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MMRF’s Landmark Study CoMMpass Poised to Uncover the Biology of Myeloma

Value-Based Care in Myeloma - Multiple Myeloma
Caroline Helwick

The Multiple Myeloma Research Foundation (MMRF)’s CoMMpass study (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile) is a groundbreaking, landmark study designed to uncover the various molecular profiles existing within multiple myeloma and to determine how they relate to disease course and response to treatment. The most ambitious study of its kind in this disease (and perhaps for all malignancies), the CoMMpass study represents the cornerstone of MMRF’s Personalized Medicine Initiative.

The CoMMpass study will collect and analyze tissue samples and genetic information from approximately 1000 patients with newly diagnosed multiple myeloma over 5 years. The goals are to determine which treatments are most effective within subsets of patients, and to provide researchers around the world access to the data. The ultimate consequence of this effort will be the personalization of myeloma therapy on an individual level, and on the larger scale, the facilitation of research and drug development.

Three myeloma specialists recently convened to discuss the CoMMpass trial and its implications—Gregory J. Orloff, MD, of Virginia Cancer Specialists in Fairfax; Sagar Lonial, MD, of Emory University in Atlanta, GA; and Sundar Jagannath, MD, of Mount Sinai Hospital in New York. The full interview can be accessed online at www.personalizedmedonc.com.

What Makes CoMMpass Different from Other Trials?
Dr Lonial emphasized the unique nature of CoMMpass. “There are many large trials around the world where eligible patients receive uniform therapy throughout the course of the study protocol. CoMMpass, on the other hand, allows us to obtain real-world experience on patients who are not selected by specific enrollment criteria, and who are treated in a variety of settings with diverse treatment approaches,” he said.

In other words, patients will be treated according to their physicians’ discretion. The genetic profile of their cancer will be known, as will their response and long-term outcome. This will help to determine which treatment works best for a specific patient subtype.

Dr Lonial stressed that the heterogeneity of myeloma makes it very challenging to treat and hard to understand. For one patient, a certain regimen is very effective; for another, it is not. “From long-term follow-up of CoMMpass, we will be able to look at the genetic profile of the patients, know which regimen they received, and know their long-term clinical outcomes. No trial to date has done this,” he said.

“CoMMpass will help us understand the disease biology in greater depth,” said Dr Jagannath. “The study gives a tremendous overview of myeloma.”

The result of CoMMpass, Dr Orloff predicted, will ultimately be prolongation of survival for patients with myeloma. “Survival for myeloma, overall, has doubled over the last 10 years; but unfortunately, there has been no significant impact in the subset of patients defined as high-risk, based on our current methodology for stratifying risk at the molecular level,” he said. “A significant goal of CoMMpass will be to identify new targets and treatment for that subset.”

Study Has an International Reach
CoMMpass will involve approximately 50 centers in the United States, as well as dozens of centers in Canada and Europe. Involvement of the international community “builds a larger team,” Dr Lonial noted, and it also enhances the genetic and clinical diversity of the patient population and the treatment approaches.

For example, in Canada and in Europe, patients typically receive a doublet, not a triplet, regimen, as is standard now in the United States, Dr Jagannath pointed out. The different regional populations may also reveal differences in the distribution of genetic subsets.

“By going global, we will be able to tell if our trial results are applicable from place to place,” Dr Jagannath said. “This is the beauty and strength of CoMMpass compared to smaller trials, or even single cooperative group trials.”

Drilling Down Molecularly
Multiple myeloma is not a single genetic disorder but a disorder with multiple abnormalities, Dr Jagannath stressed. “We now understand that even in a single patient there are a number of clones, and at any particular time, there is a driver mutation that gives that clone a certain clinical manifestation. When we treat the disease, not all clones are eradicated, and subsequently, other clones often come up. Once we understand the disease in greater depth, as we will do in CoMMpass, we will discover its Achilles heel, or driver mutation. We can target this by developing a drug specifically designed against it or by using one that is already indicated in another disease.”

The first interim analysis of CoMMPass has revealed that myeloma subclones often persist after treatment, Dr Orloff said, and that is, “unfortunately leading to incurability.” He emphasized that “the study of these subclones will be paramount.”

Dr Lonial described how an understanding of the genetic heterogeneity of myeloma will facilitate treatment planning. Almost all patients respond to a proteasome inhibitor, an immunomodulating agent, and a steroid, but durability differs among patients, “and this is where genetic heterogeneity shows up,” he explained. “CoMMpass will help us build on what we already have as a good treatment platform. We will perhaps be able to add a fourth drug, and get to that Achilles heel.”

This is already happening experimentally in patients with a mutation in the BRAF gene, where patients with relapsed and/or refractory disease who have been treated in Europe have responded well with a BRAF inhibitor. “The finding of the BRAF mutation in 5% of patients was very important,” Dr Jagannath said. The BRAF mutation is only one of what will ultimately prove to be many common driver mutations and pathways shared across tumor types, and this suggests that drugs developed for other malignancies (in this case, melanoma) could also be used in multiple myeloma.

Dr Lonial noted that the KRAS and NRAS mutations were also identified by the Multiple Myeloma Genomics Initiative as common abnormalities in a subset of patients with myeloma, and these mutations are significant in lung cancer and in colorectal cancer as well. It is possible that a drug that targets these mutations could be beneficial in multiple tumors types. “So, it’s not just our team playing against those mutations, but the larger research group attacking cancer globally,” Dr Lonial added.

He noted that the excitement in finding unusual mutations in some patients extends beyond the use of targeted treatments. “We are excited about BRAF, because we have drugs that target it, but we still don’t know the natural history of patients with BRAF mutations from the time of diagnosis. Now, we can collect a number of patients with a certain mutation, and see how they fare on treatment x versus treatment y. To me, it is incredibly exciting to learn about the natural history of patients with mutations.”

Research Easily Accessed by Scientific Community
The MMRF is also launching its Researcher Gateway, which will allow researchers outside of the CoMMpass study to access the data acquired in the trial.

 “The Researcher Gateway will allow us to parlay the information we obtain to researchers all over the world, not just those studying myeloma, but also other malignancies,” Dr Orloff said.

The design of the CoMMpass study “breaks down the barriers regarding ‘intellectual property,’…allowing scientists around the world to embrace the data at a much greater extent and utilize intellectual property to the betterment of all researchers and patients,” Dr Orloff pointed out.

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Last modified: May 20, 2015
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