LENALIDOMIDE INDUCTION AND MAINTENANCE THERAPY FOR TRANSPLANT ELIGIBLE 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
,
Graham Jackson
Affiliations:
Department of Haematology, Newcastle University,Newcastle,United Kingdom
Gareth Morgan
Affiliations:
Myeloma Institute, University of Arkansas for Medical Sciences,Little Rock,United States
EHA Library. PAWLYN C. 06/25/17; 182068; S781
Dr. Charlotte PAWLYN
Dr. Charlotte PAWLYN
Contributions
Abstract

Abstract: S781

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:30 - 08:45

Location: Hall D

Background
 

Immunomodulatory agents are effective therapies for multiple myeloma (MM) acting via the modulation of cereblon.  Lenalidomide (Len) has fewer side effects than Thalidomide (Thal), whilst retaining the benefits of oral administration, enabling long-term treatment that has been associated with better disease control. Combinations of agents induce deeper, longer remissions by targeting different clonal populations, with triplets outperforming doublets. The optimum immunomodulatory-based induction combinations and maintenance regimens are unknown.
 

Aims
 

The UK NCRI Myeloma XI study compared triplet induction regimens of Len vs Thal and examined the role of post-ASCT maintenance Len vs observation, enabling us to explore the interaction of Len induction with Len maintenance.
 

Methods

 
Myeloma XI is a multicenter, open-label, parallel group, randomised controlled trial for newly diagnosed MM patients of all ages, with pathways for transplant eligible (TE) and non-eligible patients. For TE patients the induction question compared Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to maximum response. For patients with a suboptimal response there was a subsequent randomization to a proteasome inhibitor containing triplet or no further therapy, prior to high-dose melphalan and ASCT. A maintenance randomisation at 3 months post ASCT compared Len till disease progression with observation.  High risk disease was defined as the presence of at least one of t(4;14), t(14;16), del(17p) or gain(1q).
 
2042 TE patients underwent the induction randomization (CRD 1021, CTD 1021).  After a median follow up of 36.3 months, 965 PFS and 415 OS primary endpoint events had occurred. Secondary endpoints include response and toxicity. 
 

Results

 
In TE patients, CRD induction was associated with deeper responses than CTD (≥VGPR: CRD 60% vs CTD 53%), a finding which persisted post ASCT (≥VGPR CRD 82% vs CTD 77%). This was associated with a significantly improved median PFS.  Patients receiving CRD achieved a median PFS of 35.9 months compared to 32.9 for those who received CTD (HR 0.85, 95%CI [0.75, 0.96], p=0.0116).  This also translated into an overall survival benefit, 3 year OS: CRD 82.9% vs CTD 77.0% (HR 0.77, 95%CI [0.63, 0.93], p=0.0072). There were higher rates of PN and constipation with CTD vs haematological toxicity with CRD.
 
Maintenance therapy with Len was associated with a significantly longer median PFS compared to observation (TE HR 0.47, 95%CI 0.38, 0.60).  This finding persisted across all subgroups including patients with high-risk disease. Exploratory analysis across the TE pathway suggested that CRD induction with Len maintenance was optimum: 60 month PFS CRD-R 50.2%, CTD-R 39.1%, CRD-obs 18.5%, CTD-obs 23.4%.
 

Conclusion

 
In TE patients CRD was associated with deeper responses than CTD and with a PFS and OS benefit. The best outcomes were associated with Len induction plus Len maintenance. Our findings support continuing Len therapy through induction until disease progression.
 
On behalf of the UK NCRI Haemato-oncology CSG

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

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

Abstract: S781

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:30 - 08:45

Location: Hall D

Background
 

Immunomodulatory agents are effective therapies for multiple myeloma (MM) acting via the modulation of cereblon.  Lenalidomide (Len) has fewer side effects than Thalidomide (Thal), whilst retaining the benefits of oral administration, enabling long-term treatment that has been associated with better disease control. Combinations of agents induce deeper, longer remissions by targeting different clonal populations, with triplets outperforming doublets. The optimum immunomodulatory-based induction combinations and maintenance regimens are unknown.
 

Aims
 

The UK NCRI Myeloma XI study compared triplet induction regimens of Len vs Thal and examined the role of post-ASCT maintenance Len vs observation, enabling us to explore the interaction of Len induction with Len maintenance.
 

Methods

 
Myeloma XI is a multicenter, open-label, parallel group, randomised controlled trial for newly diagnosed MM patients of all ages, with pathways for transplant eligible (TE) and non-eligible patients. For TE patients the induction question compared Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to maximum response. For patients with a suboptimal response there was a subsequent randomization to a proteasome inhibitor containing triplet or no further therapy, prior to high-dose melphalan and ASCT. A maintenance randomisation at 3 months post ASCT compared Len till disease progression with observation.  High risk disease was defined as the presence of at least one of t(4;14), t(14;16), del(17p) or gain(1q).
 
2042 TE patients underwent the induction randomization (CRD 1021, CTD 1021).  After a median follow up of 36.3 months, 965 PFS and 415 OS primary endpoint events had occurred. Secondary endpoints include response and toxicity. 
 

Results

 
In TE patients, CRD induction was associated with deeper responses than CTD (≥VGPR: CRD 60% vs CTD 53%), a finding which persisted post ASCT (≥VGPR CRD 82% vs CTD 77%). This was associated with a significantly improved median PFS.  Patients receiving CRD achieved a median PFS of 35.9 months compared to 32.9 for those who received CTD (HR 0.85, 95%CI [0.75, 0.96], p=0.0116).  This also translated into an overall survival benefit, 3 year OS: CRD 82.9% vs CTD 77.0% (HR 0.77, 95%CI [0.63, 0.93], p=0.0072). There were higher rates of PN and constipation with CTD vs haematological toxicity with CRD.
 
Maintenance therapy with Len was associated with a significantly longer median PFS compared to observation (TE HR 0.47, 95%CI 0.38, 0.60).  This finding persisted across all subgroups including patients with high-risk disease. Exploratory analysis across the TE pathway suggested that CRD induction with Len maintenance was optimum: 60 month PFS CRD-R 50.2%, CTD-R 39.1%, CRD-obs 18.5%, CTD-obs 23.4%.
 

Conclusion

 
In TE patients CRD was associated with deeper responses than CTD and with a PFS and OS benefit. The best outcomes were associated with Len induction plus Len maintenance. Our findings support continuing Len therapy through induction until disease progression.
 
On behalf of the UK NCRI Haemato-oncology CSG

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

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

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