MM is one of the most frequent hematological cancers, which until this day is considered an incurable disease. In the past years, several new drugs were introduced for the management of MM, which led to an improvement in overall survival. However, most patients relapse and their refractory disease is frequently resistant to conventional treatments. Thus, it is necessary to find new therapeutic strategies to overcome this resistance. The various chapters of this work follow the first steps of the preclinical drug discovery process, starting with the screening of natural and semi-synthetic compounds for their anti-proliferative activity in MM and studying their structure-activity relationship. This was followed by functional and mechanistic studies of one of the most active compounds. In the process, different MM models were established, namely PI resistant cells and 3D co-culture models.