The Multiple Myeloma Research Foundation is hoping that an open-access research portal containing detailed longitudinal clinical and genomic data from multiple myeloma patients will spur collaborative research that advances much needed molecularly-targeted treatments.
At an event hosted in New York City by the MMRF, the group unveiled an open-access portal, called the Researcher Gateway, through which study investigators around the world can access data being collected on multiple myeloma patients through the CoMMpass trial. Personalized medicine proponents are hoping that this approach will bring together experts from academia, industry, and community healthcare settings who can discover new targeted treatment strategies for multiple myeloma patients.
Over the next five years, the Researcher Gateway will amass detailed genomic and clinical data from 1,000 multiple myeloma patients through CoMMpass. Since its launch in 2011, CoMMpass has enrolled approximately 300 patients and has conducted whole-genome, whole-exome, and transcriptome sequencing of 90 patients' tumor and normal cells.
Separately, the MMRF also launched a Community Gateway, to which anyone can sign up to connect with others in the multiple myeloma community, share personal disease information based on their comfort level, and be matched to ongoing clinical trials. In the short time that the gateway has been in operation, it has attracted more than 600 enrollees.
"I wouldn't be surprised if this is the model for all of cancer," Eric Lander, founding director of the Broad Institute at the Massachusetts Institute of Technology, said at the event, discussing the collaborative research paradigm created by the organization. "I wouldn't be surprised if this is the model for all of medicine."
Other groups have launched data sharing portals that involve patients, researchers, and industry. A few years ago, PatientsLikeMe, a company that enables patients to share outcomes data through an online forum, and direct-to-consumer genetic testing firm 23andMe agreed to work together to recruit 10,000 Parkinson's patients for study. The trial aims to identify the genetic and environmental factors contributing to Parkinson's disease and gauge the effectiveness of treatments (PGx Reporter 6/10/2009).
Cancer Commons is working with researchers to develop molecularly-informed treatment models and identify subtypes for lung cancer, prostate cancer, and melanoma. Earlier this year, the non-profit launched the Donate Your Data campaign to encourage cancer patients to submit their medical records and urge physicians to submit case reports that researchers can use to identify new markers, subtypes, and treatment options.
However, MMRF's personalized medicine research plans for multiple myeloma are far more ambitious than these other collaborative efforts, according to Walter Capone, COO of the organization. "None of these other initiatives are mapping patients as comprehensively, [including] full clinical and genomic sequencing data, with an underlying tissue bank for future research," Capone told PGx Reporter. No other effort is "putting all of this data out to researchers worldwide to access. And no one is connecting the patient community in an initiative of this magnitude that will connect them to the research and clinical trials that are suited specifically for their subtype of disease."
Through CoMMpass, researchers will sequence patients' tumors and normal cells at baseline, when they have a complete response to treatment, and then when they relapse. By comparing the changing genomic characteristics of myeloma patients' disease, researchers hope to learn about the specific treatments that work best in patients as their illness progresses. Patients will be followed for up to 10 years and have their data analyzed at follow up every few months. Researchers will track patients' response to treatments at a range of academic and community centers, including within the Veterans Affairs system, at centers in Italy, Spain, the UK, and other EU countries.
Approximately, 41 percent of multiple myeloma patients survive for five years. This year, an estimated 20,000 adults in the US will be diagnosed with multiple myeloma, which is caused by an overproduction of abnormal plasma cells in the bone marrow. Approximately, 11,000 patients will die from the disease in 2013.
Founded in 1998, the MMRF has raised more than $225 million and contributes 90 percent of its total budget to research and programs for multiple myeloma. The non-profit has supported 350 research grants and 47 trials that have led to the approval of six new multiple myeloma drugs in the last decade, doubling the life span of patients.
Speaking at the event, FDA Commissioner Margaret Hamburg highlighted that in a little over a year the agency has approved two new drugs for multiple myeloma, Pomalyst (pomalidomide) and Kyprolis (carfilzomib), and has designated the investigational agent daratumumab as a breakthrough therapy. However, none of these agents are targeted to the specific molecular characteristics driving patients' disease. The CoMMpass trial and data-sharing portals are MMRF's attempt to build the infrastructure for advancing such personalized treatments.
MMRF has a total budget of $40 million for the next 10 years for its Precision Medicine Program, which includes the CoMMpass study. To date, 55 percent of the total budget has been raised. Approximately 15 percent of this budget will fund the Researcher and Community Gateways. Bill Bowes of US Venture Partners and the drug companies that have signed on to the effort will provide financial support on a yearly basis as CoMMpass progresses. MMRF will contribute matched dollars through fundraising efforts.
Well before launching CoMMpass and the data-sharing portals, the MMRF has been at the forefront of using genomics research to elucidate the biological mechanisms underlying multiple myeloma. Four years after researchers mapped the human genome, the MMRF launched the Multiple Myeloma Genomics Initiative in collaboration with the Broad Institute and the Translational Genomics Research Institute, which led to the development of a genomic data repository of 250 patient samples. More than 600 registered researchers have already had access to this data and to bioinformatics tools through this first initiative, and researchers will continue to have access to this data through the new Research Gateway.
Then, in 2009, researchers from the Broad Institute, MMRF, and several other institutions sequenced 38 tumor genomes and compared the findings to matched normal DNAs. According to Lander, one of the leading researchers in this effort, this was the first cancer to be probed in depth with genomic sequencing approaches.
