Multiple myeloma is an aggressive blood cancer that attacks bone marrow, the soft tissue inside your bones that makes blood and immune cells, your body’s defense system. While doctors have found better ways of treating this cancer and pushing it into remission, a persistent problem remains: patients’ immune systems remain crippled, and they are vulnerable to serious infections even years after bone marrow transplants. For myeloma patients, infections are the leading cause of death, and researchers weren't entirely sure why.  

In a new study in Cell Press Blue scientists from the Allen Institute and Fred Hutch Cancer Center have helped answer that question. They discovered that inflammatory signals stayed suppressed specifically in bone marrow, even as therapy continued. This is significant because inflammation acts like the body's alarm system: when immune cells sense a threat, they release these signals to recruit and activate other immune cells to fight it. But with that alarm muted in the marrow, immune cells stay less active.

“Since bone marrow is where new immune cells are created, this suppressed environment could indicate why the immune system didn’t fully recover even years after treatment. A regular blood test would not catch this,” said Aishwarya Chander, a computational biologist at the Allen Institute and co-author of the study.  

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blood and bone marrow tell different stories

Researchers tracked patients for two years after they were diagnosed with myeloma to observe how their immune systems changed over time and during cancer therapy. In the study, not only did blood and bone marrow tests reveal different results, they also showed almost opposite outcomes. In contrast to those in bone marrow, signs of inflammation in the blood were high.

“The field has largely treated blood and bone marrow as interchangeable windows into immune health in disease. Our study demonstrates they are not,” said Melinda Angus-Hill, lead scientist and corresponding author of the study. “We found inflammatory and metabolic programs are inverted between the two compartments.”

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building better vaccines

Another important finding could help reduce infection risk in patients who undergo chemotherapy and bone marrow transplants and could lead to the development of better vaccines. People who receive these procedures have their stem cells extracted, preserved, and then reinjected back into the body after chemotherapy kills the cancerous cells in their blood. The reinjected stem cells migrate back into the bone marrow where they begin to rebuild the immune system. But in patients with multiple myeloma, the bone marrow wasn't able to fully rebuild. Scientists discovered that they ended up with fewer memory B cells and T follicular helper cells, which help the body remember pathogens and fight infections.

Given the increased risk of infection for these patients, they receive vaccines to help their immune systems regain strength. This study found that half of patients didn’t respond to the high-dose flu vaccine, which meant they were still vulnerable to the flu. However, the COVID-19 mRNA vaccine was still effective in these same individuals. The COVID vaccine uses a special delivery method – tiny fat bubbles called lipid nanoparticles – that gives the immune system an extra push, which the high-dose flu vaccine doesn't have. Researchers call this pattern "adjuvant dependence," meaning some patients may need that extra boost to respond at all.

“What this tells us is that all multiple myeloma patients can make antibodies, but suggests that there is a barrier for some patients requiring a stronger initial signal to generate a robust response. The adjuvant-like activity of lipid nanoparticles or other adjuvants may provide that signal to restore immunity in these patients,” said Angus-Hill. “This result highlights a potential improvement to the current standard of care for patients post-transplant that could be immediately tested. The goal is to reduce infection risk in patients by increasing the protection that flu vaccination provides, hopefully improving immune responses in all multiple myeloma patients.”

takeaways from the research

Scientists believe there are a few important takeaways from this research. For one, recovery from myeloma isn't just about cancer cell counts; it's about whether the bone marrow, which is the immune system's factory, has truly healed. They hope this research will highlight the importance and accuracy of bone marrow tests (as opposed to just blood tests) in gauging the immune system’s response to myeloma therapy.  

The researchers also believe doctors should consider testing newer flu vaccines, built more like the COVID vaccine, in patients recovering from myeloma and its therapy. Given the success of mRNA vaccines in myeloma patients, they encourage clinical trials to confirm this. That change could potentially lower infection risk for this vulnerable group.