This episode of the VJHemOnc Podcast features discussions from the 2nd International Workshop on High-Risk Multiple Myeloma (iwHRMM 2025), held in Charleston, SC. First, you will hear from Ross Firestone, MD, PhD, Memorial Sloan Kettering Cancer Center, New York City, NY, Nisha Joseph, MD, Winship Cancer Institute of Emory University, Atlanta, GA, and Ajai Chari, MD, University of California San Francisco, San Francisco, CA, who provide insight into immuno- and targeted therapies in HRMM. This is followed by Peter Voorhees, MD, Levine Cancer Institute, Charlotte, NC, and Holly Lee, MD, University of Calgary, Calgary, Canada, who discuss resistance to these therapies, highlighting the mechanisms of resistance and potential strategies to overcome them.