Belantamab Mafodotin or Daratumumab with VRd for Newly Diagnosed High-Risk Myeloma

Eligibility Criteria:

* Patient must have suspected or confirmed newly diagnosed multiple myeloma (MM) by International Myeloma Working Group (IMWG) criteria and must not have received more than one cycle of any myeloma treatment.
* Patient must be considered ineligible for autologous stem cell transplantation by the treating physician because of their age (≥ 70 years) or aged 18 - 70 years with the presence of underlying medical conditions likely to have a negative impact on tolerability of high-dose chemotherapy with stem-cell transplantation, making them transplant ineligible, OR transplant-eligible and refusing stem-cell transplantation until first relapse or later.
* Patient must have measurable or evaluable disease as defined by having one or more of the following, obtained within 28 days prior to randomization.

  * ≥ 1g/dL monoclonal protein (M-protein) on serum protein electrophoresis
  * Involved free light chain ≥ 10 mg/dL or ≥ 100 mg/L AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (\<0.26 or \>1.65)
  * ≥ 200 mg/24 hours of monoclonal protein on a 24-hour urine protein electrophoresis
  * Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease)
* Patient must be ≥ 18 years and \<80 years of age.
* Patient must have an Eastern Cooperative Group (ECOG) Performance Status (PS) of 0-2 (PS 3 allowed if secondary to pain).
* Patient must have IMWG Frailty Score \<2.
* Patient must have the ability to understand and willingness to sign a written informed consent document.
* Patient must be willing to provide bone marrow (aspirate and/or biopsy) and blood samples for determination of International Myeloma Society (IMS) risk status and for research. Indeterminate patients with missing or unevaluable samples will be excluded.
* Patient must have received no more than one cycle (28 days or less) of prior chemotherapy and no more than 160 mg of prior dexamethasone (or equivalent dose of prednisone) for treatment of symptomatic myeloma. Prior radiation therapy to symptomatic lesions is allowed provided there is no residual toxicity related to radiation and blood counts meet the study requirements. NOTE: Patients who have received prior treatment for smoldering multiple myeloma (SMM) are eligible.
* Patient must have a Serum Protein Electrophoresis (SPEP), Urine Protein Electrophoresis (UPEP), and serum Free Light Chain (FLC) assay performed within 28 days prior to registration. In addition, a bone marrow biopsy and/or aspirate is required within 28 days prior to registration if measurable disease is only present in bone marrow. Otherwise, a bone marrow examination must have been performed within 90 days prior to registration.
* Patient must have adequate organ function and marrow function as defined below, obtained ≤ 2 weeks prior to registration.

  * Absolute Neutrophil Count (ANC) ≥ 1000/microliter (mcL)
  * Platelets ˃75,000/mcL
  * Creatinine clearance (CrCl) ≥ 30 mL/min
  * Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3x upper limit of normal (ULN)
  * Total Bilirubin ≤ 1.5x ULN or ≤ 3x ULN for patients with documented Gilbert's disease
* Patient must agree to register to the mandatory lenalidomide (Revlimid) Risk Evaluation and Mitigation Strategy (REMS) program and be willing and able to comply with the requirements of the REMS program.
* Patient must not be pregnant or breast-feeding due to the potential harm and teratogenic effects to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.
* Patient must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study, and for 3 months after the last dose of protocol treatment.
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Patient with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) Functional Classification. To be eligible for this trial, patient must be class 2 or better.
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Patients must not have peripheral neuropathy ≥ Grade 2 on clinical examination or Grade 1 with pain at time of registration.
* Patients must not have any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
* Patient may have a history of current or previous deep vein thrombosis (DVT) or pulmonary embolism (PE) but must be willing to take some form of anti-coagulation as prophylaxis if they are not currently on full-dose anticoagulation.
* Patients must not have any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products.
* Patients must not have current corneal epithelial disease except mild punctuate keratopathy.
* Contact lenses must be avoided for participants while they are receiving belantamab mafodotin treatment unless cleared by an eye-care specialist. If cleared for use, bandaged contact lenses are specifically recommended. Contact lens use may be restarted after discontinuation of belantamab mafodotin treatment, provided the eye-care specialist confirms there are no other contraindications.
* Patients must not have symptomatic amyloidosis or active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma-proliferative disorder, skin changes) at the time of screening.
* Patients must not receive any other concurrent chemotherapy, or any ancillary therapy considered investigational while on this protocol.