Carfilzomib, Lenalidomide, Dexamethasone, Daratumumab, Melphalan, and Stem Cell Transplant in Treating Participants with Relapsed or Refractory Multiple Myeloma

Status: Active

Description

This phase II trial studies how well carfilzomib, lenalidomide, dexamethasone, daratumumab, melphalan, and stem cell transplant work in treating participants with multiple myeloma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as carfilzomib, lenalidomide, dexamethasone, and melphalan, 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 chemotherapy before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient’s bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving carfilzomib, lenalidomide, dexamethasone, daratumumab, melphalan, and stem cell transplant may work better in treating participants with multiple myeloma.

Eligibility Criteria

Inclusion Criteria

  • Patient must be capable, willing, and able to provide written, informed consent
  • Histologic confirmation of multiple myeloma by the enrolling institution
  • Symptomatic myeloma that has progressed/relapsed after 1 to 3 prior lines of therapy
  • Patients who have received =< 1 cycle of therapy after most recent progression/relapse are eligible to enroll on study * Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with current or prior corticosteroids is permitted * Bisphosphonates are permitted * Concurrent or prior treatment with corticosteroids for indications other than multiple myeloma is permitted * Prior treatment with radiotherapy is permitted * Patients with measurable disease who received up to one cycle of any therapy within 60 days with a washout period of 4 weeks from last dose (on a trial or outside a trial) are eligible
  • More than 2 x 10^6 autologous CD34+ cells/kg cryopreserved. The graft may not be CD34+ selected or otherwise manipulated to remove tumor or other cells. The graft can be collected at the transplanting institution or by a referring center
  • Planning to receive autologous HCT per institutional standards as part of standard of care. Eligibility for autologous HCT should be based on institutional guidelines. However, at minimum all patients must meet the following criteria: * Karnofsky performance status (KPS) greater than 70 * Cardiac left ventricular ejection fraction of greater than 40% * Calculated creatinine clearance of greater than 40 cc/min * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of less than 2 x upper limit of normal * Direct bilirubin of less than 2 x upper limit of normal
  • Measurable disease as defined by any of the following International Myeloma Working Group Criteria * Monoclonal serum peak of greater than 0.5 gms per deciliter * Measurable urine peak as defined by urine protein electrophoresis of greater than 100 mg per 24 hours * Serum free light chain (FLC) assay: involved FLC level >= 10 mg/dL provided serum FLC ratio is abnormal
  • Hemoglobin >= 8 g/dL (80 g/L) within 14 days prior to enrollment (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)
  • Platelet count >= 50 x 10^9/L (>= 30 x 10^9/L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to initial treatment (subjects may be receiving platelet transfusions in accordance with institutional guidelines)
  • Women of childbearing potential (WOCBP) must agree to ongoing pregnancy testing and to practice contraception and required by the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program * A woman of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy or has not been naturally postmenopausal for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months)
  • Male subjects must agree to practice contraception
  • All study participants must be registered into the mandatory Revlimid REMS program and be willing and able to comply with the requirements of the REMS program

Exclusion Criteria

  • Plasma cell leukemia (> 20% circulating plasma cells) during screening studies
  • Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin (POEMS) syndrome
  • Pregnant or lactating females. Because there is a potential risk for adverse events nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide. These potential risks may also apply to other agents used in this study
  • Uncontrolled hypertension or diabetes
  • Active hepatitis B or C infection * Patients with hepatitis B virus (HBV) core antibody positive, but HBV polymerase chain reaction (PCR) negative are eligible if they are on medication for suppression of HBV reactivation * Patients with hepatitis C virus (HCV) antibody positive, but PCR negative are eligible
  • Serologically positive human immunodeficiency virus (HIV) (testing required during screening)
  • Significant cardiovascular disease with New York Heart Association (NYHA) class III or IV symptoms, ejection fraction (EF) =< 40% or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 6 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination. Echocardiogram will be performed during screening evaluation
  • Moderate or severe pulmonary hypertension defined as pulmonary arterial systolic pressure (PASP) > 50 mm Hg
  • Refractory gastrointestinal (GI) disease that would prevent absorption of oral agents
  • Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements
  • Significant neuropathy >= grade 3 or grade 2 neuropathy with pain at baseline
  • Contraindication to any concomitant medication, including antivirals or anticoagulation
  • Major surgery within 3 weeks prior to first dose
  • Prior allogeneic HCT (prior autologous transplant is allowed regardless of response)
  • History of central nervous system (CNS) involvement by myeloma
  • Disease progression as defined by International Myeloma Working (IMW) Criteria on the combination of carfilzomib, lenalidomide and dexamethasone (patients with progression on lenalidomide maintenance after completion of carfilzomib, lenalidomide and dexamethasone combination therapy will be eligible)
  • Disease progression on daratumumab
  • Prior dose limiting toxicity from carfilzomib or lenalidomide

