Study to Evaluate Safety Tolerability & Efficacy of Kyprolis (Carfilzomib) in Relapsed or Refractory Multiple Myeloma
Condition: Relapsed Refractory Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Drug: Carfilzomib + Dexamethasone; Drug: Carfilzomib + Lenalidomide + Dexamethasone
Intervention description: Drug: Carfilzomib + Dexamethasone
Carfilzomib will be administered as a 30-minute infusion.
Dexamethasone will be taken by mouth or intravenously.; Drug: Carfilzomib + Lenalidomide + Dexamethasone
Carfilzomib will be administered as a 10 minute infusion.
Lenalidomide will be taken orally.
Dexamethasone will be taken by mouth or intravenously.
Intervention MeSH terms: Dexamethasone; Dexamethasone acetate; Lenalidomide; BB 1101
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 101.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      To characterize safety associated with the use of Kyprolis under the locally approved label.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Documented RRMM after last treatment. Refractory is defined as meeting 1 or more of
             the following: Nonresponsive to most recent therapy (stable disease [SD] or
             progressive disease [PD]) while on treatment, or Disease progression within 60 days of
             discontinuation from the most recent therapy.

          -  Eligible to receive Kyprolis per the locally approved label.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

          -  Adequate hepatic function within 28 days prior to enrollment: bilirubin < 1.5 times
             the upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine
             aminotransferase (ALT) < 2.5 times the ULN.

          -  Absolute neutrophil count (ANC) ≥ 1.0 x 10^9 /L within 28 days prior to enrollment.
             (Screening ANC should be independent of granulocyte- and granulocyte macrophage-colony
             stimulating factor support for at least 1 week and of pegylated granulocyte
             stimulating factor for ≥ 2 weeks).

          -  Hemoglobin ≥ 80 g/L within 28 days prior to enrollment. Subjects should not have
             received red blood cell (RBC) transfusions for at least 7 days prior to obtaining the
             screening hemoglobin.

          -  Platelet count ≥ 75 x 10^9/L (≥ 50 x 10^9/L if myeloma involvement in the bone marrow
             is ≥ 50%) within 28 days prior to enrollment. Subjects should not have received
             platelet transfusions for at least 7 days prior to obtaining the screening platelet
             count.

          -  Adequate renal function within 28 days prior to enrollment (either measured or
             calculated using a standard formula such as the Cockcroft and Gault): calculated or
             measured creatinine clearance (CrCl) of ≥ 50 mL/min for subjects receiving KRd;
             calculated or measured CrCl of ≥ 15 mL/min for subjects receiving Kd.

          -  Left ventricular ejection fraction ≥ 40% as assessed by transthoracic echocardiogram
             (TTE) or multigated acquisition scan (MUGA).

          -  Females of childbearing potential (FCBP) must have a negative serum pregnancy test
             within the 10 to 14 days prior to enrollment and a negative urine pregnancy test
             within the 24 hours prior to day 1 of each cycle prior to dosing.

          -  Subject or legally acceptable representative has provided informed consent/assent
             prior to initiation of any study specific activities/procedures.

        Exclusion Criteria:

          -  Waldenström macroglobulinemia.

          -  Plasma cell leukemia (> 2.0 x 10^9/L circulating plasma cells by standard
             differentials).

          -  POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
             skin changes)

          -  Myelodysplastic síndrome.

          -  Primary amyloidosis (subjects with multiple myeloma with asymptomatic deposition of
             amyloid plaques found on biopsy would be eligible if all other criteria are met).

          -  History of other malignancy within the past 5 years, with the following exception[s]:
             Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
             disease. Adequately treated cervical carcinoma in situ without evidence of disease.
             Adequately treated breast ductal carcinoma in situ without evidence of disease.
             Prostatic intraepithelial neoplasia without evidence of prostate cáncer. Adequately
             treated urothelial papillary noninvasive carcinoma or carcinoma in situ.

          -  Known immediate or delayed hypersensitivity reaction to Captisol (a cyclodextrin
             derivative used to solubilize Kyprolis).

          -  Contraindication to any of the required concomitant drugs or supportive treatments,
             including hypersensitivity to antiviral drugs.

          -  Intolerance to hydration.

          -  Active congestive heart failure (New York Heart Association [NYHA] Class III to IV),
             symptomatic ischemia, uncontrolled arrhythmias, clinically significant echocardiogram
             (ECHO) abnormalities, screening ECG with corrected QT interval (QTc) of > 470 msec,
             pericardial disease, or myocardial infarction within 4 months prior to enrollment.

          -  Infiltrative pulmonary disease and/or known pulmonary hypertension.

          -  Active infection within 14 days prior to enrollment requiring systemic antibiotics,
             antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents.
             Such infections must be fully resolved prior to initiating study treatment.

          -  Pleural effusions requiring thoracentesis within 14 days prior to enrollment.

