The following criteria is provided for health care professionals.

Inclusion Criteria:

• Subjects must have histologically confirmed diagnosis of multiple myeloma
• Subjects must have measurable disease, as defined by at least one of the following:
  • Serum monoclonal protein M-protein level >= 0.5 g/dL
  • Urinary M-protein excretion of >= 200 mg over a 24-hour period
  • Involved free light chain level >= 10 mg/dL, along with an abnormal free light chain ratio
• Subjects must have disease that has relapsed and/or refractory after their most recent therapy, with progressive disease (PD) being defined as an increase of 25% from the lowest response value in any one or more of the following:
  • Serum M-component protein (the absolute increase must be >= 0.5 g/dL) and/or
  • Urine M-component protein (the absolute increase must be >= 200 mg/24 hours) and/or
  • Only in subjects without a measurable serum and urine M protein level: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase) must be > 10 mg/dL
  • Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas
  • Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder
• Subjects with one to three lines of therapy for their disease with lines of therapy being separated by the presence of documented disease progression; using this definition, treatment with induction therapy, followed by high dose chemotherapy and autologous stem cell transplantation, and finally by maintenance therapy, would constitute one line, provided that multiple myeloma did not meet criteria for progression at any time during this period
• Subjects must have completed their most recent drug therapy directed at multiple myeloma in the following timeframes:
  • Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy, or investigational agent) within 21 days of study day 1
  • Corticosteroids at least 3 weeks prior to starting AMG-232 + KRd, except for a dose equivalent to dexamethasone of =< 4 mg/day
  • Autologous stem cell transplantation at least 12 weeks prior to starting AMG-232 + KRd
  • Allogeneic stem cell transplantation at least 24 weeks prior to starting AMG-232 + KRd, and these subjects must also NOT have moderate to severe active acute or chronic graft versus host disease (GVHD)
• Subjects must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Absolute neutrophil count (ANC) >= 1,000/mcL without growth factors within 2 week of initiation of treatment
• Platelets >= 50,000 cells/mm3 if marrow plasmacytosis < 50% OR platelet count >= 30,000 cells/mm^3 if marrow plasmacytosis >= 50%
• Hemoglobin >= 8 g/dL within 2 weeks of the initiation of treatment
• Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (< 2.0 x ULN for subjects with documented Gilbert's syndrome or < 3.0 x ULN for subjects for whom the indirect bilirubin level suggests an extrahepatic source of elevation)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
• Alkaline phosphatase < 2.0 x ULN (if liver or bone disease are present, < 3.0 x ULN)
• Creatinine clearance >= 50 mL/min/1.73 m^2
• Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of normal (ULN), OR international normalized ratio (INR) < 1.5
• Subjects must have normal corrected QT interval (QTc) =< 470 msec (based on average of screening triplicates)
• Subjects who have received radiation therapy targeting > 10% of the bone marrow space must have completed this at least 2 weeks prior to starting therapy with AMG-232 + KRd
• Subjects must be able and willing to provide bone marrow biopsies/aspirates as requested by the protocol
• Subjects must be willing to undergo myeloma genotyping for TP53 mutation, insertion, or deletion at screening
• Subjects must have an estimated life expectancy of at least 3 months
• Women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation through 5 weeks (women) after receiving the last dose of AMG 232; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of AMG 232 administration; adequate methods of effective birth control include sexual abstinence (men, women); vasectomy; or a condom with spermicide (men) in combination with barrier methods, hormonal birth control or intrauterine device (IUD) (women)
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Subjects with myeloma that is relapsed and/or refractory to KRd when used in combination defined as progression of disease while on therapy or within 60 days of completing therapy
• Subjects with a malignancy that contains a non-synonymous mutation, insertion, or deletion in the TP53 gene determined prior to screening; TP53 mutation status at screening is NOT required prior to AMG-232 dosing; however, subjects found to have TP53 mutation and/or deletion from screening bone marrow biopsy as assessed by central deoxyribonucleic acid (DNA) sequencing conducted at Dr. Jeffrey Sklar's laboratory at Yale University Cancer Center, will be removed from study after C1 and continue on standard-of-care KRd alone
• Subjects who have not recovered from toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 0 or 1, or to levels dictated in the eligibility criteria with the exception of alopecia (grade 2 or 3 toxicities from prior antitumor therapy that are considered irreversible [defined as having been present and stable for > 6 months], such as grade 2 chemotherapy-induced peripheral neuropathy, may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor)
• Subjects who are receiving any other investigational agents
• Subjects who have undergone major surgery within 28 days of study day 1; vertebroplasty and/or kyphoplasty, which must have been performed at least 1 week prior to starting AMG-232 + KRd
• Subjects with known central nervous system involvement of myeloma should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• Subjects with history of allergic reactions attributed to compounds of similar chemical or biologic composition to AMG 232 or carfilzomib, lenalidomide, or dexamethasone
• All herbal medicines (e.g., St. John's wort), vitamins, and supplements consumed by the subject within the 30 days prior to receiving the first dose of AMG 232, and continuing use, if applicable, will be reviewed by the principal investigator
• Use of any known CYP3A4 substrates with narrow therapeutic window (such as alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, sirolimus, or terfanide) within the 14 days prior to receiving the first dose of AMG 232 is not permitted; other medications (such as fentanyl and oxycodone) may be allowed per investigator's assessment/evaluation
• Treatment with medications known to cause QTc interval prolongation within 7 days of study day 1 unless is not permitted unless approved by the sponsor; use of ondansetron is permitted for treatment of nausea and vomiting
• Current use of warfarin, factor Xa inhibitors and direct thrombin inhibitors; Note: low molecular weight heparin and prophylactic low dose warfarin are permitted; PT/PTT must meet the inclusion criteria; subjects taking warfarin must have their INR followed closely
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; subjects with myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association [NYHA] class III and higher), unstable angina, or cardiac arrhythmia requiring medication are excluded
• Subjects with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, requirement for intravenous alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)
• Subjects with history of bleeding diathesis
• Subjects with active infection requiring IV antibiotics within 2 weeks of study enrollment (day 1) are excluded
• Positive hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B), positive hepatitis total core antibody with negative HBsAG (suggestive of occult hepatitis B), or detectable hepatitis C virus RNA by a polymerase-chain reaction (PCR) assay (indicative of active hepatitis C - screening is generally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNA by PCR if HepCAb is positive); subjects with hepatitis B virus suppressed on therapy, and previously treated/eradicated hepatitis C virus are eligible for study
• Human immunodeficiency virus (HIV)-positive subjects positive for human immunodeficiency virus (HIV) are NOT excluded from this study, but HIV-positive subjects must have:
  • A stable regimen of highly active anti-retroviral therapy (HAART)
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
  • CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard PCR-based test
• Men and women of reproductive potential who are unwilling to practice acceptable methods of effective birth control while on study through 5 weeks (women) or 3 months (men) after receiving the last dose of AMG 232; acceptable methods of effective birth control include sexual abstinence (men, women); vasectomy; or a condom with spermicide (men) in combination with barrier methods, hormonal birth control or IUD (women)
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AMG 232; these potential risks may also apply to other agents used in this study
• Women who are lactating/breast feeding or who plan to breastfeed while on study through 1 week after receiving the last dose of study drug
• Subjects with prior treatment with an MDM2 inhibitor