DEPTH OF RESPONSE AND MRD STATUS IN ULTRA HIGH-RISK MYELOMA AND PLASMA CELL LEUKEMIA TREATED WITH DARA-CVRD AND AUGMENTED AUTOLOGOUS TRANSPLANT: RESULTS OF THE RISK-STRATIFIED UK OPTIMUM/MUKNINE TRIAL
Author(s): ,
Martin Kaiser
Affiliations:
The Institute of Cancer Research and Royal Marsden Hospital,London,United Kingdom
,
Andrew Hall
Affiliations:
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research,University of Leeds,Leeds,United Kingdom
,
Katrina Walker
Affiliations:
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research,University of Leeds,Leeds,United Kingdom
,
Ruth de Tute
Affiliations:
HMDS,St James Hospital,Leeds,United Kingdom
,
Roberts Sadie
Affiliations:
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research,University of Leeds,Leeds,United Kingdom
,
Emma Ingleson
Affiliations:
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research,University of Leeds,Leeds,United Kingdom
,
Kristian Bowles
Affiliations:
Norfolk and Norwich University Hospitals NHS Trust,Norwich,United Kingdom
,
Mamta Garg
Affiliations:
Leicester Royal Infirmary,Leicester,United Kingdom
,
Anand Lokare
Affiliations:
Birmingham Heartlands Hospital,Birmingham,United Kingdom
,
Christina Messiou
Affiliations:
The Royal Marsden Hospital & The Institute of Cancer Research,London,United Kingdom
,
Graham Jackson
Affiliations:
Newcastle University,Newcastle,United Kingdom
,
Guy Pratt
Affiliations:
University of Birmingham,Birmingham,United Kingdom
,
Gordon Cook
Affiliations:
University of Leeds,Leeds,United Kingdom
,
Mark Drayson
Affiliations:
University of Birmingham,Birmingham,United Kingdom
,
Roger Owen
Affiliations:
HMDS,St James Hospital,Leeds,United Kingdom
,
Sarah Brown
Affiliations:
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research,University of Leeds,Leeds,United Kingdom
Matthew Jenner
Affiliations:
University Hospital Southampton,Southampton,United Kingdom
EHA Library. Kaiser M. 06/09/21; 324589; S181
Dr. Martin Kaiser
Dr. Martin Kaiser
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S181

Type: Oral Presentation

Session title: New treatment strategies for newly diagnosed multiple myeloma

Background
Patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) as well as patients with plasma cell leukemia (PCL) continue to have dismal outcomes and are underrepresented in clinical trials. Recently, improved and deepened responses with anti-CD38 monoclonal antibody combination therapy have been reported for NDMM patients. We report here outcomes for NDMM UHiR and PCL patients treated in the OPTIMUM/MUKnine (NCT03188172) trial with daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction, augmented high-dose melphalan (HDMEL) and ASCT. With final analysis follow-up surpassed in Feb 2021, we report here early protocol defined endpoints from induction to day 100 post ASCT. 

Aims
To demonstrate response and MRD-negativity rate in UHiR NDMM and PCL prospectively identified by central molecular screening and treated in a risk-stratified trial with Dara-CVRd and augmented ASCT.

Methods
Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM by central trial genetic (≥2 high-risk lesions (double-hit): t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts >20%) were included in OPTIMUM across 39 UK hospitals. Patients received a maximum of 6 cycles of Dara-CVRd induction, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Data is complete but subject to further data cleaning prior to conference.

Results

Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). Median age was 60 (range 35 to 78) years, 59.8% of patients were male. Ninety eight patients (92%) were included based on UHiR status by central tumour molecular analysis, and 9 because of PCL (8%). At baseline, 22.4% of patients were ISS stage I, 37.4% stage II and 26.2% stage 3 with 14.0% missing data. Two patients died during induction due to infection. Bone marrow aspirates suitable for MRD assessment by flow cytometry (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the intention-to-treat population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% timepoint not reached. MRD status was 41% MRD-negative, 40% MRD-positive and 19% not evaluable post induction and 64% MRD-negative, 14% MRD-positive and 22% not evaluable at D100 post ASCT. Responses at D100 post ASCT were lower in PCL with 22% CR, 22% VGPR, 22% PR, 22% PD, 12% timepoint not reached. Most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Grade 3 neuropathy rate was at 3.7%.

