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QUADRUPLET VS SEQUENTIAL TRIPLET INDUCTION THERAPY FOR MYELOMA PATIENTS: RESULTS OF THE MYELOMA XI STUDY.
Author(s): ,
Charlotte Pawlyn
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
Faith Davies
Affiliations:
Myeloma Institute, University of Arkansas for Medical Sciences,Little Rock,United States
,
David Cairns
Affiliations:
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research,Leeds,United Kingdom
,
Alina Striha
Affiliations:
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research,Leeds,United Kingdom
,
Anna Waterhouse
Affiliations:
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research,Leeds,United Kingdom
,
Corinne Collett
Affiliations:
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research,Leeds,United Kingdom
,
John Jones
Affiliations:
The Institute of Cancer Research,London,United Kingdom
,
Bhuvan Kishore
Affiliations:
Heart of England NHS Foundation Trust,Birmingham,United Kingdom
,
Mamta Garg
Affiliations:
Leicester Royal Infirmary,Leicester,United Kingdom
,
Cathy Williams
Affiliations:
Centre for Clinical Haematology, Nottingham University Hospital,Nottingham,United Kingdom
,
Kamaraj Karunanithi
Affiliations:
University Hospitals of North Midlands,Stoke-on-Trent,United Kingdom
,
Jindriska Lindsay
Affiliations:
Kent and Canterbury NHS Trust,Canterbury,United Kingdom
,
Matthew Jenner
Affiliations:
Southampton Hospital,Southampton,United Kingdom
,
Gordon Cook
Affiliations:
Universtiy of Leeds,Leeds,United Kingdom
,
Martin Kaiser
Affiliations:
The Institute of Cancer Research,London,United Kingdom;The Royal Marsden Hospital,London,United Kingdom
,
Mark Drayson
Affiliations:
Institute of Immunology and Immunotherapy, University of Birmingham,Birmingham,United Kingdom
,
Roger Owen
Affiliations:
Haematological Malignancy Diagnostic Service (HMDS), St James's University Hospital,Leeds,United Kingdom
,
Nigel Russell
Affiliations:
Centre for Clinical Haematology, Nottingham University Hospital,Nottingham,United Kingdom
,
Walter Gregory
Affiliations:
Clinical Trial Research Unit, Leeds Institute of Clinical Trials Research,Leeds,United Kingdom
,
Gareth Morgan
Affiliations:
Myeloma Institute, University of Arkansas for Medical Sciences,Little Rock,United States
Graham Jackson
Affiliations:
Department of Haematology, Newcastle University,Newcastle,United Kingdom
(Abstract release date: 05/18/17) EHA Library. Pawlyn C. 06/24/17; 181694; S407
Dr. Charlotte Pawlyn
Dr. Charlotte Pawlyn
Contributions
Abstract

Abstract: S407

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 11:30 - 11:45

Location: Hall A

Background
Combining anti-myeloma induction therapies limits the impact of clonal heterogeneity on resistance to therapy, maximising response and associated clinical outcomes.  Triplet combinations induce deeper, longer remissions than doublets and those containing an immunomodulatory agent, a proteasome inhibitor (PI) or both are the current standard of care in Europe/US.  Potential approaches to further improve outcomes include response-adapted induction, treating suboptimal responders with sequential treatment using an agent with a different mechanism of action, or intensifying induction for all patients by the use of quadruplet combinations upfront.

 
 

Aims
The UK NCRI Myeloma XI trial is a large, phase III study comparing, in transplant eligible (TE) patients, the induction quadruplet carfilzomib, cyclophosphamide, lenalidomide and dexamethasone (KCRD) to the sequential strategy of triplet immunomodulatory combinations (with thalidomide or lenalidomide) followed by additional pre-transplant consolidation with PI triplet therapy for those with a suboptimal response.

 

Methods
In 2013, the TE pathway of the Myeloma XI study was amended to include KCRD given in 28 day cycles (carfilzomib 36mg/m2 IV d1-2,8-9,15-16 (20mg/m2 #1d1-2), cyclophosphamide (cyclo) 500mg PO d1,8, lenalidomide (len) 25mg PO d1-21, dexamethasone (dex) 40mg PO d1-4,8-9,15-16). Patients were randomised to this up-front quadruplet or the sequential strategy of CRD (cyclo 500mg PO d1,8, len 25mg PO d1-21 PO daily, dex 40mg PO d1-4, 12-15) or CTD (cyclo 500mg PO d1,8,15 thalidomide 100-200mg PO daily, dex 40mg PO d1-4,12-15) given to max. response. Patients with VGPR/CR proceeded straight to ASCT, those with PR/MR were randomised to sequential CVD (cyclo 500mg d1,8,15, bortezomib 1.3mg/m2 IV/SC d1,4,8,11, dex 20mg PO d1,2,4,5,8,9,11,12) or nothing and those with SD/PD all received sequential CVD. At day 100 post ASCT there was a maintenance randomisation between lenalidomide and observation.  The trial has now closed to recruitment and all patients have completed induction therapy.  This analysis compares responses and toxicity of the different regimens.

