway and 634 in the non-intensive pathway. Across both pathways, of the refractory patients with no response to induction treatment, an upgrade in response from NC or PD to ≥MR was seen after CVD treatment in 58% of patients, with 31% going on to achieve a VGPR or CR. In the other group of patients, those with a suboptimal response to induction treatment and randomised to receive CVD, 45% went on to achieve VGPR or CR. These patients reduced their paraprotein value by a mean of 74% from the start of CVD suggesting that the improvement in response is significant and not the result of patients marginally crossing the boundaries of response criteria. It seems that even in a group of maximally treated patients that response rates can be increased further by the use of a proteosome inhibitor drug.
In the MRC Myeloma IX study the response rates at a similar time point for those treated with similar thalidomide based induction were PD/NC 7.1%, MR/PR 41.8%, VGPR/CR 37.5%. Assuming at least the same response rates in the current study then we calculate that it would be possible to get approximately 45% extra patients from MR/PR and 31% from PD/NC to ≥VGPR, equating to an approximate 21% increase in the ≥VGPR rate to 59% of the total patients.

Conclusions
We have demonstrated an improvement in response with the addition of a bortezomib based regimen in the group of patients who had a suboptimal response following induction chemotherapy with an IMiD based regimen. Particularly encouraging is the excellent rate of achievement of CR/VGPR in patients with no initial response to treatment. We anticipate that together this will significantly improve the percentage of patients achieving ≥VGPR, approximating 60% of all patients following induction, a response rate that should improve further following ASCT. Further follow up is required to know whether or not this will translate into an improvement in OS or PFS, however from previous studies we would expect this to be the case.

Disclosures:
Pawlyn: Celgene: Unrestricted educational grant Other. Off Label Use: Lenalidomide and vorinostat as maintenence therapy. Davies:Celgene: Honoraria, Speakers Bureau, Unrestricted educational grant, Unrestricted educational grant Other; Ortho Biotech: Honoraria, Speakers Bureau. Gregory:Celgene: Unrestricted educational grant Other. Szubert:Celgene: Unrestricted educational grant Other. Bell:Celgene: Unrestricted educational grant Other. Ouzman:Celgene: Unrestricted educational grant Other. Drayson:Celgene: Unrestricted educational grant Other. Owen:Celgene: Unrestricted educational grant Other. Jackson:Celgene: Honoraria, Unrestricted educational grant Other. Russell:Celgene: Unrestricted educational grant Other. Morgan:Ortho Biotech: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau, Unrestricted educational grant, Unrestricted educational grant Other.