The Myeloma Crowd Research Initiative (MCRI) Final Projects

The Myeloma Crowd Research Initiative (MCRI) is the first crowdsourced and patient-funded effort to find effective solutions for multiple myeloma patients with high-risk disease. As patients, we believe that we can make a difference in the pace of research and we are willing to pitch in and do whatever is required to do just that. Our goal is simple - help find and fund a cure for multiple myeloma. The new arsenal for most myeloma patients is impressive, but for patients with high-risk genetic features or aggressive relapsed/refractory myeloma, the outcomes are still alarming. We asked researchers all over the world to submit their research proposals for high-risk myeloma, and we received 36 high-quality responses. From that list, we asked our Scientific Advisory Board to help narrow the list to 10. Those 10 were invited to participate on Myeloma Crowd Radio in order for patients to understand what the proposals aimed to accomplish. What we found was that most of the 10 research proposals were equally exciting for low or standard risk myeloma patients. Two of the proposals were able to receive funding through other sources, so 8 of the 10 submitted full proposals for review. On August 17th, this Monday, we will announce the proposals selected for the patient-driven funding initiative. We will be including these proposals on our MCRI fundraising page and we invite you to help make their research a reality by creating your personal fundraising page for this campaign. You can upload your own photo, change the text and send a link to your friends and family, asking them to support you by funding research that has been carefully selected by leading myeloma specialists and educated myeloma patients. The research from all of the proposals is impressive and selecting just a few from the list below is incredibly challenging.   Dr. Craig Hofmeister, MD, Ohio State University - CAR T cells targeting CS1 Dr. Hofmeister aims to use one of the most promising areas of research using CAR T cells to target a common myeloma protein, CS1. The new drug elotuzumab helped pave the way to find that CS1 was an effective target in myeloma. In this approach, T cells are withdrawn from a patient's blood sample, re-engineered to target the CS1 protein, grown up and expanded and then given back to the patient by injection. Once inside the patient, the CAR T cells replicate, finding the cells that express that CS1 protein on their surface. Once the CAR T cells find their target, they destroy the cells with that protein. CS1 is a target that is found on myeloma cells but not on many other cells in the body, making it an attractive target. It is a one-time therapy that is appropriate not only for patients with high-risk myeloma, but all types of myeloma regardless of genetic features. In time, it could also be used as a preventative approach for smoldering myeloma patients. With background in NK cells (natural killer cells) at Ohio State, Dr. Hofmeister seeks to potentially add in other immunotherapies to the mix over time. The approach is close to in-human studies but is not yet in clinical trials. Learn More.   Dr. Guenther Koehne, MD, PhD, Memorial Sloan Kettering Cancer Center - Safer allo transplant plus immunotherapies for high-risk multiple myeloma and PCL patients Dr. Koehne aims to implement a unique approach for patients with few or no options - patients with highly relapsed/refractory myeloma and plasma cell leukemia. First, he uses a T-cell depleted allogeneic (donor) transplant, which is a new type of allo transplant. The goal of removing the T cells during transplant is to avoid the dreaded graft vs. host effects typical of allo transplant. Next, he identified a target found from his work in leukemia, WT1, which is also expressed on many myeloma cells. He can engineer the T cells to find that receptor and initiate cell death without the side effects that can be found in other CAR T cell approaches. As a third step, he is now working to increase the power by training those WT1 cells to secrete Interleukin-12. IL-12 enhances the survival of these T cells and acts as a "homing" device to help the T cells find the WT1 signal, rounding up the cells that need to be eliminated. In his prior trials, patients did not experience typical host vs. graft effects and he has been able to achieve complete remission even in plasma cell leukemia patients, which is remarkable. He is now opening up a third clinical trial to continue his work. Learn More.   Dr. Ivan Borrello, MD, Johns Hopkins University School of Medicine - Auto transplant plus T cell Immunotherapy Dr. Borrello introduces a completely new immunotherapy approach, using enhanced marrow infiltrating lymphocytes (MILs) from a patient's own bone marrow, for truly personalized medicine. Traditionally, the immune system cells are removed from blood samples, but Dr. Borrello has found that MILs that reside inside of the bone marrow are more representative of an individual patient's disease. After a bone marrow sample is taken, the T cells are extracted, expanded a hundredfold outside of the body in the presence of the tumor cells, and then after autologous transplant, are given back to the patient. The auto transplant serves to de-bulk the tumor, giving the new engineered immune system T cells more power to do their job. When they are re-introduced, they target the hundreds of unique proteins that could be causing tumor growth for that patient, not just a single protein. This offers the promise of a broad-spectrum approach to the many different kinds of myeloma within a single patient, custom-tailored to that patient's disease. He compares this type of immunotherapy with the CAR T cell therapies and notes that this approach does not have side effects that can be found with CAR T cell use. This proposal is in its third clinical trial which is now open for high-risk multiple myeloma patients who have not had prior autologous transplant. Learn More.   