Conclusion
We report, to our knowledge for the first time, on a trial for UHiR NDMM and PCL investigating Dara-CVRd induction and augmented ASCT. Response rates and MRD-negativity were high in this difficult-to-treat patient population, with toxicity comparable to other induction regimens. However, some early progressions highlight the need for innovative approaches to UHiR NDMM and PCL.

Keyword(s): Clinical trial, Gene expression profile, Molecular cytogenetics, Myeloma

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S181

Type: Oral Presentation

Session title: New treatment strategies for newly diagnosed multiple myeloma

Background
Patients with ultra high-risk (UHiR) newly diagnosed multiple myeloma (NDMM) as well as patients with plasma cell leukemia (PCL) continue to have dismal outcomes and are underrepresented in clinical trials. Recently, improved and deepened responses with anti-CD38 monoclonal antibody combination therapy have been reported for NDMM patients. We report here outcomes for NDMM UHiR and PCL patients treated in the OPTIMUM/MUKnine (NCT03188172) trial with daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction, augmented high-dose melphalan (HDMEL) and ASCT. With final analysis follow-up surpassed in Feb 2021, we report here early protocol defined endpoints from induction to day 100 post ASCT. 

Aims
To demonstrate response and MRD-negativity rate in UHiR NDMM and PCL prospectively identified by central molecular screening and treated in a risk-stratified trial with Dara-CVRd and augmented ASCT.

Methods
Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM by central trial genetic (≥2 high-risk lesions (double-hit): t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with PCL (circulating plasmablasts >20%) were included in OPTIMUM across 39 UK hospitals. Patients received a maximum of 6 cycles of Dara-CVRd induction, HDMEL and ASCT augmented with bortezomib, followed by Dara-VR(d) consolidation for 18 cycles and Dara-R maintenance. Primary trial endpoints are minimal residual disease (MRD) status post ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. Data is complete but subject to further data cleaning prior to conference.

Results

Median follow-up for the 107 patients in the safety population was 22.2 months (95% CI: 20.6 – 23.9). Median age was 60 (range 35 to 78) years, 59.8% of patients were male. Ninety eight patients (92%) were included based on UHiR status by central tumour molecular analysis, and 9 because of PCL (8%). At baseline, 22.4% of patients were ISS stage I, 37.4% stage II and 26.2% stage 3 with 14.0% missing data. Two patients died during induction due to infection. Bone marrow aspirates suitable for MRD assessment by flow cytometry (10-5 sensitivity) were available for 81% of patients at end of induction and 78% at D100 post ASCT. Responses in the intention-to-treat population at end of induction were 94% ORR with 22% CR, 58% VGPR, 15% PR, 1% PD, 5% timepoint not reached (withdrew, became ineligible or died) and at D100 post ASCT 83% ORR with 47% CR, 32% VGPR, 5% PR, 7% PD, 10% timepoint not reached. MRD status was 41% MRD-negative, 40% MRD-positive and 19% not evaluable post induction and 64% MRD-negative, 14% MRD-positive and 22% not evaluable at D100 post ASCT. Responses at D100 post ASCT were lower in PCL with 22% CR, 22% VGPR, 22% PR, 22% PD, 12% timepoint not reached. Most frequent grade 3/4 AEs during induction were neutropenia (21%), thrombocytopenia (12%) and infection (12%). Grade 3 neuropathy rate was at 3.7%.

Conclusion
We report, to our knowledge for the first time, on a trial for UHiR NDMM and PCL investigating Dara-CVRd induction and augmented ASCT. Response rates and MRD-negativity were high in this difficult-to-treat patient population, with toxicity comparable to other induction regimens. However, some early progressions highlight the need for innovative approaches to UHiR NDMM and PCL.

Keyword(s): Clinical trial, Gene expression profile, Molecular cytogenetics, Myeloma

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