Study Comparing Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Subjects With Newly Diagnosed Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT02874742
• Recruitment Status: Active, not recruiting
• First Posted: August 22, 2016
• Results First Posted: February 7, 2020
• Last Update Posted: February 16, 2021
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

Brief Summary:

The purpose of this study is to determine if the addition of daratumumab to lenalidomide-bortezomib-dexamethasone (RVd) will increase the proportion of participants achieving stringent complete response (sCR), as defined by the International Myeloma Working Group (IMWG) criteria, by the time of completion of post autologous stem cell transplantation (ASCT) consolidation treatment, compared with RVd alone.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: Lenalidomide; Drug: Bortezomib; Drug: Dexamethasone; Drug: Daratumumab	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 224 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2, Randomized, Open-Label Study Comparing Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Subjects With Newly Diagnosed Multiple Myeloma Eligible for High-Dose Chemotherapy and Autologous Stem Cell Transplantation
• Actual Study Start Date: January 2017
• Actual Primary Completion Date: January 2019
• Estimated Study Completion Date: April 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Daratumumab+Lenalidomide+Bortezomib+Dexamethasone (D-RVd); Participants will receive lenalidomide, bortezomib, dexamethasone and daratumumab.	Drug: Lenalidomide; Cycles 1 through 6: lenalidomide 25 (milligram) mg orally on Days 1 through 14 and each cycle is of 21-days followed by maintenance treatment with lenalidomide 10 mg on days 1-21 throughout each 28-day cycle on Cycles 7 through 9. Beginning at Cycle 10, the lenalidomide dose will be increased to 15 mg unless there is a tolerability concern.; Drug: Bortezomib; Bortezomib 1.3 mg/m^2 subcutaneously on Days 1, 4, 8, and 11 during Cycles 1-6.; Drug: Dexamethasone; Dexamethasone 40 mg orally every week (20 mg on Days 1, 2, 8, 9, 15, and 16).; Drug: Daratumumab; Daratumumab intravenously at a dose of 16 milligram per kilogram (mg/kg) weekly during induction treatment (Days 1, 8, and 15 of Cycles 1 through 4), and every 3 weeks during consolidation treatment (Day 1 of Cycles 5 and 6), followed by maintenance treatment with daratumumab every 4 or 8 weeks.
Experimental: Lenalidomide+Bortezomib+Dexamethasone (RVd); Participants will receive lenalidomide, bortezomib and dexamethasone.	Drug: Lenalidomide; Cycles 1 through 6: lenalidomide 25 (milligram) mg orally on Days 1 through 14 and each cycle is of 21-days followed by maintenance treatment with lenalidomide 10 mg on days 1-21 throughout each 28-day cycle on Cycles 7 through 9. Beginning at Cycle 10, the lenalidomide dose will be increased to 15 mg unless there is a tolerability concern.; Drug: Bortezomib; Bortezomib 1.3 mg/m^2 subcutaneously on Days 1, 4, 8, and 11 during Cycles 1-6.; Drug: Dexamethasone; Dexamethasone 40 mg orally every week (20 mg on Days 1, 2, 8, 9, 15, and 16).

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Stringent Complete Response (sCR) [ Time Frame: From randomization to post-ASCT consolidation (after Cycle 6) before maintenance treatment (up to 10 months) ]
   Percentage of participants who have achieved sCR as determined by the validated computer algorithm according to the International Myeloma Working Group (IMWG) criteria, by the end of post-autologous stem cell transplantation (post-ASCT) consolidation treatment were reported. Complete response (CR) is defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and less than (<) 5 percent (%) PCs in bone marrow. sCR is defined as in addition to CR a normal FLC ratio, and absence of clonal PCs by immunohistochemistry or immunofluorescence or 2 to 4-color flow cytometry.

Secondary Outcome Measures :