The study, published in Nature in 2011, identified a number of new molecular mechanisms as potential drivers of multiple myeloma. The authors also reported the finding that approximately 4 percent of multiple myeloma patients in the study harbored mutations in the BRAF gene, a marker that at the time was identified as a driver mutation in 50 percent of melanoma patients.
Through this work and other efforts, approximately 50 gene mutations are now known to characterize different multiple myeloma subtypes. This heterogeneity, however, poses barriers for drug developers that want to advance treatments targeting these molecular abnormalities.
Primarily, the low prevalence of many of the gene mutations implicated in multiple myeloma means that very large numbers of people will have to be screened in order to study the patients with the marker of interest. Furthermore, participants don't merely have to have the gene mutation being studied, but also have to match trial enrollment requirements in terms of disease stage and treatment history.
"There is no practical way for a company to conduct 15 different clinical trials" to investigate gene mutations at "rates that are between 1 percent to 4 percent of the population … It's not just impossible technically but it's also economically unfeasible," said Kiran Patel, VP and medical development lead at GlaxoSmithKline, at the New York event. Patel headed up the clinical development programs for two recently approved melanoma drugs, Tafinlar (dabrafenib) and Mekinist (trametinib), indicated for metastatic patients with BRAF-mutated tumors (PGx Reporter 5/29/2013).
Gareth Morgan, hematology professor at the Institute of Cancer Research, highlighted how one myeloma patient with a BRAF mutation enrolled in a study called Basket very quickly saw 50 percent of his lesions disappear when treated with Roche's Zelboraf (vemurafenib), approved currently as a treatment for melanoma patients with BRAF mutated tumors. The Basket study is looking to enroll cancer patients with a BRAF mutated tumor to investigate the efficacy of Zelboraf in other tumor types. However, Morgan said that only three patients have been enrolled into Basket, illustrating one of the major difficulties inherent in conducting pharmcogenomic cancer research.
"This is a massive problem," Morgan said. "To find 4 percent of [myeloma patients with BRAF mutations], you have to screen a hundred to get four patients. That patient has to be at the right time of his disease. We've got patients lined up, [but] we have to wait until they relapse."
Environment for sharing
These are the types of challenges that the MMRF, with its community and research portals and the CoMMpass trial, hope to ameliorate. By collecting clinical and genomic data over the course of patients' disease, CoMMpass researchers will be able to compare subsets of patients grouped based on their demographics, medical history, lab results, and the molecular features of their disease.
MMRF enlisted the help of GenoSpace, a company that builds software systems for storing genomics data, to create the research portal that will enable investigators to visualize the collected information. As an example of the types of queries that investigators will be able to perform, John Quackenbush, GenoSpace CEO and bioinformatics professor at Harvard School of Public Health, demonstrated how researchers can identify the rare myeloma patients who harbor mutations in the KRAS and BRAF gene, even though it is well known from the literature that these mutations don't simultaneously occur in the majority of cancer patients.
"This allows us to begin to think about asking questions that we couldn't ask if we didn't have access to the underlying data," Quackenbush said. "[Multiple myeloma] is very complex. Genomics really tells us how complex the disease really is."
The Translational Genomics Research Institute is conducting the genomic analysis for CoMMpass. Washington University and Mount Sinai Medical Center have joined the research effort with MMRF. Drug companies that joined CoMMpass when it first started, Millennium Pharmaceuticals and Onyx, have had early access to the data in the research portal. According to Quackenbush, these pharma companies have already been able to use the data to advance knowledge internally on multiple myeloma treatments. More recently, Bristol-Myers Squibb and Janssen have also signed on to the study.
In exchange for access to the data in the Research Gateway, however, researchers, as well as drug companies, have to agree to certain conditions. "All data, findings, and discoveries contained in or derived from CoMMpass are dedicated to the public domain. This means if a scientist makes a discovery in the data like a new biomarker, it can't be patented," MMRF's Capone said. If an invention derived from CoMMpass is patented, then the filing party must provide MMRF and all its partners and collaborators a perpetual, royalty-free, worldwide license to the discovery or technology, Capone added.
For the community portal, GenoSpace has included controls that allow enrollees to maintain their privacy, and specify with whom their data can be shared and how it can be used. Quackenbush noted that even those who decide to not broadly share their information within the online community can still benefit from the knowledge being accumulated in the portal. For example, regardless of people's level of participation in the Community Gateway, the administrators can still use the information they provided to inform them of clinical trials for which they might be eligible.
"Our feeling was that we have a greater chance to enroll large numbers of patients if they can control who sees their own data," he told PGx Reporter. "We also believe that as patients participate and see what sharing data can enable, they will elect to share data more broadly.
For the time being, the data collected through the Research Gateway and Community Gateway will remain separate. However, Community Gateway enrollees may give MMRF permission to share their information with researchers, and in the future, the foundation can decided to create a separate research database out of the information in that portal.
"What we have enabled is the ability for patients who have enrolled in CoMMpass to transfer their information to the Community Gateway," Quackenbush said. "We also envision connecting patients to trusted providers who can work with them to generate genomic data and to load it to the Community Gateway."
In Quackenbush's experience, patients are most motivated to share data in an open forum, followed by their family members. "These are the parties who have a vested interest in having anyone and everyone with the potential to find a cure," Quackenbush said. "But I can see many situations where healthy controls could be very interested in sharing data, and I hope they do."