Introduction: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by neoplastic proliferation of plasma cells. Despite advances in treatment, therapeutic uncertainties persist. The addition of a fourth drug with the standard regimen gives a favorable prognosis and efficacy profile in MM. This systematic review highlights four-drug regimens' efficacy and safety for the treatment of newly diagnosed (ND) and relapsed refractory (RR) MM. Methodology: We performed a comprehensive literature search using four major databases (Pubmed, Cochrane Library, Embase, and ClinicalTrials.gov). Our search strategy included MeSH terms and keywords for multiple myeloma and antineoplastic agents from the date of inception to June 2020. The initial search revealed 6104 articles. After excluding review articles, duplicates, and non-relevant articles, we included 10 phase II/III clinical trials reporting the efficacy of four-drug regimens for treatment of MM. Results: Out of 2464 enrolled patients, 2321 patients had NDMM, and 143 patients had RRMM, 1791 patients were in phase III trials, and 673 patients were in phase II trials. Phase III trials: Moreau et al. (2019) studied the efficacy of daratumumab (D), bortezomib (V), thalidomide (T) and dexamethasone (d) vs VTd in NDMM patients (pts) (n=1085) in CASSIOPEIA trial. DVTd group showed better progression free survival (PFS) 93% vs 85% at 18 months (mo) (hazard ratio (HR) 0.42 [0.34-0.51]; pConclusion:Four drug combinations, primarily daratumumab based regimens, are very effective and well-tolerated. The achievement of higher MRD negative status implies a more profound response. Long term follow-up is needed to see the effect on long-term survival.