1. Percentage of Participants With Overall Complete Response (CR) [ Time Frame: From randomization to end of following: induction treatment, ASCT, post-ASCT consolidation (after Cycle 6) and during maintenance treatment (up to 24 months) ]
   Overall CR rate is defined as the percentage of participants who achieve CR, according to the IMWG criteria. CR is negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and < 5% PCs in bone marrow.
2. Percentage of Participants With Overall Stringent Complete Response (sCR) [ Time Frame: From randomization to end of following: induction treatment, ASCT, post-ASCT consolidation (after Cycle 6) and during maintenance treatment (up to 24 months) ]
   Overall sCR rate is defined as the percentage of participants who achieved sCR, according to the IMWG criteria. CR is defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and < 5 % PCs in bone marrow. sCR is defined as in addition to CR a normal FLC ratio, and absence of clonal PCs by immunohistochemistry or immunofluorescence or 2 to 4-color flow cytometry.
3. Percentage of Participants With Overall Response Rate (ORR) [ Time Frame: From randomization to end of following: induction treatment, ASCT, post-ASCT consolidation (after Cycle 6) and during maintenance treatment (up to 24 months) ]
   ORR -percentage of participants who achieved partial response (PR) or better (PR, Very Good Partial Response [VGPR], CR or sCR) based on computerized algorithm as per IMWG criteria. PR -greater than or equal to (>=) 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg//24 hours. If serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels is required. A >=50% reduction in the size of soft tissue plasmacytomas is also required; VGPR-serum and urine M-component detectable by immunofixation but not on electrophoresis, or >= 90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours; CR-negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow. sCR- in addition to CR a normal FLC ratio, and absence of clonal PCs by immunohistochemistry or immunofluorescence or 2 to 4-color flow cytometry.
4. Percentage of Participants Who Achieved Very Good Partial Response (VGPR) or Better [ Time Frame: From randomization to end of following: induction treatment, ASCT, post-ASCT consolidation (after Cycle 6) and during maintenance treatment (up to 24 months) ]
   VGPR or better rate is defined as the percentage of participants who achieved VGPR or better, according to the IMWG criteria. VGPR is defined as serum and urine M-component detectable by immunofixation but not on electrophoresis, or >= 90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours.
5. Percentage of Participants With Negative Minimal Residual Disease (MRD) [ Time Frame: From randomization to end of following: induction treatment, post-ASCT consolidation (after Cycle 6) (up to 4.5 months) ]
   Minimal residual disease negative rate is defined as the percentage of participants who achieve MRD negative status by the respective time point. Minimal residual disease was evaluated in participants who achieved CR or sCR (including participants with VGPR or better and suspected daratumumab interference) using next-generation sequencing which utilizes multiple myeloma cell DNA from bone marrow aspirates at a threshold of less than (<) 10^5.
6. Duration of Complete Response [ Time Frame: From randomization to the date of first documented evidence of progressive disease or relapse from CR (up to 2 years and 5 months) ]
   Duration of CR is the duration from the date of initial documentation of a CR response, according to the IMWG criteria, to the date of first documented evidence of progressive disease (PR), or relapse from CR. PD is defined as an increase of 25 % from the lowest response value in one of the following: serum and urine M-component (absolute increase must be greater than or equal to [>=] 0.5 gram per deciliter [g/dL] and >=200 milligram [mg]/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL); Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to Plasma cell (PC) proliferative disorder.
7. Duration of Stringent Complete Response (sCR) [ Time Frame: From randomization to the date of first documented evidence of progressive disease or relapse from sCR (up to 2 years and 5 months) ]
   Duration of sCR is the duration from the date of initial documentation of a sCR response, according to the IMWG criteria, to the date of first documented evidence of progressive disease, or relapse from sCR. PD is defined as an increase of 25 % from the lowest response value in one of the following: serum and urine M component (absolute increase must be >= 0.5 g/dL and >=200 mg/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL); Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
8. Time to Stringent Complete Response (sCR) [ Time Frame: From randomization to the date of initial documentation of sCR (up to 2 years and 5 months) ]
   Time to sCR is the duration from the date of randomization to the date of initial documentation of sCR, which was confirmed by a repeated measurement as required by the IMWG criteria.
9. Time to Complete Response or Better [ Time Frame: From randomization to the date of initial documentation of CR (Up to 2 years and 5 months) ]
   Time to CR or better is the duration from the date of randomization to the date of initial documentation of CR or better, which was confirmed by a repeated measurement as required by the IMWG criteria.
10. Time to Very Good Partial Response (VGPR) or Better [ Time Frame: From randomization to the date of initial documentation of VGPR or better (up to 2 years and 5 months) ]
    Time to VGPR or better is the duration from the date of randomization to the date of initial documentation of VGPR or better, which was confirmed by a repeated measurement as required by the IMWG criteria.
11. Time to Partial Response (PR) or Better [ Time Frame: From randomization to the date of initial documentation of PR or better (up to 2 years and 5 months) ]
    Time to PR or better is the duration from the date of randomization to the date of initial documentation of PR or better, which was confirmed by a repeated measurement as required by the IMWG criteria.
12. Progression-free Survival (PFS) [ Time Frame: Up to 24 months ]
    PFS is defined as the duration from the date of randomization to the date of first documented evidence of progressive disease or death, whichever comes first. PD is defined as an increase of 25 % from the lowest response value in one of the following: serum and urine M-component (absolute increase must be >= 0.5 g/dL and >=200 mg/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL); Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
13. Overall Survival (OS) [ Time Frame: From randomization to the date of initial documentation of participant's death (up to 2 years and 5 months) ]
    OS is measured from the date of randomization to the date of the participant's death.
14. Time to Progression (TTP) [ Time Frame: From randomization to the date of first documented evidence of progressive disease (up to 2 years and 5 months) ]
    TTP is defined as the duration from the date of randomization to the date of first documented evidence of progressive disease according to the IMWG criteria.
15. Duration of Response [ Time Frame: From the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive (up to 2 years and 5 months) ]
    Duration of response is defined as the duration from the date of initial documentation of a response (PR or better) according to the IMWG criteria to the date of first documented evidence of progressive disease according to the IMWG criteria. PD is defined as an increase of 25 % from the lowest response value in one of the following: serum and urine M-component (absolute increase must be >= 0.5 g/dL and >=200 mg/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be > 10 mg/dL); Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Considered by the investigator to be eligible for high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) according to the institution's criteria based on age, medical history, cardiac and pulmonary status, overall health and condition, co-morbid condition(s), physical examination, and laboratory studies
• Has not had prior systemic therapy for multiple myeloma. An emergency course of steroids (defined as no greater than 40 milligram [mg] of dexamethasone, or equivalent per day for a maximum of 4 days (that is, a total of 160 mg) is permitted. In addition, radiation therapy is permitted prior to study entry, during screening, and during Cycles 1-2 of study treatment as needed for lytic bone disease
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
• Woman of childbearing potential must have 2 negative highly sensitive serum (beta-human chorionic gonadotropin [b-hCG]) during screening, the first one within 10 to 14 days prior to the first dose of any component of study treatment and the second within 24 hours prior to the first dose of any component of study treatment
• A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study (including during dose interruptions), and for 4 weeks following discontinuation of lenalidomide, and if receiving daratumumab, for 3 months after the last dose

