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Hassaan Imtiaz,1 Maimoona Khan,2 Hamid Ehsan,3 Ahsan Wahab,4 Abdul Rafae,5 Ali Y Khan,6 Abdur Jamil,7 Muhammad Khawar Sana,8 Abdullah Jamal,1 Taimoor Jaffar Ali,1 Iqraa Ansar,2 Muzammil M Khan,9 Jack Khouri,10 Faiz Anwer10 1Department of Internal Medicine, King Edward Medical University, Lahore, Punjab, Pakistan; 2Department of Medicine, Shifa College of Medicine, Islamabad, Pakistan; 3Department of Hematology/Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA; 4Hospital Medicine/Internal Medicine, Baptist Medical Center South, Montgomery, AL, USA; 5Department of Internal Medicine, McLaren Regional Medical Center, Flint, MI, USA; 6Department of Internal Medicine, St. Joseph Mercy Oakland Hospital, Pontiac, MI, USA; 7Department of Internal Medicine, Central Michigan University, Saginaw, MI, USA; 8Department of Internal Medicine, John H. Stroger Jr. Hospital of Cook County, Chicago, IL, USA; 9Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA, USA; 10Hematology, Oncology, Stem Cell Transplantation, Multiple Myeloma Program, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, 44195, USACorrespondence: Muhammad Khawar SanaDepartment of Internal Medicine, John H. Stroger Jr. Hospital of Cook County, Chicago, IL, USAEmail khawar_sana@yahoo.comAbstract: Carfilzomib (CFZ) is a proteasome inhibitor currently approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Multiple trials are ongoing to evaluate its efficacy and safety in newly diagnosed multiple myeloma (NDMM). The use of CFZ-based two- or three-drug combination regimens as induction for the management of NDMM is an emerging approach. CFZ-based regimens include combinations of immunomodulators, alkylating agents, and monoclonal antibodies along with dexamethasone. In this review, we assess the efficacy and toxicity of CFZ-based regimens in NDMM. We reviewed a total of 27 studies (n=4538 patients) with overall response rates (ORR) ranging between 80% and 100%. Studies evaluating the combination of CFZ with daratumumab reported an ORR of approximately 100%. Achievement of minimal residual disease (MRD) negativity, measured by multi-parameter flow cytometry (MPFC), ranged between 60% and 95% in 4 (n=251) out of 6 studies that measured MRD-negativity. The interim results of the ENDURANCE trial failed to show superior efficacy and progression-free survival (PFS) of carfilzomib-lenalidomide when compared to bortezomib–lenalidomide combination, albeit with a lower incidence of neuropathy. Hematological toxicity was the most common adverse event observed with these regimens, and the most common non-hematological adverse events were related to cardiovascular and electrolyte disturbances. We need to further evaluate the role of CFZ in NDMM by conducting more Phase III trials with different combinations.Keywords: carfilzomib, newly diagnosed multiple myeloma, safety, efficacy, systematic review