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EFFICACY BY CYTOGENETIC RISK STATUS FOR DARATUMUMAB IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE OR BORTEZOMIB AND DEXAMETHASONE IN RELAPSED OR REFRACTORY MULTIPLE MYELOMA
Author(s):
Jesus San-Miguel
,
Jesus San-Miguel
Affiliations:
Clínica Universidad de Navarra-CIMA, IDISNA,Pamplona,Spain
Katja Weisel
,
Katja Weisel
Affiliations:
Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II,Tuebingen,Germany
Gordon Cook
,
Gordon Cook
Affiliations:
St James's Institute of Oncology, Leeds Teaching Hospitals NHS Trust and University of Leeds,Leeds,United Kingdom
Merav Leiba
,
Merav Leiba
Affiliations:
Sheba Medical Center, Tel Hashomer,Ramat Gan,Israel
Kenshi Suzuki
,
Kenshi Suzuki
Affiliations:
Japanese Red Cross Medical Center, Department of Hematology,Tokyo,Japan
Shaji Kumar
,
Shaji Kumar
Affiliations:
Division of Hematology, Mayo Clinic,Rochester, MN,United States
Michele Cavo
,
Michele Cavo
Affiliations:
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna,Bologna,Italy
Herve Avet-Loiseau
,
Herve Avet-Loiseau
Affiliations:
Unite de Genomique du Myelome, CHU Rangueil,Toulouse,France
Hang Quach
,
Hang Quach
Affiliations:
University of Melbourne, St. Vincent's Hospital,Victoria,Australia
Vania Hungria
,
Vania Hungria
Affiliations:
Irmandade Da Santa Casa De Misericordia De São Paulo,São Paulo,Brazil
Suzanne Lentzsch
,
Suzanne Lentzsch
Affiliations:
Division of Hematology/Oncology, Columbia University,New York, NY,United States
Roman Hajek
,
Roman Hajek
Affiliations:
Department of Haematooncology, University Hospital Ostrava and Faculty of Medicine and Faculty of Science, University of Ostrava,Ostrava,Czech Republic
Pieter Sonneveld
,
Pieter Sonneveld
Affiliations:
Department of Hematology, Erasmus MC,Rotterdam,Netherlands
Kaida Wu
,
Kaida Wu
Affiliations:
Janssen Research & Development, LLC,Spring House, PA,United States
Xiang Qin
,
Xiang Qin
Affiliations:
Janssen Research & Development, LLC,Spring House, PA,United States
Christopher Chiu
,
Christopher Chiu
Affiliations:
Janssen Research & Development, LLC,Spring House, PA,United States
David Soong
,
David Soong
Affiliations:
Janssen Research & Development, LLC,Spring House, PA,United States
Ming Qi
,
Ming Qi
Affiliations:
Janssen Research & Development, LLC,Spring House, PA,United States
Jordan Schecter
,
Jordan Schecter
Affiliations:
Janssen Research & Development,Raritan, NJ,United States
Meletios A. Dimopoulos
Meletios A. Dimopoulos
Affiliations:
National and Kapodistrian University of Athens,Athens,Greece
(Abstract release date: 05/18/17) EHA Library. San Miguel J. 06/23/17; 181388; S101
Prof. Jesús San Miguel
Prof. Jesús San Miguel
Contributions
PDF Abstract
Abstract

Abstract: S101

Type: Oral Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00

Location: Hall A

Background
Daratumumab (D) is a human CD38-targeting monoclonal antibody that exerts its antimyeloma activity through both direct (on-tumor) and indirect (immunomodulatory) mechanisms of action. Two randomized phase 3 trials in patients with relapsed or refractory multiple myeloma (RRMM) demonstrated that combining D with the standard-of-care regimens lenalidomide + dexamethasone (Rd, POLLUX) or bortezomib + dexamethasone (Vd, CASTOR) significantly improved progression-free survival (PFS) and achieved higher overall response rates (ORRs) compared with the respective standard-of-care regimen alone (Dimopoulos MA et al, N Engl J Med 2016;375(14):1319-1331; Palumbo A et al, N Engl J Med 2016;375(8):754-766.). Due to its novel mechanisms of action, addition of D to standard-of-care regimens may benefit RRMM patients who have poor prognoses resulting from high-risk cytogenetic abnormalities. 

Aims
To examine the efficacy of DRd and DVd in RRMM patients with standard or high cytogenetic risk status. 

Methods
Bone marrow aspirates were collected at screening visits from 311/569 patients from POLLUX and from 353/498 patients from CASTOR, and cytogenetic abnormalities were detected via next-generation sequencing (NGS). Patients were considered to be of high cytogenetic risk status if they had ≥1 of the following abnormalities: t(4;14), t(14;16), or del17p; patients were considered to be of standard cytogenetic risk if they lacked these abnormalities. Minimal residual disease (MRD) was assessed at suspected complete response (CR) at 3 sensitivity thresholds (10–4, 10–5, and 10–6) using the ClonoSEQ™ NGS-based assay (Adaptive Biotechnologies, Seattle, WA). Efficacy analyses included PFS, ORR, and MRD-negative rates.

