Background: New treatments for multiple myeloma (MM) improved both the clinical course and survival. These differ in their mode of action, safety profile, and adverse events (AEs). The goal of this study is to establish the benchmark for an integrated systematic investigation to assess the toxicity of different anti-MM drug regimens (AMDR). Methods: We curated 342,213 MM patient information from 2016–2022 from the FDA Adverse Event Reporting System. A total of 71 AMDR were evaluated in 7 different system organ classes when mapped to MedDRA. Drug-associated genes and AEs were also quantified as genetic evidence of a drug-AE combination. Gene-gene associations were then explored using the STRING database. We then developed a novel risk assessment metric that combined historical data from MM patients with drug-AE scores regarding the AE occurrence, the number of reported AE, and the genetic evidence of drug-gene and gene-AE associations (GAA). This likelihood-based rating metric includes (vH): (very) high MDR risk–(very) frequent AEs and mortality with (very) significant GAA evidence; and similarly computed for M: medium risk; and L: low risk. Results: Our risk assessment findings revealed single agents (carfilzomib (K), bortezomib (V), daratumumab (D), lenalidomide (R), melphalan (Mel), thalidomide (T), ixazomib (Ix), elotuzumab (El), isatuximab (Is) or dexamethasone (d)) illustrated very low profile of toxicity compared to combination regimens. Overall, we found that AMDR profiles showed higher toxicities in 4 different SyOCs (hepatobiliary, cardiac, nervous, renal) with nominal issues in 3 SyOCs (vascular, neoplasm, GI). AMDR toxicity significantly increased when d was added to the treatment compared to AMDR without d. Cardiac and vascular AEs were higher with K-based combinations. Hepatobiliary toxicities were higher with V, K, or T-based combinations. Secondary neoplasms were seen more frequently in patients who received high dose Mel followed by R. Conclusions: Our analysis of large data shows the association of SyOCs and graded toxicity profiles with unique AMDR. The single drug or doublets without dexamethasone seemed to show an improved AE profile compared to those with dexamethasone used as doublets, triplets, or quadruplets. Secondary cancer risk was much higher with high dose Mel followed by R compared with other AMDR. Our assessment system provides a framework for AMDR comparison toward future precision MM therapeutics based on unique drug doses, combination regimens, patient phenotypic risk profiles, secondary cancer surveillance and interplay of genetics and comorbidities.