 

Results
2568 TE patients underwent induction randomisation (CTD 1021, CRD 1021, KCRD 526).  Patients were comparable with respect to age (median 59 years), sex and other key laboratory parameters.  Patients were mandated to receive a minimum of 4 cycles of initial induction with therapy continued to maximum response.  The median number of cycles delivered was CTD: 5, CRD: 5, KCRD: 4.  Grade ≥3 haematological toxicities differed between the groups. (Neutropenia CTD: 12%, CRD: 22%, KCRD: 16%; Thrombocytopenia CTD: 3.4%, CRD: 4.5%, KCRD: 8.1%; Anaemia CTD: 6.7%, CRD: 9.6%, KCRD 10%).  Grade ≥2 neurological toxicity was greater with the thalidomide-containing regimen (Sensory neuropathy CTD: 9.5%, CRD: 3.4%, KCRD: 2.3%). There was no statistically significant difference in rates of investigator reported, all-grade, thromboembolic events between regimens (CTD: 11.8%, CRD 11.1%, KCRD 14.7%). 

 
Response to initial induction and following ASCT is shown in Table 1 indicating deeper responses with the quadruplet compared to triplets both at the end of first induction regimen (p<0.0001) and, importantly, post-ASCT (p<0.0001).  These differences were observed despite the use of randomised pre-transplant consolidation for suboptimal responders to triplet immunomodulatory therapy.
 

Conclusion
Induction therapy with KCRD, an outpatient delivered quadruplet regimen, was associated with deeper responses than immunomodulatory triplet therapy (CRD/CTD) and was well tolerated.  Deeper responses persisted after ASCT, with an impressive response rate ≥VGPR of 92% with KCRD.

 
On behalf of the UK NCRI Haemato-oncology CSG

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Proteasome inhibitor, Myeloma, Induction chemotherapy, Immunomodulatory thalidomide analog

Abstract: S407

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 11:30 - 11:45

Location: Hall A

Background
Combining anti-myeloma induction therapies limits the impact of clonal heterogeneity on resistance to therapy, maximising response and associated clinical outcomes.  Triplet combinations induce deeper, longer remissions than doublets and those containing an immunomodulatory agent, a proteasome inhibitor (PI) or both are the current standard of care in Europe/US.  Potential approaches to further improve outcomes include response-adapted induction, treating suboptimal responders with sequential treatment using an agent with a different mechanism of action, or intensifying induction for all patients by the use of quadruplet combinations upfront.

 
 

Aims
The UK NCRI Myeloma XI trial is a large, phase III study comparing, in transplant eligible (TE) patients, the induction quadruplet carfilzomib, cyclophosphamide, lenalidomide and dexamethasone (KCRD) to the sequential strategy of triplet immunomodulatory combinations (with thalidomide or lenalidomide) followed by additional pre-transplant consolidation with PI triplet therapy for those with a suboptimal response.

 

Methods
In 2013, the TE pathway of the Myeloma XI study was amended to include KCRD given in 28 day cycles (carfilzomib 36mg/m2 IV d1-2,8-9,15-16 (20mg/m2 #1d1-2), cyclophosphamide (cyclo) 500mg PO d1,8, lenalidomide (len) 25mg PO d1-21, dexamethasone (dex) 40mg PO d1-4,8-9,15-16). Patients were randomised to this up-front quadruplet or the sequential strategy of CRD (cyclo 500mg PO d1,8, len 25mg PO d1-21 PO daily, dex 40mg PO d1-4, 12-15) or CTD (cyclo 500mg PO d1,8,15 thalidomide 100-200mg PO daily, dex 40mg PO d1-4,12-15) given to max. response. Patients with VGPR/CR proceeded straight to ASCT, those with PR/MR were randomised to sequential CVD (cyclo 500mg d1,8,15, bortezomib 1.3mg/m2 IV/SC d1,4,8,11, dex 20mg PO d1,2,4,5,8,9,11,12) or nothing and those with SD/PD all received sequential CVD. At day 100 post ASCT there was a maintenance randomisation between lenalidomide and observation.  The trial has now closed to recruitment and all patients have completed induction therapy.  This analysis compares responses and toxicity of the different regimens.

 

Results
2568 TE patients underwent induction randomisation (CTD 1021, CRD 1021, KCRD 526).  Patients were comparable with respect to age (median 59 years), sex and other key laboratory parameters.  Patients were mandated to receive a minimum of 4 cycles of initial induction with therapy continued to maximum response.  The median number of cycles delivered was CTD: 5, CRD: 5, KCRD: 4.  Grade ≥3 haematological toxicities differed between the groups. (Neutropenia CTD: 12%, CRD: 22%, KCRD: 16%; Thrombocytopenia CTD: 3.4%, CRD: 4.5%, KCRD: 8.1%; Anaemia CTD: 6.7%, CRD: 9.6%, KCRD 10%).  Grade ≥2 neurological toxicity was greater with the thalidomide-containing regimen (Sensory neuropathy CTD: 9.5%, CRD: 3.4%, KCRD: 2.3%). There was no statistically significant difference in rates of investigator reported, all-grade, thromboembolic events between regimens (CTD: 11.8%, CRD 11.1%, KCRD 14.7%). 

 
Response to initial induction and following ASCT is shown in Table 1 indicating deeper responses with the quadruplet compared to triplets both at the end of first induction regimen (p<0.0001) and, importantly, post-ASCT (p<0.0001).  These differences were observed despite the use of randomised pre-transplant consolidation for suboptimal responders to triplet immunomodulatory therapy.
 

Conclusion
Induction therapy with KCRD, an outpatient delivered quadruplet regimen, was associated with deeper responses than immunomodulatory triplet therapy (CRD/CTD) and was well tolerated.  Deeper responses persisted after ASCT, with an impressive response rate ≥VGPR of 92% with KCRD.

 
On behalf of the UK NCRI Haemato-oncology CSG

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Proteasome inhibitor, Myeloma, Induction chemotherapy, Immunomodulatory thalidomide analog

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