Locations & Contacts

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: Approved
Contact: Luciano Jose Megale Costa
Email: ljcosta@uabmc.edu

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Gunjan L. Shah
Phone: 212-639-8356
Cherry Hill
University of Pennsylvania Health System
Status: Approved
Contact: Dan T Vogl
Email: Dan.Vogl@uphs.upenn.edu
Hackensack
Hackensack University Medical Center
Status: Approved
Contact: Joshua Richter
Phone: 212-639-8356
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Gunjan L. Shah
Phone: 212-639-8356
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Gunjan L. Shah
Phone: 212-639-8356

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Gunjan L. Shah
Phone: 212-639-8356
Manhasset
Northwell Health
Status: Approved
Contact: Ruthee-Lu Bayer
Email: RBayer@northwell.edu
New York
Columbia University / Herbert Irving Cancer Center
Status: Approved
Contact: Markus Y. Mapara
Email: mym2111@cumc.columbia.edu
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Gunjan L. Shah
Phone: 212-639-8356
Rockville Centre
Memorial Sloan Kettering Rockville Centre
Status: Active
Contact: Gunjan L. Shah
Phone: 212-639-8356
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Gunjan L. Shah
Phone: 212-639-8356

North Carolina

Durham
Duke University Medical Center
Status: Approved
Contact: Christina Gasparetto
Email: cristina.gasparetto@duke.edu
Winston-Salem
Wake Forest University Health Sciences
Status: Approved
Contact: Cesar Rodriguez
Email: cerodrig@wakehealth.edu

Wisconsin

Milwaukee
Froedtert and the Medical College of Wisconsin
Status: Approved
Contact: Saurabh Chhabra
Email: schhabra@mcw.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Determine the complete remission rate (CR) of a treatment strategy that includes 4 cycles of re-induction therapy with carfilzomib-lenalidomide-dexamethasone and daratumumab (Dara-CRd) followed by high dose melphalan and autologous hematopoietic cell transplantation (HCT) followed by 4 cycles of consolidation with the same regimen in patients with multiple myeloma (MM) that have received between 1 to 3 lines of prior therapy.

SECONDARY OBJECTIVES:

I. Determine the toxicity of the proposed treatment strategy.

II. Prospectively characterize the longitudinal symptom burden of the proposed treatment strategy.

III. Evaluate impact of depth of response (=< partial response [PR] versus [vs] >= very good partial response [VGPR] after the 4 cycles of reinduction) on the progression free survival (PFS) of this treatment strategy from the time of transplant.

IV. Estimate overall survival and progression-free survival for proposed treatment strategy from treatment initiation and time of transplant.

V. Evaluate the rate of minimal residual disease negative complete response (CR) rate (minimal residual disease [MRD]-CR) of the proposed treatment strategy using both multi-parametric flow cytometry (MFC) and next generation sequencing (NGS). (Memorial Sloan Kettering [MSK] patients)

VI. Explore outcomes based on MRD negativity by multi-parametric flow cytometry (MFC) and next generation sequencing (NGS). (MSK patients)

OUTLINE:

INDUCTION: Participants receive carfilzomib intravenously (IV) over 30 minutes on days 1, 2, 8, 9, 15, and 16, lenalidomide orally (PO) on days 1-21, dexamethasone PO or IV on days 1, 2, 8, 9, 15, 16, 22, and 23, 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 up to 4 courses in the absence of disease progression or unaccepted toxicity.

Within 4-6 weeks of the 4th INDUCTION course, participants receive melphalan IV on days -2 or -1, and undergo autologous HCT on day 0.

CONSOLIDATION: 60-90 days after autologous HCT, participants receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16, lenalidomide PO on days 1-21, dexamethasone PO or IV on days 1, 2, 8, 9, 15, 16, 22, and 23, daratumumab IV on days of 1 and 15 of courses 1-2 and on day 1 of courses 3-4. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unaccepted toxicity.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Gunjan L. Shah

Trial IDs

Primary ID 17-493
Secondary IDs NCI-2018-01445
Clinicaltrials.gov ID NCT03556332