The challenges of treatment
resistance and relapse


The course of MM is characterized by a repeating pattern of remission and relapse as patients cycle through available treatment options. Therapy has improved to where the majority of patients can now experience a long remission, so myeloma is getting closer to being a chronic illness vs a lethal cancer, said Ehsan Malek, MD, a hematologist and oncologist at UH Cleveland Medical Center (Cleveland, OH). Despite the improvements in outcomes with new drug regimens, most patients still relapse or become refractory to the available treatments. “We all know that [in most cases] myeloma will eventually start to grow back despite the treatment,” said Cristina Gasparetto, MD, a multiple myeloma specialist at Duke University School of Medicine (Durham, NC).

One reason is that every drug has a lifespan for patients with MM. When a clinician starts a patient on a drug, the clock starts ticking, said Dr Gasparetto. “The drug isn’t going to last forever. Eventually the myeloma will acquire a resistance to that drug. That’s why it is such a difficult disease.” Triplet therapy can be used to avoid the patient developing a resistance relatively quickly. Eventually, though, nearly all MM patients will become refractory to all medications tried, Dr Gasparetto said.

There are many theories about why patients with MM relapse and become refractory, and this is a subject of ongoing research, said Dr Malek. Most traditional chemotherapy agents work through protein synthesis, said Dr Callander. Plasma cells grow relatively slowly, so with low cell turnover, some traditional agents will not work on them, making it impossible to fully eradicate them. There is also strong evidence that plasma cells are protected in bone marrow, where the macrophages and dendritic cells do not recognize that they are harmful.6 MM is dependent on its protective and permissive microenvironment, which prevents the agents from eradicating the disease. There is also the concept of clonal evolution, where MM cells evolve and acquire new, sometimes more aggressive genetic mutations, making them resistant to current therapy.6 Dr Callander said there are probably multiple mechanisms at work.

Each subsequent remission is typically shorter than the last. Researchers reviewed almost 5,000 MM patient charts for a study in the British Journal of Haematology.7 They found that 74% of patients achieved at least a very good partial response to first-line treatment, whereas only 11% of patients had the same type of response at the fifth line. As for complete response, they estimated that 32% experienced a complete response from the first line, down to 2% at the fifth line. The time from starting treatment to progression also decreased as the patient progressed through the treatment lines. For the first line, the time to progression was 18 months, whereas for the second line the median time to progression was 13 months. For third and fourth treatment lines, it decreased to 7 and 5 months respectively.