The purpose of this study is to evaluate the safety, tolerability, and dose regimen of daratumumab when administered in combination with various treatment regimens for the treatment of multiple myeloma.

This is an open-label (identity of assigned study drug will be known) study to evaluate the safety, tolerability, and dose of daratumumab when administered in combination with various treatment regimens for different settings of multiple myeloma. The various treatment regimens to be combined with daratumumab in this study include Velcade-dexamethasone (VD), Velcade-melphalan-prednisone (VMP), Velcade-thalidomide-dexamethasone (VTD), pomalidomide-dexamethasone (Pom-dex), carfilzomib-dexamethasone (CFZ-dex) and carfilzomib-lenalidomide-dexamethasone (KRd). Approximately 250 patients (approximately 12 participants per VTD and VMP backbone treatment regimen, 6 for the VD regimen, up to 100 participants in the Pom-dex regimen, 80 for the CFZ-dex regimen [10 participants will receive a single-dose of daratumumab and the remaining participants will receive a split-dose of daratumumab], and up to 40 for the KRd regimen) will be enrolled in this study. The study will consist of screening, treatment, and follow-up phases. Treatment will extend to either the planned treatment duration for a maximum of 1 year (in Velcade-dexamethasone, Velcade-melphalan-prednisone, Velcade-thalidomide-dexamethasone regimens and KRd regimens), or in the Pom-dex and CFZ-dex regimens, until disease progression, unacceptable toxicity, or until the end of study. Follow-up will continue until the study ends (approximately 25 months after the last patient receives the first dose of daratumumab). Serial pharmacokinetic (study of what a drug does to the body) blood samples will be collected. Clinical efficacy outcomes and safety will be monitored throughout the study.

Inclusion Criteria:

• Confirmed diagnosis of symptomatic multiple myeloma and measurable secretory disease
• For carfilzomib-lenalidomide-dexamethasone (KRd) regimen: newly diagnosed myeloma. For carfilzomib-dexamethasone (CFZ-dex) regimen: relapsed or refractory disease
• Eastern Cooperative Oncology Group performance status score of 0, 1, or 2
• Pretreatment clinical laboratory values must meet protocol-defined parameters during the screening phase

Exclusion Criteria:

• Previously received daratumumab or other anti-CD38 therapies
• Diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, Waldenström's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions
• Peripheral neuropathy or neuropathic pain Grade 2 or higher
• Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years of study start
• Exhibiting clinical signs of meningeal involvement of multiple myeloma
• Known chronic obstructive pulmonary disease, persistent asthma, or a history of asthma within 2 years
• Seropositive for human immunodeficiency virus, hepatitis B, or hepatitis C
• Any concurrent medical or psychiatric condition or disease that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study
• Clinically significant cardiac disease
• Plasma cell leukemia or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome