MMRF CureCloud Study Launches to Democratize Access to Genomic Data in Multiple Myeloma

Hearn Jay Cho, MD, PhD

On July 14, 2020, the Multiple Myeloma Research Foundation (MMRF) launched the historic and disruptive CureCloud study (NCT03657251) to amass genomic and real-world clinical data of a large population of patients with multiple myeloma for the advancement of precision medicine and clinical research in myeloma.

Irene M. Ghobrial, MD

The study plans to obtain genomic data from 5000 patients with active or smoldering myeloma using the first CLIA-grade liquid biopsy specifically developed for multiple myeloma. Next-generation sequencing will be performed using cell-free DNA (cfDNA) testing, which is DNA released into the bloodstream by cells, including cancer cells such as myeloma and it is important that the patient demonstrate sufficient disease burden that there will be enough tumor DNA in the blood sample to run the 70-gene panel. Eligibility to join the study will hinge upon the patient’s M-spike and/or kappa/lambda light chain values as a surrogate for disease burden, to increase the likelihood of useful data from the assay.

Data pertaining to the patient’s specific disease characteristics will be shared with the patient and physician to advance data-driven treatment decision-making as well as stored in an online database for future clinical research.

CureCloud is currently open to all eligible patients with multiple myeloma, but the investigators already have an eye toward future expansion of the study to include a broader patient population, such as certain patients with smoldering multiple myeloma.

In an interview with Targeted Oncology, Hearn Jay Cho, MD, PhD, Chief Medical Officer of MMRF and associate professor of Hematology and Medical Oncology at Mount Sinai Hospital Ruttenberg Treatment Center, and Irene M. Ghobrial, MD, director, Clinical Investigator Research Program, Dana-Farber Cancer Institute, and professor of Medicine, Harvard Medical School, both discussed the importance of the CureCloud study for the multiple myeloma community, and their hopes for what this study can achieve for myeloma patients and their physicians.

TARGETED ONCOLOGY: Can you explain what the MMRF CureCloud is? Who is the sponsor and who wrote the protocol for the study?

Cho: MMRF CureCloud is a clinical trial, which is sponsored by the Multiple Myeloma Research Foundation. CureCloud is open to any patient with multiple myeloma, except for patients living in Hawaii and Alaska, where lengthy shipping time prohibits a successful sequencing test, and New York, which requires additional laboratory certifications which we are currently working on but have not completed at this time. Eligibility requirements also include an M-spike value of 0.3 g/dL or greater, and a free light chain ratio (involved/uninvolved) of 8 or more.

The intention is to provide information back to the patient about their disease and to amass patient data. This will be real-world data collected in a longitudinal fashion for approximately 5000 patients with multiple myeloma. The protocol was developed in a collaborative effort between the research, clinical, and data teams at the MMRF.

TARGETED ONCOLOGY: What goes into participating in CureCloud for both patients with multiple myeloma and physicians, and what information do they receive?

Cho: The intention of this project is to bring information of value directly to patients.

A patient with myeloma can go online, review the information about the project, enter their M-spike and kappa/lambda data to confirm their eligibility, review the consent form, and sign it online. That triggers a process where an order for a blood draw from the patient is provided. The patient can then go to their treating physician and get the order signed. When a signed order is received by the MMRF, this triggers two processes related to the blood draw. First, a blood kit is sent to the patient's home, and a blood draw is scheduled for the patient at their home. A mobile phlebotomist will go to the patient's home, take the blood samples, and then those samples are sent back to the MMRF.

Part of the sample goes to our collaborators at the Broad Institute in Boston, and there the sample will be subjected to a cell-free DNA assay that will sequence 70 genes that are related to cancer and relevant to multiple myeloma. Another sample goes to our tissue bank where its stored for potential future use in other types of laboratory assays.

Second, the signed consent form allows us to access the patient's electronic medical records at all institutions where they receive medical care, and we will collect these clinical data and combine them with the genomic data obtained from the 70-gene assay at the Broad Institute.

Also, the protocol is designed to add future cassettes of data. If in the future immunologic assays are performed on the stored samples or additional data is gathered electronically from the patient's medical records, these will be added to the database so that we will have a comprehensive store of real-world patient data, in addition to cutting-edge molecular and genomic assay results.

TARGETED ONCOLOGY: What specific information will the report show for both patients and physician?

Cho: The 70-gene panel, which was designed for our cell-free DNA sequencing assay,

are all cancer-related genes, some of which are very commonly mutated in multiple myeloma. The information that is derived from this assay will be provided to the ordering physician in the form of a molecular pathology report from our collaborating pathologists at the Dana-Farber Cancer Institute in Boston. In addition, that information will be rewritten for patients in lay person form by a company called My Gene Counsel, which has experience producing patient-level reports on complex genetic information.

In particular, we have identified a group of genes that are commonly mutated in cancers, including multiple myeloma, for which there are certain targeted drugs available which have been approved for use in other types of cancers. In some cases, there are clinical trials examining the activity of these same drugs in multiple myeloma.

What will be reported back to patients is the mutations that have been detected in their blood and if there are clinical trials for which this patient may potentially be eligible based on these mutations. That gives the patient additional options to discuss with their physician in order to find the most appropriate treatment regimens for them.

TARGETED ONCOLOGY: How do you think this will help guide treatment decision making?

Ghobrial: We’re now in the era of precision medicine, and I think the first example of that is venetoclax [Venclexta], it’s a drug that specifically works on a subset of patients who have t(11;14) translocation or have a high BCL-2 level. And we know that there are so many other aberrations that will have specific treatment [associations]. We know, for example, if [a patient has] high-risk cytogenetics, we want to treat [these patients] specifically with certain drugs or be more aggressive in our treatment versus someone else who has better prognostic markers we may not want to push too much with the treatment. So, altering treatment based on what we understand from the biology is very important. And we always say that multiple myeloma is truly multiple types of myeloma and we shouldn’t expect to treat all patients the same way.

