Inclusion criteria:
Age of at least 18 years old at the time of randomization
Willingness for signing and having signed the written informed consent form
Diagnosis of multiple myeloma per IMWG criteria:3.1. Clonal bone marrow plasma cells ≥10% at some point in their disease history or presence of a biopsy-proven plasmacytoma3.2. Measurable disease as defined by any of the following:3.2.1. IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24h3.2.2. IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24h
Subject must have received at least one prior line of therapy for multiple myeloma.A line of therapy consists of 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens (eg, 3-6 cycles of initial therapy with bortezomib-dexamethasone followed by stem cell transplantation, consolidation, and lenalidomide maintenance is considered 1 line).
Subject must have achieved a response (Partial Response or Better based on investigator’s determination) to at least one prior regimen.
Subject must have progressive disease, based on investigator’s determination, on or after their last regimen
Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
Exclusion criteria:
Subject has received daratumumab or other anti-CD38 therapies previously.
Subject’s disease shows evidence of refractoriness to any dose of lenalidomide, defined either:2.1. Subjects whose disease progresses within 60 days of the last dose of lenalidomide; or2.2. Subjects whose disease is nonresponsive while on lenalidomide. Nonresponsive disease is defined as either failure to achieve at least a Minimal Response or development of PD while on lenalidomide.
Subject has received anti-myeloma treatment within 2 weeks before the date of randomization. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum 4 days) before treatment.
Subject has received more than two prior lines of therapy for multiple myeloma.
Subject has received autologous stem cell transplant within 12 weeks before the date of randomization, or subject has previously received an allogeneic stem cell transplant (regardless of timing)
Subject in need of stem cell transplant during the study period (in investigator’s opinion), or planning to undergo a stem cell transplant prior to disease progression in this study, ie, these subjects should not be enrolled in order to reduce disease burden prior to transplant.
A history of malignancy (other than multiple myeloma) within 5 years before the date of randomization, with the exception of squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix, or a malignancy that in the opinion of the investigator is considered cured with minimal risk of recurrence within 5 years
Subject has known meningeal involvement of multiple myeloma
Known chronic obstructive pulmonary disease (COPD) of grade GOLD 3 (severe) or GOLD 4 (very severe) based on Global Initiative for Chronic Obstructive Lung Disease (GOLD)
Current uncontrolled persistent asthma in time of screening (per American Lung Association’s classification)
Human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) seropositivity; This criterion is assessed via HBs-Ag, HBc-Ab, HCV-Ab, and HIV-Ab tests at screening.
Subject has any of the following laboratory test results during the Screening Phase:12.1. Aspartate aminotransferase (AST) or alanine aminotransferase level (ALT) ≥ 2.5 times the upper limit of normal (ULN)12.2. Alkaline phosphatase level ≥ 2.5 × ULN12.3. Total bilirubin level ≥ 1.5 × ULN, (except for Gilbert Syndrome: direct bilirubin 1.5 × ULN)
Subject has known hypersensitivity to monoclonal antibodies or human proteins
Subject has plasma cell leukemia (> 2.0 × 109/L circulating plasma cells by standard differential), Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, or amyloidosis
Pregnant or nursing women, or female/male subject planning to become pregnant while enrolled in this study, within 4 weeks after the last dose of lenalidomide, or within 12 weeks after the last dose of daratumumab. Female and male subjects in the reproductive age must use reliable methods of contraception.
Subject has received an investigational drug within 4 weeks before randomization (except for investigational anti-myeloma agents, which cannot be taken within 2 weeks prior to randomization, as described in exclusion criterion #3)
Subject has had major surgery within 2 weeks before randomization, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study treatment. Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery.
Has had a plasmapheresis within 28 days before randomization
Radiation therapy (with the exception of palliative radiation therapy) within 14 days before randomization
Subject has any concurrent medical condition or disease (eg, active systemic infection) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study