Exclusion Criteria:

• Patients with progressive or refractory plasma cell myeloma, as defined by International Myeloma Workshop Consensus Panel criteria.
• History of disease refractory to lenalidomide or daratumumab, as defined by the IMWG as failure to achieve minimal response or development of progressive disease while on therapy.
• Multiple myeloma patients who have received prior anti myeloma therapy for smoldering myeloma
• Patients who are receiving any other investigational agents with the intent to treat myeloma. Permitted concurrent therapies include:
• Bisphosphonates/RANK ligand inhibitors (denosumab)
• Plasma cell leukemia
• Pregnant or breastfeeding females. Because there is a potential risk for adverse events to nursing infants secondary to treatment of the mother with lenalidomide, lactating females must agree not to breastfeed while taking lenalidomide.
• Risk for adverse events to nursing infants secondary to treatment of the mother with daratumumab is unknown, as such lactating females must agree not to breastfeed while on daratumumab.
• Patient has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal).
• Patient has known moderate or severe persistent asthma, within the last 2 years, or currently has uncontrolled asthma of any classification (refer to Appendix D). (Subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.)
• Uncontrolled hypertension or diabetes
• Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (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 by PCR.  If Hep B PCR positive then patient will screen fail. They must first be treated and have a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy after which they can be re screened.
• Seropositive for hepatitis C must be screened using Hepatitis C PCR. If hepatitis C PCR is positive then the patient is excluded (If antibody positive and PCR negative they will be eligible but must have PCR testing every 3-6 months for 3 years; If Hep C PCR positive then patient will screen fail. They must first be treated and have a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy after which they can be rescreened).
• Diagnosed or treated for another malignancy within 3 years prior to study enrollment, with the exception of complete resection of non-melanoma skin cancer, or an in-situ malignancy.
• Previous diagnosis of another malignancy with any evidence of residual or active disease.
• Uncontrolled or detectable HIV viral load excluded. (Patients seropositive for the human immunodeficiency virus (HIV), and/or those who are taking antiretroviral treatment for HIV/AIDS with undetectable viral load will be eligible. Patients must have PCR testing every 3-6 months for 3 years and be compliant with antiretroviral treatment.)
• Prior organ transplant requiring immunosuppressive therapy
• Prior allogeneic stem cell transplant
• Patients requiring continuous, systemic immunosuppressive therapy
• Patients with myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled cardiac arrhythmias, or electrocardiographic evidence of acute ischemia
• Patients with conditions that would prevent absorption of the study drug
• Uncontrolled intercurrent illness including but not limited to uncontrolled infection or psychiatric illness/social situations that would compromise compliance with study requirements
• Unresolved prior treatment related AE ≥ grade 2 except for alopecia and neuropathy
• Neuropathy ≥ Grade 3 at baseline
• Contraindication to required concomitant anticoagulation or antiviral prophylaxis
• Major surgery within 1 month prior to enrollment
• Patients who were previously exposed and who developed severe adverse events, hypersensitivity or desquamating rash to either thalidomide or lenalidomide
• Patients who speak a language that does not have an EORTC QLQ-C30, MY20 or PRO-CTCAE version translated into their language (Available languages include Chinese, Czech, Danish, Dutch, French, German, Greek, Hugarian, Italian, Japanese, Korean, Malay, Polish, Protugese, Romanian, Russian, Spanish, Turkish, Ukranian).