Dexamethasone, Lenalidomide, Carfilzomib, and Daratumumab in Treating Participants with Multiple Myeloma

Status: Active

Description

This phase II trial studies how well dexamethasone, lenalidomide, carfilzomib, and daratumumab work in treating participants with multiple myeloma. Drugs used in chemotherapy, such as dexamethasone, lenalidomide, and carfilzomib, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as daratumumab, may interfere with the ability of cancer cells to grow and spread. Giving dexamethasone, lenalidomide, carfilzomib, and daratumumab may work better in treating participants with multiple myeloma.

Eligibility Criteria

Inclusion Criteria

  • 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/m^2) and/or cyclophosphamide up to 1000 mg/m^2 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, characterized by one of the following parameters: * Serum monoclonal (M) protein >= 1 g/dl by protein electrophoresis * > 200 mg of M protein in the urine on 24 hour electrophoresis * Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
  • Life expectancy >= 12 months
  • Serum alanine aminotransferase (ALT) =< 3.5 times the upper limit of normal within 21 days prior to initiation of therapy
  • Serum direct bilirubin =< 2 mg/dL (34 umol/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 (e.g., Cockcroft and Gault)
  • Written informed consent in accordance with federal, local, and institutional guidelines
  • Females of childbearing potential (FCBP) 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 Risk Evaluation and Mitigation Strategy (REMS) program

Exclusion Criteria

  • Diagnosis of amyloidosis, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS), Waldenstrom’s macroglobulinemia
  • Major surgery, radiotherapy or infection requiring therapy within 14 days of starting treatment
  • Known forced expiratory volume in 1 second (FEV1) or corrected carbon monoxide diffusing capability (cDLCO) < 50% of predicted
  • Pregnant or lactating females
  • Known human immunodeficiency virus infection
  • Active hepatitis B (hepatitis [Hep] B core antibody positive and subsequent Hep B surface antigen positive or Hep B deoxyribonucleic acid [DNA] positive) or hepatitis C infection (Hep C antibody positive and subsequent detectable viral load)
  • Unstable angina or myocardial infarction within 4 months prior to registration, New York Heart Association (NYHA) 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 transient ischemic attack (TIA) in the 12 months prior to initiation of therapy
  • Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or 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
  • Contra indication 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

Locations & Contacts

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: Active
Contact: Luciano Jose Megale Costa
Phone: 205-975-3371

Oregon

Portland
Oregon Health and Science University
Status: Active
Contact: Eva Medvedova
Email: medvedov@ohsu.edu

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: Active
Contact: Robert Frank Cornell
Email: robert.f.cornell@vanderbilt.edu

Wisconsin

Madison
University of Wisconsin Hospital and Clinics
Status: Active
Contact: Natalie Scott Callander
Email: nsc@medicine.wisc.edu
Milwaukee
Froedtert and the Medical College of Wisconsin
Status: Active
Contact: Saurabh Chhabra
Phone: 414-805-0505

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the frequency of minimal residual disease (MRD)(-) remissions (=< 10^-5 multiple myeloma [MM]-associated molecules) after completion of intense treatment plan that consist of induction therapy, followed by consolidation therapy with a multi-drug regimen combined with continuous daratumumab therapy in patients with newly diagnosed multiple myeloma.

SECONDARY OBJECTIVES:

I. To determine the toxicity profile of the combination of carfilzomib, lenalidomide, dexamethasone and daratumumab (KRdD) in the treatment of patients with newly diagnosed MM.

II. To determine the frequency of Imaging plus MRD-negative patients (=< 10^-5 MM-associated molecules in bone marrow and no area of positron emission tomography (PET)/computed tomography (CT) fludeoxyglucose F-18 (FDG) uptake greater than mediastinal blood pool or surrounding normal tissue).

III. To determine the frequency of MRD(-) status after induction therapy with KRdD.

IV. To determine the frequency of conversion from MRD(+) to MRD(-) status with autologous hematopoietic cell transplantation (auto-HCT) after completion of KRdD induction.

V. To determine the frequency of patients achieving complete remission (CR) with the above mentioned treatment regimen.

VI. To determine the feasibility and effectiveness of MRD-guided treatment discontinuation in newly diagnosed MM patients that have confirmed MRD(-).

VII. To determine the risk and timing of resurgence of MRD (>= 10^-5) after discontinuation of therapy in confirmed MRD(-) patients.

OUTLINE:

INDUCTION: Participants receive dexamethasone orally (PO) on days 1, 8, 15, and 22, lenalidomide PO daily on day 1-21, carfilzomib intravenously (IV) over 30 minutes on days 8 and 15 of course 1 and on days 1, 8, and 15 of courses 2-4, and daratumumab IV on days 1, 8, 15, and 22 of courses 1-2 and on days 1 and 15 of courses 3-4. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unaccepted toxicity.

Participants then undergo standard of care auto-HCT.

CONSOLIDATION BLOCK 1: Participants receive dexamethasone PO on days 1, 8, 15, and 22, lenalidomide PO daily on days 1-21, carfilzomib IV over 30 minutes on days 1, 8, and 15, and daratumumab IV on days 1 and 15 of courses 1-2 and on day 1 of courses 3-4. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unaccepted toxicity. Participants not achieving confirmed MRD(-) status continue to Block 2.

CONSOLIDATION BLOCK 2: Participants receive dexamethasone, lenalidomide, carfilzomib, and daratumumab as in Block 1. Participants not achieving confirmed MRD(-) status continue to Block 3.

CONSOLIDATION BLOCK 3: Participants receive dexamethasone, lenalidomide, and carfilzomib as in Block 1. Participants also receive daratumumab IV on day 1. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unaccepted toxicity.

Participants with confirmed MRD(-) status then undergo active surveillance over 72 weeks. Participants with confirm MRD(+) status continue to receive lenalidomide PO daily in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, participants are followed up every 16 weeks.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Alabama at Birmingham Cancer Center

Principal Investigator
Luciano Jose Megale Costa

Trial IDs

Primary ID UAB1735
Secondary IDs NCI-2018-01447
Clinicaltrials.gov ID NCT03224507