Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma

NCT03224507 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: F170525008 (UAB 1735)
• Study Type: interventional
• Target: 123
• Locations: 1 country
• Sites: 4

Brief Summary

Multiple myeloma (MM), a plasma cell disorder, is the second most common hematologic malignancy in the U.S. No standard curative therapy has yet been found. A variety of therapeutic measures including high dose melphalan, induction therapy, and continuous therapy have been used but the goal of complete response without relapse has not been achieved. More active treatment regimens and better tools for response assessment are needed.

Conditions

Multiple Myeloma

Keywords

multiple myeloma; induction therapy; autologous hematopoietic cell transplantation; KRdD; Daratumumab; Carfilzomib; Lenalidomide

Outcome Measures

Primary Outcomes (1)

• Percentage of Patients With MRD(-) Remissions at the Completion of Consolidation Therapy

  The primary endpoint of MRD(-) rate, or percentage of patients with MRD(-) remissions, will be estimated along with two-sided 95% confidence interval using Clopper-Pearson exact method. Simon's optimal two-stage design will be utilized in determining the rate of MRD(-) cases. MRD assessment will be done with ClonoSEQ to identify myeloma-specific sequences.

  Baseline until MRD(-) is reached estimated to be up to 15 months.

Secondary Outcomes (7)

• Serious Adverse Events (SAEs) From the KRdD Treatment

  Baseline until the progression of disease or MRD(-) status up to an estimated 15 months.

• Percentage of Patients With MRD(-) Status at the Completion of Induction Therapy

  Baseline until MRD(-) status estimated at 6 months or until disease progression

• Percentage of Patients With Auto-HCT That Convert From Positive to Negative MRD

  From baseline up to an estimated 9 months

• Percentage of Patients Achieving Complete Remission Following Complete Therapy

  Baseline up to 15 months

• Percentage of Patients That Convert From MRD(-) to MRD(+) Following Treatment Discontinuation

  Baseline to 2 years

Study Arms (2)

KRdD followed by auto-HCT

EXPERIMENTAL

Cycle 1-Dexamethasone 40mg orally days 1/8/15/22; Lenalidomide 25mg orally days 1-21; Carfilzomib 20mg/m2 days 8/9 then 36mg/m2 venous days 15/16; Daratumumab 16mg/kg venous days 1/8/15/22 (KRd-Dara). Cycle 2 the same except Carfilzomib 36mg/m2 venous days 1/2/8/9/15/16. Cycles 3,4 the same but no Daratumumab Days 8 and 22. Dosage adjusted for last tolerated dose (LTD). Following induction therapy, auto-HCT is done (consolidation 1), then up to two 4-cycle blocks of KRd-Dara consolidation (consolidations 2 and 3). Minimum residual disease (MRD) checked after each phase. Patients with confirmed MRD(-) at or after consolidation 1 will not undergo maintenance and will be actively monitored for resurgence of MRD or clinical relapse. After consolidation if MRD+ patients will undergo standard of care lenalidomide maintenance.

Drug: KRdD followed by auto-HCT

KRdD only

EXPERIMENTAL

Cycle 1-Dexamethasone 40mg orally days 1/8/15/22; Lenalidomide 25mg orally days 1-21; Carfilzomib 20mg/m2 days 8/9 then @ 36mg/m2 venous days 15/16; Daratumumab 16mg/kg venous days 1/8/15/22. Cycle 2 the same except Carfilzomib 36mg/m2 venous days 1/2/8/9/15/16. Cycles 3,4 the same but no Daratumumab Day 22. Dosage adjusted for last tolerated dose (LTD). Following induction therapy, Following induction therapy, patients will receive up to three 4-cycle blocks of KRd-Dara consolidation (consolidations 1, 2 and 3). Minimum residual disease (MRD) checked after each phase. Patients with confirmed MRD(-) at or after consolidation 1 will not undergo maintenance and will be actively monitored for resurgence of MRD or clinical relapse. After consolidation if MRD+ patients will undergo standard of care lenalidomide maintenance.

Drug: KRdD only

Interventions

KRdD followed by auto-HCT DRUG

Dosages of each drug will vary depending on therapy type and cycle number. KRdD therapy will be followed by autologous hematopoietic cell transplantation and KRdD consolidation.

Also known as: KRdD = Kyprolis (Carfilzomib), Revlimid (Lenalidomide), dexamethasone, Darzalex (Daratumumab)

KRdD followed by auto-HCT

KRdD only DRUG

Dosages of each drug will vary depending on therapy type and cycle number. KRdD therapy will not be followed by autologous hematopoietic cell transplantation but will proceed with KRdD consolidation.

