Monoclonal Antibody-Based Sequential Therapy for Deep Remission in Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: KRdD followed by auto-HCT; KRdD only
Intervention description: 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.; 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 MeSH terms: Dexamethasone; Dexamethasone acetate; Lenalidomide; Daratumumab; BB 1101; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
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.
Masking: None (Open Label)
Enrollment: 123.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: multiple myeloma; induction therapy; autologous hematopoietic cell transplantation; KRdD; Daratumumab; Carfilzomib; Lenalidomide

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.
    

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.