What Makes Immunotherapy Work for Multiple Myeloma?

Study finds molecular predictions of remission for patients treated with a four-drug combo.

The treatment landscape for multiple myeloma, a cancer of the bone marrow, looks very different now than it did just a decade ago. With the advent of immunotherapy, newly diagnosed patients now have better options for treatment.

Recently, the immunotherapy drug daratumumab, which targets the CD38 protein on the surface of cancer cells, was shown to improve outcomes. Newly diagnosed patients taking a four-drug combination that included daratumumab were much more likely to go into remission. Approximately 70% of patients in that trial were negative for minimal residual disease, a sensitive cancer-detecting threshold.

The Biology Behind Myeloma Remission

Scientists at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine are working to understand the biology behind myeloma remission and progression.

Why didn’t the other 30% of patients go into remission, and do the factors associated with remission tell us anything that could guide treatment decisions?

“We don’t understand the mechanism that would explain why some patients progress and others don’t,” said Francesco Maura, M.D., assistant professor at Sylvester who studies myeloma. “It’s important for us to understand the mechanism of this disease and to identify alternatives for these patients.”

The Sylvester team, working with collaborators at Perlmutter Cancer Center at NYU Langone Health, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, published a paper today in the journal Nature Cancer describing their findings.

The researchers identified immune cells and DNA alterations in the tumors that are correlated with better outcomes for patients on the four-drug treatment.

The Tumor-immune Interplay

To understand the differences between patients who progress or go into remission, the scientists wanted to study not only their cancer, but the complex environs surrounding cancer cells, known as the tumor microenvironment. Especially important in this microenvironment are immune cells, which can play both helpful and harmful roles in the context of cancer treatment.

The research team used bone marrow samples collected from 49 patients who were part of the MANHATTAN trial, a clinical trial testing the four-drug combination. That trial was led by C. Ola Landgren, M.D., Ph.D., chief of the Division of Myeloma at Sylvester. Dr. Landgren is also the co-senior author on the Nature Cancer study, along with Gareth Morgan, M.D., Ph.D., director of myeloma research at Perlmutter.

“Since the introduction of advanced, targeted immunotherapy regimens, there has been a pressing need to better understand the tumor genomic and immune interactions that drive resistance to combination treatment approaches. We believe this study adds significant information that will result in better clinical trials and more effective therapies for patients with high-risk disease,” Dr. Landgren said.

Whole Genome Sequencing and Immune Cell Profiling

The scientists sequenced the genomes of tumor cells from bone marrow samples collected before and after treatment. They also used single-cell RNA sequencing to profile the immune cells in the tumor microenvironment. This is one of the first studies to combine tumor whole genome sequencing with immune cell profiling for multiple myeloma, said Dr. Maura, who was one of the lead authors on the study.

The research team found several genetic alterations in tumor cells that correlated with poor outcomes. Some had been seen in the context of other treatments and some are newly identified in this study. Certain genetic changes previously shown to predict progression didn’t show up in the new study, meaning that the immunotherapy drug daratumumab seems to take a different path to killing cancer cells than previous therapies.

The scientists also found high levels of the immune cells known as natural killer cells in patients who responded well to the drug combination. Previous studies found that these cells are important for daratumumab’s cancer-killing activity, in part by spurring the growth of another kind of immune cell, monocytes. The study found that patients with higher levels of monocytes after treatment tended to have better responses.

A Complete View of Multiple Myeloma

These findings line up with another recent Sylvester-led study following multiple myeloma patients a year after treatment, said David Coffey, M.D., a Sylvester hematologic oncologist who was also one of the lead authors of the Nature Cancer study.

That study, published in September, also found immune differences in patients who were in long-term remission and those who weren’t.

Now, the team is studying the stages before multiple myeloma starts. Certain conditions—monoclonal gammopathy of undetermined significance and smoldering myeloma—are often precursors to multiple myeloma. The scientists are working to understand the immune differences between patients who develop multiple myeloma and those who don’t, with the ultimate goal of devising treatments that could intervene in earlier stages of the disease.

“We’re really studying all aspects of the disease, from the inception of the disease to the first treatment through the maintenance phase, and working to understand factors associated with both good and bad outcomes,” Dr. Coffey said.

Tags: Dr. C. Ola Landgren, Dr. David Coffey, Dr. Francesco Maura, multiple myeloma, Sylvester Comprehensive Cancer Center, USNWR Oncology