Exclusion Criteria:

• Diagnosed or treated for malignancy other than multiple myeloma, except: a) Malignancy treated with curative intent and with no known active disease present for more than equal to (>= )3 years before randomization; b) Adequately treated non-melanoma skin cancer, lentigo maligna or in situ malignancies (including but not limited to, cervical, breast) with no evidence of disease
• Exhibiting clinical signs of or has a known history of meningeal or central nervous system involvement by multiple myeloma
• Known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) less than (<)50 percent (%) of predicted normal
• Known moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification
• Known to be seropositive for human immunodeficiency virus, known to have hepatitis B surface antigen positivity, or known to have a history of hepatitis C. Participants who completed treatment for hepatitis C at least 6 months prior to screening and have no detectable circulating hepatitis C virus (HCV) at screening, may participate in the study. Such participants will be required to undergo regular assessment for HCV reactivation during their participation in the study. Participants who test positive for HCV at any time during these assessments will be withdrawn from the study

Contacts and Locations

Locations

United States, Alabama

Birmingham, Alabama, United States

United States, California

Duarte, California, United States

La Jolla, California, United States

Los Angeles, California, United States

San Francisco, California, United States

United States, Colorado

Aurora, Colorado, United States

United States, District of Columbia

Washington, District of Columbia, United States

United States, Florida

Orlando, Florida, United States

Tampa, Florida, United States

United States, Georgia

Atlanta, Georgia, United States

United States, Illinois

Chicago, Illinois, United States

United States, Kansas

Westwood, Kansas, United States

United States, Louisiana

New Orleans, Louisiana, United States

United States, Maryland

Baltimore, Maryland, United States

United States, Massachusetts

Boston, Massachusetts, United States

Worcester, Massachusetts, United States

United States, Michigan

Detroit, Michigan, United States

United States, Missouri

Saint Louis, Missouri, United States

United States, Nebraska

Omaha, Nebraska, United States

United States, New York

Buffalo, New York, United States

New York, New York, United States

United States, North Carolina

Chapel Hill, North Carolina, United States

Charlotte, North Carolina, United States

Durham, North Carolina, United States

Winston-Salem, North Carolina, United States

United States, Ohio

Columbus, Ohio, United States

United States, Oregon

Portland, Oregon, United States

United States, Pennsylvania

Abington, Pennsylvania, United States

Philadelphia, Pennsylvania, United States

United States, Tennessee

Nashville, Tennessee, United States

United States, Texas

Dallas, Texas, United States

Houston, Texas, United States

United States, Utah

Salt Lake City, Utah, United States

United States, Washington

Seattle, Washington, United States

Spokane, Washington, United States

United States, Wisconsin

Milwaukee, Wisconsin, United States

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

  Study Documents (Full-Text)

Documents provided by Janssen Research & Development, LLC:

Study Protocol  [PDF] January 10, 2019

Statistical Analysis Plan  [PDF] February 27, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Voorhees PM, Rodriguez C, Reeves B, Nathwani N, Costa LJ, Lutska Y, Bobba P, Hoehn D, Pei H, Ukropec J, Qi M, Lin TS, Richardson PG. Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN. Blood Adv. 2021 Feb 23;5(4):1092-1096. doi: 10.1182/bloodadvances.2020003642.

Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, Chari A, Silbermann R, Costa LJ, Anderson LD Jr, Nathwani N, Shah N, Efebera YA, Holstein SA, Costello C, Jakubowiak A, Wildes TM, Orlowski RZ, Shain KH, Cowan AJ, Murphy S, Lutska Y, Pei H, Ukropec J, Vermeulen J, de Boer C, Hoehn D, Lin TS, Richardson PG. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020 Aug 20;136(8):936-945. doi: 10.1182/blood.2020005288.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT02874742
• Other Study ID Numbers: CR108195; 54767414MMY2004 ( Other Identifier: Janssen Research & Development, LLC )
• First Posted: August 22, 2016
• Results First Posted: February 7, 2020
• Last Update Posted: February 16, 2021
• Last Verified: January 2021

• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Dexamethasone; Lenalidomide; Bortezomib; Daratumumab; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Immunologic Factors