Clinical trial NCT03224507: Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma
Official title: Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma - MASTER Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: multiple myeloma
induction therapy
autologous hematopoietic cell transplantation
KRdD
Daratumumab
Carfilzomib
Lenalidomide
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: Amgen
name: Janssen Scientific Affairs, LLC
First posted: 2017-07-21
Enrollment: 123
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Patients With MRD(-) Remissions at the Completion of Consolidation Therapy
timeFrame: Baseline until MRD(-) is reached estimated to be up to 15 months.
Secondary outcomes:
measure: Serious Adverse Events (SAEs) From the KRdD Treatment
timeFrame: Baseline until the progression of disease or MRD(-) status up to an estimated 15 months.
measure: Percentage of Patients With MRD(-) Status at the Completion of Induction Therapy
timeFrame: Baseline until MRD(-) status estimated at 6 months or until disease progression
measure: Percentage of Patients With Auto-HCT That Convert From Positive to Negative MRD
timeFrame: From baseline up to an estimated 9 months
measure: Percentage of Patients Achieving Complete Remission Following Complete Therapy
timeFrame: Baseline up to 15 months
measure: Percentage of Patients That Convert From MRD(-) to MRD(+) Following Treatment Discontinuation
timeFrame: Baseline to 2 years
measure: Progression-free Survival
timeFrame: From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months.
measure: Overall Survival
timeFrame: From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 58 months.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt Ingram Cancer Center
state: Tennessee
city: Madison
country: United States
facility: University of Wisconsin, school of medicine and public health
state: Wisconsin
Study officials:
affiliation: University of Alabama at Birmingham
name: Luciano J Costa, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.