Also known as: KRdD = Kyprolis (Carfilzomib), Revlimid (Lenalidomide), dexamethasone, Darzalex (Daratumumab)

KRdD only

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>18 years with no upper age limit
• Diagnosis of newly diagnosed multiple myeloma with indication for initiation of therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• No prior MM-directed therapy except for dexamethasone (up to 160 mg) and/or bortezomib (up to 5.2 mg/m2) and/or cyclophosphamide up to 1000 mg/m2 administered for management of acute manifestations of MM (hypercalcemia, renal impairment, pain) for no longer than 4 weeks prior to enrollment. If subject received any prior therapy, pretreatment parameters necessary for disease characterization and response assessment must be available.
• Measurable disease meeting at least one of the following criteria:
• Serum monoclonal (M) protein ≥1.0 g/dl
• ≥ 200 mg of M protein/24h in the urine
• Serum-free light chain ≥10 mg/dL and abnormal kappa to lambda ratio.
• Life expectancy ≥12 months.
• Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 μmol/L) within 21 days prior to initiation of therapy.
• Creatinine clearance (CrCl) ≥ 40 mL/minute within 21 days prior to start of therapy either measured or calculated using a standard formula (eg. Cockcroft and Gault).
• Written informed consent in accordance with federal, local, and institutional guidelines.
• Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception. Male subjects must agree to practice contraception.
• All subjects must agree to comply with and be enrolled in Revlimid REMS program.

You may not qualify if:

• Diagnosis of amyloidosis, Crow-Fukase syndrome, Waldenstrom's macroglobulinemia, smoldering MM.
• Major surgery, radiotherapy or infection requiring therapy within 14 days of starting treatment.
• Known FEV1 or cDLCO \< 50% of predicted.
• Pregnant or lactating females.
• Known human immunodeficiency virus infection.
• Active hepatitis B (Hepatitis B core antibody positive and subsequent Hepatitis B surface antigen positive or Hepatitis B DNA positive) or C infection (Hepatitis C antibody positive and subsequent detectable viral load).
• Unstable angina or myocardial infarction within 4 months prior to registration, New York Heart Association Class II, III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker.
• Cerebrovascular disease manifested as prior stroke at any time or TIA in the 12 months prior to initiation of therapy
• Non-hematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or localized thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas.
• Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 21 days prior to registration.
• Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
• Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 21 days prior to registration.
• Contraindication or intolerance to required supportive care medications (Aspirin and Acyclovir).
• Any other clinically significant medical disease or condition that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.

Sponsors & Collaborators

• University of Alabama at Birmingham: lead
• Amgen: collaborator
• Janssen Scientific Affairs, LLC: collaborator

Study Sites (4)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

University of Wisconsin, school of medicine and public health

Madison, Wisconsin, 53792, United States

Location

Related Publications (4)

• Giri S, Dhakal B, Callander NS, Medvedova E, Godby K, Dholaria BR, Bal S, Ravi G, Chhabra S, Silbermann RW, Costa L. Optimal MRD-based end point to support response-adapted treatment cessation in newly diagnosed multiple myeloma. Blood. 2025 Aug 7;146(6):707-716. doi: 10.1182/blood.2024027674.

  PMID: 40193714 DERIVED

• Callander NS, Silbermann R, Kaufman JL, Godby KN, Laubach J, Schmidt TM, Sborov DW, Medvedova E, Reeves B, Dhakal B, Rodriguez C, Chhabra S, Chari A, Bal S, Anderson LD Jr, Dholaria BR, Nathwani N, Hari P, Shah N, Bumma N, Holstein SA, Costello C, Jakubowiak A, Wildes TM, Orlowski RZ, Shain KH, Cowan AJ, Pei H, Cortoos A, Patel S, Lin TS, Giri S, Costa LJ, Usmani SZ, Richardson PG, Voorhees PM. Daratumumab-based quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma with high cytogenetic risk. Blood Cancer J. 2024 Apr 22;14(1):69. doi: 10.1038/s41408-024-01030-w.

  PMID: 38649340 DERIVED

• Costa LJ, Chhabra S, Medvedova E, Dholaria BR, Schmidt TM, Godby KN, Silbermann R, Dhakal B, Bal S, Giri S, D'Souza A, Hall AC, Hardwick P, Omel J, Cornell RF, Hari P, Callander NS. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol. 2023 Nov;10(11):e890-e901. doi: 10.1016/S2352-3026(23)00236-3. Epub 2023 Sep 27.

  PMID: 37776872 DERIVED

• Costa LJ, Chhabra S, Medvedova E, Dholaria BR, Schmidt TM, Godby KN, Silbermann R, Dhakal B, Bal S, Giri S, D'Souza A, Hall A, Hardwick P, Omel J, Cornell RF, Hari P, Callander NS. Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2022 Sep 1;40(25):2901-2912. doi: 10.1200/JCO.21.01935. Epub 2021 Dec 13.

  PMID: 34898239 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

carfilzomib; Lenalidomide; Dexamethasone; daratumumab

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Luciano J Costa- Principal Investigator
• Organization: University of Alabama at Birmingham

ljcosta@uabmc.edu

2059349695

Study Officials

• Luciano J Costa, MD, PhD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: The study has four cycles (28-days each) of drug therapy prior to being evaluated for auto-HCT. After the completion of induction therapy, the patient will be evaluated for a transplant of their own hematopoietic stem cells. If, after the transplant, the patient still has detectable multiple myeloma, the patient will proceed to a series of consolidation blocks, up to three, consisting of four cycles of the KRdD at specified dosages and time frames. After completion of consolidation therapy, maintenance therapy will begin until disease progression or intolerance.

Study Record Dates

• First Submitted: July 10, 2017
• First Posted: July 21, 2017
• Study Start: March 14, 2018
• Primary Completion: May 1, 2023
• Study Completion: June 30, 2023
• Last Updated: November 24, 2023
• Results First Posted: November 22, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)