Study of Combination POM, BTZ, Low-Dose DEX, and DARA (PVD-DARA) in Patients With RRMM

Key Inclusion Criteria: 1. Histologically confirmed diagnosis of symptomatic multiple myeloma. 2. Evidence of disease progression or refractoriness to 1 to 3 prior lines of therapy by IMWG standard criteria. 3. Prior exposure to lenalidomide and a proteasome inhibitor is mandatory. 4. Daratumumab naïve patients or Daratumumab exposed patients who are not refractory to weekly or bi-weekly daratumumab. 5. Measurable disease: * Serum M protein ≥ 0.5 g/dL * Urine M protein ≥ 200 mg/24 hours * Involved serum free light chains ≥ 10 mg/dL AND an abnormal serum free light chain ratio 6. ECOG Status 0-2 ≤ 14 days prior to registration 7. Adequate organ function including ≤ 14 days prior to registration defined as: * ANC ≥ 1.0 x 10\^9/L. (Patients cannot have received G-CSF or GM-CSF within 1 week of screening or pegfilgrastim within 2 weeks of screening) * Platelets ≥ 75 x 10\^9/L * Calculated Creatinine Clearance ≥ 30 mL/min * Total Bilirubin ≤ 1.5 x ULN except for patients with a history of elevated total bilirubin, such as in Gilbert's * AST, AP, ALT ≤ 3 x ULN * Hepatic Child-Pugh score at worse A (eligible for the phase 2 part but not for the Run-in-Period). 8. Adequate cardiac function within 8 weeks prior to registration defined as LVEF ≥ 40%. Key Exclusion Criteria: 1. Disease refractory to weekly or bi-weekly daratumumab therapy. 2. Female patients who are lactating or have a positive serum pregnancy test ≤ 14 days from registration during the screening period. 3. Failure to have fully recovered from the reversible effects of prior anti-cancer therapy. 4. Major surgery within 14 days before registration. 5. Focal radiation therapy within 14 days prior to randomization with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma. 6. Disease-related central nervous system involvement. 7. Plasma cell leukemia, AL amyloidosis, or POEMS syndrome. 8. The subject has uncontrolled significant intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled congestive heart failure, New York Heart Association Class III-IV, unstable angina pectoris, stroke, myocardial infarction, uncontrolled cardiac arrhythmias \< 6 months prior to registration, or uncontrolled hypertension. 9. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. 10. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 11. Known GI disease or GI procedure that could interfere with the oral absorption of study medication including difficulty swallowing. 12. Concurrent malignancy except for treated non-melanoma skin cancer, cervical carcinoma in situ and low-risk prostate CA being monitored without treatment. 13. Grade 2 and higher peripheral neuropathy on clinical examination ≤ 14 days prior to registration. 14. Chemotherapy ≤ 14 days prior to registration. 15. Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer. 16. Patients with known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \<50% of predicted normal; moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note. 17. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate. 18. Patients who have a contraindication to the use of any form of anticoagulation or antiplatelet agents. 19. Patient who are on a strong CYP34A or CYP1A2 inducer or inhibitors 20. Patients with Hepatic Child-Pugh score B and C. Note that Hepatic Child-Pugh score A are excluded from the Run-in-Period of the trial 21. Patient is: * seropositive for human immunodeficiency virus (HIV). * 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. * seropositive for hepatitis C (except in the setting of a sustained virologic response \[SVR\], defined as aviremia at least 12 weeks after completion of antiviral therapy).