Results

For POLLUX, the median follow-up was 17.3 months. Treating high-risk patients with DRd significantly prolonged median PFS vs Rd (top panel figure) and numerically increased ORR (85% vs 67%; P=0.14). Responses to DRd vs Rd included CR or better in 33% vs 6% of these patients, and very good partial responses (VGPR) or better in 63% vs 31%. In standard-risk patients, DRd vs Rd also resulted in significant improvements in median PFS (Figure) as well as ORR (95% vs 82%; P=0.0020). Responses to DRd vs Rd included CR or better in 52% vs 24% of these patients, and VGPR or better in 84% vs 51%. At 10–5 sensitivity threshold, MRD-negative rates for DRd vs Rd were 18% vs 0% (P=0.0027) among high-risk patients and 30% vs 10% (P<0.0001) for standard-risk patients.
 
For CASTOR, the median follow-up was 13.0 months. Treating both high- and standard-risk patients with DVd vs Vd significantly prolonged median PFS (bottom panel figure) and increased ORR (high risk: 82% vs 62%; P=0.039; standard risk: 85% vs 64%; P=0.0003). Responses to DVd vs Vd among high-risk patients included CR or better in 30% vs 9% of patients and VGPR or better in 64% vs 34%; among standard-risk patients, responses included CR or better in 25% vs 8% of patients and VGPR or better in 64% vs 27%. At 10–5 sensitivity threshold, MRD-negative rates for DVd vs Vd were 14% vs 0% (P=0.0018) among high-risk patients and 12% vs 2% (P=0.0011) for standard-risk patients.

Conclusion
Adding D to Rd or Vd improved treatment outcomes irrespective of cytogenetic risk status in patients with RRMM. Both DRd and DVd appear to benefit RRMM patients who have poor prognoses due to high-risk cytogenetic abnormalities. Updated data, including analyses based on individual cytogenetic abnormalities, will be presented at the meeting based on longer follow-up.

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

Keyword(s): CD38, Multiple Myeloma, Minimal residual disease (MRD), Cytogenetic abnormalities

Abstract: S101

Type: Oral Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00

Location: Hall A

Background
Daratumumab (D) is a human CD38-targeting monoclonal antibody that exerts its antimyeloma activity through both direct (on-tumor) and indirect (immunomodulatory) mechanisms of action. Two randomized phase 3 trials in patients with relapsed or refractory multiple myeloma (RRMM) demonstrated that combining D with the standard-of-care regimens lenalidomide + dexamethasone (Rd, POLLUX) or bortezomib + dexamethasone (Vd, CASTOR) significantly improved progression-free survival (PFS) and achieved higher overall response rates (ORRs) compared with the respective standard-of-care regimen alone (Dimopoulos MA et al, N Engl J Med 2016;375(14):1319-1331; Palumbo A et al, N Engl J Med 2016;375(8):754-766.). Due to its novel mechanisms of action, addition of D to standard-of-care regimens may benefit RRMM patients who have poor prognoses resulting from high-risk cytogenetic abnormalities. 

Aims
To examine the efficacy of DRd and DVd in RRMM patients with standard or high cytogenetic risk status. 

Methods
Bone marrow aspirates were collected at screening visits from 311/569 patients from POLLUX and from 353/498 patients from CASTOR, and cytogenetic abnormalities were detected via next-generation sequencing (NGS). Patients were considered to be of high cytogenetic risk status if they had ≥1 of the following abnormalities: t(4;14), t(14;16), or del17p; patients were considered to be of standard cytogenetic risk if they lacked these abnormalities. Minimal residual disease (MRD) was assessed at suspected complete response (CR) at 3 sensitivity thresholds (10–4, 10–5, and 10–6) using the ClonoSEQ™ NGS-based assay (Adaptive Biotechnologies, Seattle, WA). Efficacy analyses included PFS, ORR, and MRD-negative rates.

Results

For POLLUX, the median follow-up was 17.3 months. Treating high-risk patients with DRd significantly prolonged median PFS vs Rd (top panel figure) and numerically increased ORR (85% vs 67%; P=0.14). Responses to DRd vs Rd included CR or better in 33% vs 6% of these patients, and very good partial responses (VGPR) or better in 63% vs 31%. In standard-risk patients, DRd vs Rd also resulted in significant improvements in median PFS (Figure) as well as ORR (95% vs 82%; P=0.0020). Responses to DRd vs Rd included CR or better in 52% vs 24% of these patients, and VGPR or better in 84% vs 51%. At 10–5 sensitivity threshold, MRD-negative rates for DRd vs Rd were 18% vs 0% (P=0.0027) among high-risk patients and 30% vs 10% (P<0.0001) for standard-risk patients.
 
For CASTOR, the median follow-up was 13.0 months. Treating both high- and standard-risk patients with DVd vs Vd significantly prolonged median PFS (bottom panel figure) and increased ORR (high risk: 82% vs 62%; P=0.039; standard risk: 85% vs 64%; P=0.0003). Responses to DVd vs Vd among high-risk patients included CR or better in 30% vs 9% of patients and VGPR or better in 64% vs 34%; among standard-risk patients, responses included CR or better in 25% vs 8% of patients and VGPR or better in 64% vs 27%. At 10–5 sensitivity threshold, MRD-negative rates for DVd vs Vd were 14% vs 0% (P=0.0018) among high-risk patients and 12% vs 2% (P=0.0011) for standard-risk patients.

Conclusion
Adding D to Rd or Vd improved treatment outcomes irrespective of cytogenetic risk status in patients with RRMM. Both DRd and DVd appear to benefit RRMM patients who have poor prognoses due to high-risk cytogenetic abnormalities. Updated data, including analyses based on individual cytogenetic abnormalities, will be presented at the meeting based on longer follow-up.

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

Keyword(s): CD38, Multiple Myeloma, Minimal residual disease (MRD), Cytogenetic abnormalities

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