TARGETED ONCOLOGY: What if the patient does not have any actionable alterations?

Cho: There is a possibility that there may be no mutations detected a patient’s blood that can be specifically targeted. In those cases, we will not recommend any clinical trials.

TARGETED ONCOLOGY: This test appears to be offered free for patients. How is it that the MMRF is able to offer this test for free?

Cho: The MMRF is the sponsor of this protocol, and we have committed substantial funds in order to provide these tests to the patient free of charge. We’re covering the cost as part of the research program.

TARGETED ONCOLOGY: Tell us more about the CureCloud assay. What method of sequencing does it use and what is it looking for? What does this mean for CureCloud and the future of liquid biopsies for multiple myeloma in clinical practice?

Cho: The CureCloud assay is the first liquid biopsy for multiple myeloma. It is a CLIA [Clinical Laboratory Improvement Amendments]–certified assay that was developed in collaboration with our colleagues at the Broad Institute. This is a cell-free DNA assay, so DNA that was released by cells, including cancer cells, is isolated from the peripheral blood and those pieces of DNA are sequenced using probes that are specific to 70 common cancer-associated genes. These probes will provide sufficient depth of sequencing that we will be able to [identify] mutations, with confidence, if they are present in some of the genes that are detected.

The raw data from this assay are sent to our colleagues at the Dana-Farber Cancer Institute in the Department of Molecular Pathology. These data are interpreted so that a report can be generated detailing the specific mutations detected in these specific cancer-associated genes. This is a first-of-its-kind liquid biopsy specifically tailored for multiple myeloma that will return this important information to the patients and their treating physicians.

TARGETED ONCOLOGY: What can you tell other physicians about why their patients should participate in CureCloud?

Cho: We’re trying to return what we've learned to the patients. In previous studies, such as the CoMMpass study (NCT01454297), which enrolled over 1000 newly diagnosed patients with multiple myeloma, we learned an enormous amount about the genomics of multiple myeloma. We learnedhow it drives the disease, and in particular, we discovered that certain genes, which are commonly mutated in other cancers, are commonly mutated in multiple myeloma as well.

We wanted to be able to provide this information to patients, even if they're not being treated at an academic medical center or in a big, academic multiple myeloma program. So, this is for patients who are being treated by community physicians who don't necessarily have access to this cutting-edge technology.

We are bringing the discoveries that we made in the laboratory directly to patients so they can learn more about their disease and so they can have more informed, data-driven discussions with their providers about treatment decisions.

Ghobrial: In general, patients with multiple myeloma want to know what their underlying genetics are. They want to know what is going on with them so that they can have a better sense of which treatment option would be best for them.

Currently, we do [tests] on the bone marrow biopsy. CureCloud is taking it to the next step with liquid biopsy. It’s much easier for patients compared with bone marrow biopsy, and it's taking it to something called next-generation sequencing. Instead of looking at the big pieces of chromosomes with FISH [fluorescence in situ hybridization] and cytogenetics, we now can truly look at specific mutations and copy number alterations and make better decisions for patients based [on data]. That’s the power of CureCloud, taking it to the next step of precision medicine.

TARGETED ONCOLOGY: Once enough data have been received, how can patients and physicians access and use the aggregated data sets?

Cho: When patients enroll in this study, [they’re given access to] a personal web portal. In addition, the physician who signs the order form for the liquid biopsy has access to a physician portal. The data that are generated by the biopsy are made available to the treating physician through that portal. The patients also receive an interpreted report from My Gene Counsel. These will all be dynamic documents. In the future, as more information is added to CureCloud, we will be able to provide overview information about patients who are participating in CureCloud.

TARGETED ONCOLOGY: When CureCloud expands to include patients with smoldering myeloma, what do you expect to be different for these patients compared with patients with multiple myeloma?

Ghobrial: We started the collaboration between MMRF and Dana-Farber Cancer Institute through PROMISE and PCROWD. They are the first United States screening studies for multiple myeloma, and we're very excited because through this collaboration now our patients who are enrolled on PROMISE or PCROWD, patients who have smoldering myeloma, will have access to clinical data through this liquid biopsy, through CureCloud.

All of my patients are already ready to start. They know that they have been screened and that they can potentially get this information for smoldering myeloma but they want to have that clinically available and in their hands so that we can decide together, are they going to be on a clinical trial to prevent progression, are they in a low-risk setting and can continue to watch and wait, etc.

TARGETED ONCOLOGY: Do you think clinical research looking at the aggregate data from the CureCloud could help determine why patients with smoldering myeloma progress to multiple myeloma?

Ghobrial: We started looking at the genomic data trying to understand what causes progression from MGUS or smoldering myeloma to multiple myeloma. We looked at only 250 patients and now we have thousands of patients, and this would only happen with CureCloud and our PROMISE/PCROWD studies. By having these large numbers, we can truly dissect what causes progression from smoldering to myeloma. The hope is that patients get to know what their true risk for progression to overt disease is. Physicians and patients can then make decisions together on which clinical trials to go on, rather than relying on vague clinical markers that cannot truly predict whether they would progress or not.

TARGETED ONCOLOGY: What is the most unique thing about the information obtained through the CureCloud study?

Ghobrial: The important thing about CureCloud is that you're getting information that would be beyond what every patient would be part of. We've learned from the CoMMpass study where we had 1000 patients, and from those data we're still learning so much for every other patient. That’s the power of a large data cohort, of large aggregated data so that we can truly understand for a small cohort of patients what’s good for them. Only by [looking at] large cohorts can we understand what is unique for a subset of patients.