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

NCT ID: NCT03224507

Last Updated: 2023-11-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 123 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-14
• Study Completion Date: 2023-06-30

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.

Detailed Description

This trial will assess the safety and efficacy of an induction therapy using the combination of dexamethasone, lenalidomide (revlimid), daratumumab (Darzalex) and carfilzomib (Kyprolis) to treat patients with newly diagnosed multiple myeloma. The therapy with KRdD (Kyprolis, Revlimid, dexamethasone, Darzalex) will be followed by autologous hematopoietic cell transplantation (auto-HCT) and KRdD consolidation. Duration of therapy will be guided by eradication of minimal residual disease (MRD). The hypothesis is that the KRdD therapy particularly in combination with the auto-HCT will be safe and lead to deep remission. Patients who become MRD- will discontinue therapy (no maintenance therapy) and be actively monitored for resurgence of MRD or clinical relapse.

Conditions

Multiple Myeloma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

KRdD followed by auto-HCT

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.

Group Type: EXPERIMENTAL

KRdD followed by auto-HCT

Intervention Type: 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.

KRdD only

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.

Group Type: EXPERIMENTAL

KRdD only

Intervention Type: 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.

Interventions

KRdD followed by auto-HCT

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.

Intervention Type: DRUG

KRdD only

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.

Intervention Type: DRUG

Other Intervention Names

KRdD = Kyprolis (Carfilzomib), Revlimid (Lenalidomide), dexamethasone, Darzalex (Daratumumab); KRdD = Kyprolis (Carfilzomib), Revlimid (Lenalidomide), dexamethasone, Darzalex (Daratumumab)

Eligibility Criteria

Inclusion Criteria

• 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:

1. Serum monoclonal (M) protein ≥1.0 g/dl

2. ≥ 200 mg of M protein/24h in the urine

3. 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.

Exclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: collaborator

Janssen Scientific Affairs, LLC

INDUSTRY

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Luciano Jose Costa, MD

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Luciano J Costa, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Oregon Health and Science University

Portland, Oregon, United States

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, United States

University of Wisconsin, school of medicine and public health

Madison, Wisconsin, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 40193714 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38649340 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37776872 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34898239 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

F170525008 (UAB 1735)

Identifier Type: -

Identifier Source: org_study_id