Rewriting the Rules on Multiple Myeloma Resistance: Ajai Chari, MD

What if the central assumption guiding how we treat multiple myeloma (MM)—that every patient will eventually relapse—turns out to be wrong? This is the kind of question that drives Ajai Chari, MD, professor of clinical medicine and director of the Multiple Myeloma Program at the University of California, San Francisco. Chari is a leading voice in a field that is moving so fast, he explains that whatever he predicts today will likely be obsolete within a year or two.

Chari has spent his career pushing at the edges of what myeloma treatment can accomplish. His work spans the full landscape of modern therapeutic approaches—from chimeric antigen receptor T-cell therapies and bispecific antibodies to antibody-drug conjugates—from the lens of synthesizing the science and the strategy. He thinks carefully about not just which treatments work, but why they stop working and what that means for how to sequence care. His lens is always the patient in front of him: What’s the best regimen for this person, at this moment, given what we know right now?

In this conversation, Chari digs into the mechanisms driving resistance to today’s most powerful myeloma therapies: disease burden, high-risk genetics, extramedullary disease, and, critically, what happens to antigens like B-cell maturation antigen when they’re targeted repeatedly over time. He explores the exciting early data from trials like CARTITUDE-4 (NCT04133636) and MajesTEC-3 (NCT05083169), which suggest that a meaningful fraction of patients may be reaching something that looks like long-term cure. He also wrestles with one of the field’s most urgent open questions: How do you sequence therapies intelligently when you don’t yet know which patients will ever need a second act?

As he puts it to patients, “I don’t like to speculate too much about the future, because whatever I tell you will probably be obsolete within a year or two.”