A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis
Condition: Amyloidosis
MeSH terms: Amyloidosis
Intervention: Cyclophosphamide; Bortezomib; Dexamethasone, 40 mg; Daratumumab
Intervention description: Participants will receive 300 mg/m^2 of cyclophosphamide as an oral or IV dose.; Participants will receive 1.3 mg/m^2 of bortezomib as an subcutaneous (SC) injection.; Participants of CyBorD alone arm will receive 40 mg dexamethasone orally or IV dose. Participants of CyBorD plus daratumumab arm will receive dexamethasone 20 mg orally or IV dose as premedication and 20 mg on the day after daratumumab dosing to make a total of 40 mg.; Participants will receive 1800 mg of daratumumab subcutaneously.
Intervention MeSH terms: Dexamethasone; Cyclophosphamide; Bortezomib; Daratumumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 416.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the efficacy and safety of daratumumab plus
      cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared with CyBorD alone in
      treatment of newly diagnosed amyloid light chain (AL) amyloidosis participants.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry
             and polarizing light microscopy of green bi-refringent material in congo red stained
             tissue specimens (in an organ other than bone marrow) or characteristic electron
             microscopy appearance

          -  Measurable disease of amyloid light-chain (AL) amyloidosis as defined by at least one
             of the following:

               1. serum monoclonal (M)-protein greater than or equal (>=) 0.5 grams/deciliter
                  (g/dL) by protein electrophoresis (routine serum protein electrophoresis and
                  immunofixation [IFE] performed at a central laboratory)

               2. serum free light chain greater than or equal to (>=) 50 milligram/Liter (mg/L)
                  with an abnormal kappa:lambda ratio or the difference between involved and
                  uninvolved free light chains (dFLC) >= 50 mg/L

          -  One or more organs impacted by AL amyloidosis according to consensus guidelines

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2

        Exclusion Criteria:

          -  Prior therapy for AL amyloidosis or multiple myeloma including medications that target
             CD38, with the exception of 160 mg dexamethasone (or equivalent corticosteroid)
             maximum exposure prior to randomization

          -  Previous or current diagnosis of symptomatic multiple myeloma, including the presence
             of lytic bone disease, plasmacytomas, >= 60 percent (%) plasma cells in the bone
             marrow, or hypercalcemia

          -  Evidence of significant cardiovascular conditions as specified below:

               1. NT-ProBNP > 8500 nanogram per liter (ng/L)

               2. New York Heart Association (NYHA) classification IIIB or IV heart failure

               3. Heart failure that in the opinion of the investigator is on the basis of ischemic
                  heart disease (eg, prior myocardial infarction with documented history of cardiac
                  enzyme elevation and electrocardiogram [ECG] changes) or uncorrected valvular
                  disease and not primarily due to AL amyloid cardiomyopathy

               4. Inpatient admission to a hospital for unstable angina or myocardial infarction
                  within the last 6 months prior to first dose or percutaneous cardiac intervention
                  with recent stent within 6 months or coronary artery bypass grafting within 6
                  months

               5. For participants with congestive heart failure, cardiovascular-related
                  hospitalizations within 4 weeks prior to randomization

               6. Participants with a history of sustained ventricular tachycardia or aborted
                  ventricular fibrillation or with a history of atrioventricular (AV) nodal or
                  sinoatrial (SA) nodal dysfunction for which a pacemaker/implantable
                  cardioverter-defibrillators [ICD] is indicated but not placed (participants who
                  do have a pacemaker/ICD are allowed on study)

               7. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's
                  formula (QTcF) > 500 milliseconds (msec). Participants who have a pacemaker may
                  be included regardless of calculated QTc interval

               8. Supine systolic blood pressure < 90 millimeter of mercury (mmHg), or symptomatic
                  orthostatic hypotension, defined as a decrease in systolic blood pressure upon
                  standing of > 20 mmHg despite medical management (eg, midodrine,
                  fludrocortisones) in the absence of volume depletion

          -  Planned stem cell transplant during the first 6 cycles of protocol therapy are
             excluded. Stem cell collection during the first 6 cycles of protocol therapy is
             permitted

          -  Known to be seropositive for human immunodeficiency virus (HIV)

          -  Any one of the following:

               1. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
                  antigen [HBsAg]). Participants with resolved infection (ie, participants who are
                  HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc]
                  and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened
                  using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus
                  (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be
                  excluded

               2. Known to be seropositive for hepatitis C (except in the setting of a sustained
                  virologic response [SVR], defined as aviremia at least 12 weeks after completion
                  of antiviral therapy)

          -  Grade 2 sensory or Grade 1 painful peripheral neuropathy