          -  Ascites requiring paracentesis within 14 days prior to enrollment.

          -  Uncontrolled hypertension, defined as an average systolic blood pressure > 159 mmHg or
             diastolic > 99 mm/Hg despite optimal treatment (measured following European Society of
             Hypertension/European Society of Cardiology [ESH/ESC] 2013 guidelines.

          -  Active hepatitis B virus (HBV) infection. Subjects with positive hepatitis B surface
             antigen (HBsAg) or core antibody (anti-HBc) that achieve sustained virologic response
             with antiviral therapy directed at hepatitis B are allowed. Subjects with known
             history or resolved infection (negative for HBsAg but positive for antibodies to
             surface antigen, and/or core antigen) must be screened with HBV DNA levels. EXCEPTION:
             Subjects with serologic findings suggestive of HBV vaccination (hepatitis B surface
             antibody [anti-HBs] positivity as the only serologic marker) AND a known history of
             prior HBV vaccination, do not need to be tested for HBV DNA.

          -  Known human immunodeficiency virus (HIV) infection, hepatitis C infection (subjects
             with hepatitis C that achieve a sustained virologic response following antiviral
             therapy are allowed).

          -  Ongoing graft-versus-host disease.

          -  Subjects with grade 3 or worse neuropathy within 14 days prior to enrollment.

          -  Antitumor therapy (eg, chemotherapy, immunotherapy, antibody therapy) or
             investigational agent within 28 days before enrollment or not recovered from any acute
             toxicity.

          -  Subjects on immunosuppressive therapy for graft versus host disease, even if it has
             resolved.

          -  Glucocorticoid therapy within 14 days before first dose that exceeds a cumulative dose
             of 160 mg or dexamethasone or equivalent dose of other corticosteroids.

          -  Focal radiation therapy within 7 days before enrollment. Radiation therapy to an
             extended field involving significant volume of bone marrow within 28 days prior to
             enrollment (ie, prior radiation must have been to less than 30% of the bone marrow).

          -  Autologous stem cell transplant less than 100 days prior to enrollment.

          -  Prior treatment with Kyprolis (carfilzomib).

          -  Currently receiving treatment in another investigational device or drug study, or less
             than 30 days since ending treatment on another investigational device or drug study.
             Other investigational procedures while participating in this study are excluded.

          -  Female subject is pregnant or breastfeeding or planning to become pregnant or
             breastfeed during treatment, during any breaks (interruptions) in the treatment, and
             for an additional 30 days after the last dose of Kyprolis. Females of childbearing
             potential should only be included in the study after a confirmed menstrual period and
             a negative highly sensitive urine or serum pregnancy test.

          -  Female subjects of childbearing potential unwilling to use 1 highly effective method
             of contraception during treatment, during any breaks (interruptions) in the treatment,
             and for an additional 30 days after the last dose of Kyprolis.

        NOTE: Female subjects of childbearing potential being treated with lenalidomide must agree
        to use 2 methods of contraception for at least 28 days before starting treatment, during
        treatment, during any breaks (interruptions) in the treatment, and for an additional 30
        days after the last dose of treatment.

        • Male subjects with a female partner of childbearing potential who are unwilling to
        practice sexual abstinence (refrain from heterosexual intercourse) or use contraception
        during treatment and for an additional 90 days after the last dose of Kyprolis.

        NOTE: Male subjects being treated with lenalidomide must agree to use a male condom with
        spermicide even if they have undergone a successful vasectomy.

          -  Male subjects with a pregnant partner who are unwilling to practice abstinence or use
             a condom during treatment and for an additional 90 days after the last dose of
             Kyprolis.

          -  Male subjects unwilling to abstain from donating sperm during treatment and for an
             additional 90 days after the last dose of Kyprolis.

          -  Subject likely to not be available to complete all protocol required study visits or
             procedures, and/or to comply with all required study procedures to the best of the
             subject and investigator's knowledge.

          -  History or evidence of any other clinically significant disorder, condition or disease
             (with the exception of those outlined above) that, in the opinion of the investigator
             or Amgen physician, if consulted, would pose a risk to subject safety or interfere
             with the study evaluation, procedures or completion.

          -  Active hepatitis B virus (HBV) infection. Subjects with positive hepatitis B surface
             antigen (HBsAg) or core antibody (anti-HBc) that achieve sustained virologic response
             with antiviral therapy directed at hepatitis B are allowed. Subjects with known
             history or resolved infection (negative for HBsAg but positive for antibodies to
             surface antigen, and/or core antigen) must be screened with HBV DNA levels. EXCEPTION:
             Subjects with serologic findings suggestive of HBV vaccination (hepatitis B surface
             antibody [anti-HBs] positivity as the only serologic marker) AND a known history of
             prior HBV vaccination, do not need to be tested for HBV DNA.