OBJECTIVES: To determine whether the issuance of a new or revised Black Box Warning (BBW) for an Adverse Drug Reaction (ADR) by United States Food and Drug Administration (FDA) increases the proportional reporting of the ADR to the FDA’s Adverse Event Reporting System (AERS). METHODS: We compiled a list of Multiple Myeloma (MM) drugs with BBWs issued after the drug approval: melphalan, thalidomide, vincristine, carmustine, and doxorubicin. We searched the AERS database for MM drugs and ADRs listed in BBWs and retrieved all cases. We calculated the empiric bayes geometric mean (EBGM) values and clinical outcomes (chi-square analyses) for each drug and ADR combination and compared them before and after the issuance of the BBW. RESULTS: EBGM signals increased for 8 of 10 BBW drug/events: melphalan/leukemia (12.83 to 15.97); melphalan/chromosomal aberrations (0 to 18.677); melaphalan/bone marrow suppression (5.926 to 7.629); thalidomide/venous thrombosis (1.201 to 2.464); intrathecal vincristine/death (1.690 to 6.852); doxorubicin/congestive heart failure (1.154 to 5.004); and carmustine/leukopenia (3.796 to 5.650) and thrombocytopenia (3.796 to 5.644). Furthermore, the percentage of AERS reports associated with outcomes of hospitalization increased as follows: melphalan causing leukemia (0% to 37%, p<0.001), chromosomal aberrations (0% to 15.55%, p<0.001), bone marrow suppression (4.0% to 40.9%, p<0.001), or hypersensitivity (30.77% to 50.0%, p<0.01).  The mortality outcome increased only for melphalan/leukemia (8.9% to 54.8%, p<0.001). Life-threatening outcomes increased for melphalan/leukemia (0% to 17.7%, p=0.016), melphalan/chromosomal aberrations (0 to 8.7%, p<0.001), carmustine leukopenia (0 to 17.7%, p=0.016), and carmustine/thrombocytopenia (0-20.3%, P=0.045). CONCLUSIONS: Prior to the BBWs, health professionals do not appear to associate the ADRs with the drug and/or do not report the events to the FDA.  Issuance of BBWs appears to result in increased awareness and reporting.   Since pre-marketing research may not identify rare ADRs and voluntary post-marketing reporting may be inadequate, proactive pharmacovigilance programs should be implemented.