Somatic mutations in multiple myeloma can be immunogenic, and neoantigen-targeted immunotherapy can generate an immune response in these tumors, a recent study showed.1

Researchers analyzed DNA and RNA from sorted CD138-positive cells from bone marrow aspirate from 92 patients with relapsed/refractory multiple myeloma and 92 newly diagnosed multiple myeloma patients. They found that patients with relapsed disease had a greater tumor mutation burden, with a median of 67 coding somatic mutations per megabase compared with a median of 16 coding somatic aberrations per megabase in those who were newly diagnosed. Patients who experienced disease relapse also had a greater number of predicted neoantigens, with a median of 142 neoantigens compared with a median of 62 neoantigens in those who are newly diagnosed.

“Myeloma is considered to be a cold tumor for immune approaches such as checkpoint inhibitors,” because it has fewer mutations than many solid tumors, said the study’s senior author Samir Parekh, MBBS, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York City. Yet, immunotherapies such as thalidomide analogs and monoclonal antibodies are often used to treat myeloma. “Next-generation sequencing showed us that both newly diagnosed and relapsed patients have tumors with immunogenic antigens. This suggested we could use treatments that harness the immune system for clinical benefit in myeloma.”

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Dr Parekh and his colleagues confirmed the neoantigenic T-cell responses in 3 of the relapsed patients. Their article described 2 of these patients. The first, a patient aged 63 years who had received 4 prior lines of chemotherapy, obtained a stringent complete response following treatment based on a combination of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed death-1 (PD-1) inhibitor, followed by nivolumab and lenalidomide. The second, an individual aged 79 years who relapsed after induction therapy, had a complete remission after a similar treatment approach — combination immunotherapy, followed by a mini-autologous stem cell transplantation, followed by combination immunotherapy. 

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“We knew we had to design a novel strategy for the first patient,” said Dr Parekh. “We used our knowledge of the neoantigens and mouse modeling to develop a dual checkpoint inhibitor approach. Checkpoint inhibitors are not really used in myeloma and previous trials had raised concerns about toxicity, but those trials were not designed to look specifically at patients with tumors that expressed neoantigens.”