Study to Evaluate Safety Tolerability & Efficacy of Kyprolis (Carfilzomib) in Relapsed or Refractory Multiple Myeloma

Inclusion Criteria:

• Documented RRMM after last treatment. Refractory is defined as meeting 1 or more ofthe following: Nonresponsive to most recent therapy (stable disease [SD] orprogressive disease [PD]) while on treatment, or Disease progression within 60 daysof 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 timesthe upper limit of normal (ULN); aspartate aminotransferase (AST) and alanineaminotransferase (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 granulocytemacrophage-colony stimulating factor support for at least 1 week and of pegylatedgranulocyte stimulating factor for ≥ 2 weeks).

• Hemoglobin ≥ 80 g/L within 28 days prior to enrollment. Subjects should not havereceived red blood cell (RBC) transfusions for at least 7 days prior to obtainingthe screening hemoglobin.

• Platelet count ≥ 75 x 10^9/L (≥ 50 x 10^9/L if myeloma involvement in the bonemarrow is ≥ 50%) within 28 days prior to enrollment. Subjects should not havereceived platelet transfusions for at least 7 days prior to obtaining the screeningplatelet count.

• Adequate renal function within 28 days prior to enrollment (either measured orcalculated using a standard formula such as the Cockcroft and Gault): calculated ormeasured 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 testwithin the 10 to 14 days prior to enrollment and a negative urine pregnancy testwithin the 24 hours prior to day 1 of each cycle prior to dosing.

• Subject or legally acceptable representative has provided informed consent/assentprior 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 standarddifferentials).

• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,and skin changes)

• Myelodysplastic síndrome.

• Primary amyloidosis (subjects with multiple myeloma with asymptomatic deposition ofamyloid plaques found on biopsy would be eligible if all other criteria are met).

• History of other malignancy within the past 5 years, with the followingexception[s]: Adequately treated non-melanoma skin cancer or lentigo maligna withoutevidence of disease. Adequately treated cervical carcinoma in situ without evidenceof disease. Adequately treated breast ductal carcinoma in situ without evidence ofdisease. 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 cyclodextrinderivative 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 significantechocardiogram (ECHO) abnormalities, screening ECG with corrected QT interval (QTc)of > 470 msec, pericardial disease, or myocardial infarction within 4 months priorto 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 mmHgor diastolic > 99 mm/Hg despite optimal treatment (measured following EuropeanSociety of Hypertension/European Society of Cardiology [ESH/ESC] 2013 guidelines.

• Active hepatitis B virus (HBV) infection. Subjects with positive hepatitis B surfaceantigen (HBsAg) or core antibody (anti-HBc) that achieve sustained virologicresponse with antiviral therapy directed at hepatitis B are allowed. Subjects withknown history or resolved infection (negative for HBsAg but positive for antibodiesto surface antigen, and/or core antigen) must be screened with HBV DNA levels.EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (hepatitisB surface antibody [anti-HBs] positivity as the only serologic marker) AND a knownhistory of prior HBV vaccination, do not need to be tested for HBV DNA.

• Known human immunodeficiency virus (HIV) infection, hepatitis C infection (subjectswith hepatitis C that achieve a sustained virologic response following antiviraltherapy 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) orinvestigational agent within 28 days before enrollment or not recovered from anyacute toxicity.

• Subjects on immunosuppressive therapy for graft versus host disease, even if it hasresolved.

• Glucocorticoid therapy within 14 days before first dose that exceeds a cumulativedose of 160 mg or dexamethasone or equivalent dose of other corticosteroids.

• Focal radiation therapy within 7 days before enrollment. Radiation therapy to anextended field involving significant volume of bone marrow within 28 days prior toenrollment (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, orless than 30 days since ending treatment on another investigational device or drugstudy. Other investigational procedures while participating in this study areexcluded.

• Female subject is pregnant or breastfeeding or planning to become pregnant orbreastfeed during treatment, during any breaks (interruptions) in the treatment, andfor an additional 30 days after the last dose of Kyprolis. Females of childbearingpotential should only be included in the study after a confirmed menstrual periodand a negative highly sensitive urine or serum pregnancy test.

• Female subjects of childbearing potential unwilling to use 1 highly effective methodof contraception during treatment, during any breaks (interruptions) in thetreatment, 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 oruse a condom during treatment and for an additional 90 days after the last dose ofKyprolis.

• Male subjects unwilling to abstain from donating sperm during treatment and for anadditional 90 days after the last dose of Kyprolis.

• Subject likely to not be available to complete all protocol required study visits orprocedures, and/or to comply with all required study procedures to the best of thesubject and investigator's knowledge.

• History or evidence of any other clinically significant disorder, condition ordisease (with the exception of those outlined above) that, in the opinion of theinvestigator or Amgen physician, if consulted, would pose a risk to subject safetyor interfere with the study evaluation, procedures or completion.

• Active hepatitis B virus (HBV) infection. Subjects with positive hepatitis B surfaceantigen (HBsAg) or core antibody (anti-HBc) that achieve sustained virologicresponse with antiviral therapy directed at hepatitis B are allowed. Subjects withknown history or resolved infection (negative for HBsAg but positive for antibodiesto surface antigen, and/or core antigen) must be screened with HBV DNA levels.EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (hepatitisB surface antibody [anti-HBs] positivity as the only serologic marker) AND a knownhistory of prior HBV vaccination, do not need to be tested for HBV DNA.