Dr. Frank Zhan, MD, PhD, University of Iowa - Specific target for high-risk 14;16 and 14;20 patients The 14;16 and 14;20 myeloma translocations are rare – in about 6% of all patients. These patients can respond to therapy just like normal risk patients, but the duration of their remission can be much shorter. Dr. Frank Zhan performed extensive research to search a genetic database to find 100 genes that may be affected in the 14;16 and 14;120 myeloma translocations. That work led to search a compound database to find 5 possible drug targets that would impact the genes that are changed by these translocations (c-MAF for 14;16 and MAFB for 14;20). After testing these in the lab,  one compound stood out that could stop the growth of cancer cells for c-MAF and MAFB – Allsterpaullone. In addition, Dr. Zhan found that expression of Notch2 is strongly regulated in this MAF subgroup. Notch2 is an important gene related to cancer stem cells, drug resistance and the bone marrow microenvironment. The proposed research is to use Allsterpaullone and a new Notch2 antibody now in clinical trials to provide the same length of remission (and beyond!) for this high-risk patient group. Learn More.   Dr. Carmen Baldino and Dr. Kelvin Lee - Jasco Pharmaceuticals and Roswell Park Cancer Institute - PIM2 kinase inhibitor targeting the CD28 protein Drs. Baldino and Lee have collaborated to target a protein that increases in frequency as myeloma progresses and becomes more aggressive. In newly diagnosed patients this protein is present in 25% of patients, after first relapse it is found in 50% of patients, at second relapse it is found in 80-80% of patients, and in plasma cell leukemia patients, it is found in 100% of patients. Together they used this significant observation to develop and test a new PIM2 kinase inhibitor that targets this protein. The new drug also affects the MAF gene - a gene that can be changed somewhat in all myeloma patients, and especially those with the high-risk 14;16 translocation. The goal of the proposal is to both bring patients back to a state where they are sensitive to chemo again and also to kill myeloma cells outright. They are currently at the stage of compiling toxicity data in order to present an application to the FDA for approval and then a Phase I study would follow. This work will address the very big issue of aggressive, chemo-resistant myeloma. Learn More.          Dr. Gareth Morgan, MD, FRCP, FRCPath, PhD, Dr. Christoph Heuck, MD, Dr. Niels Weinhold, PhD, Dr. Jacob Epstein, DSC, Dr. Shmuel Yaccoby, PhD, University of Arkansas, Myeloma Institute - Your own mouse avatar Dr. Morgan, Heuck, Weinhold, Epstein, and Yaccoby aim to determine how to shorten the time to personalized discoveries using a new mouse avatar. With the increasing number of drugs and drug combinations in the myeloma pipeline, the prospect of taking these drugs through the standard clinical trial process could take years or even decades to determine which therapies or combination therapies are right for individual patients. The Myeloma Institute group proposes the creation of a mouse avatar that has your exact kind of myeloma. With this avatar, they can test how a drug or combination of drugs could act before the drugs are used in live patients, determining how effective they would truly be and shaving years off of important discoveries. In the first phase of their study, the doctors propose to create 10 mouse avatars and test them against a myeloma standard drug, bortezomib, and then use molecular analyzers and whole exome and RNA sequencing on the treated high-risk avatars to determine how the various types of high-risk myeloma reacted to the drug. Learn More.    Dr. Hermann Einsele, MD and Dr. Michael Hudecek, MD, University of Würzburg, Germany - CAR T cell therapy targeting CS1 and BCMA with contingency planning and a specific, proven target domain Drs. Einsele and Hudecek have performed many years of immunotherapy research. Their aim is to use the exciting, non-transplant therapy option of CAR T cells to target two specific proteins found on myeloma cells - CS1 and BCMA. CAR T cells are becoming an exciting area of research with multiple groups and pharmaceutical companies now jumping into its study. Celgene, for example, is now moving forward to develop CAR T cells for BCMA. Again, CAR T cells are manufactured by removing blood samples from a patient, engineering them to target both of these proteins and then expanding them before they are given back to the patient. This is a non-transplant approach that stays active in patients for years. They decided to go after two targets instead of one based on their experience in leukemia where they found that some diseased cells could lose the targeted protein to hide from the treatments. They find this "immune escape" or loss of the targeted protein in 5-10% of patients. Because CAR T cells can be extremely powerful but potentially curative, they have developed an emergency break using a specific antibody in case they see any possible negative reaction in patients. Because CAR T cells are also a manufactured, engineered product, they are using the HuLuc63 targeting domain, already proven to be safe with the elotuzumab studies. Their work is in the preclinical stage and they estimate it to be 2-3 years before it enters clinical trials. Learn More.    Dr. Frits van Rhee, MD, PhD, MRCP, FRCPath, University of Arkansas and Dr. Stephen Russell, MD, PhD, Mayo Clinic - Measles virus in myeloma The measles virus grabbed media attention with one patient’s amazing outcome. Dr. Russell and Dr. van Rhee aim to expand those results into more patients with lessons learned from the first clinical trials. Phase I was a trial of six patients and now phase II is running at the Mayo Clinic for 42 patients with the measles virus alone. The proposed work for the MCRI is a collaboration between UAMS and the Mayo Clinic to treat 16 patients in a now-open clinical trial using a lower dose of the measles virus in combination with cyclophosphamide. To date, the doctors found that patients with an absence of the measles antibody and a low tumor burden responded the best to the treatment. Cyclophosphamide is being used with the measles vaccine to keep the immune system from mounting a response to the measles virus when it is given and allow the virus to attack more myeloma cells. Their project will continue the study of this non-toxic approach to myeloma therapy and will additionally utilize imaging as a key tool to show where the measles virus is going and staying in the body.  The clinical trial is now open at UAMS. Learn More.  As you can see, each of the projects are promising and selecting the few we can initially support will be a challenge. We are thrilled that patients will drive research that has the potential to extend life and offer potentially curative options for high-risk myeloma patients as well as normal and low-risk patients. We invite you to help drive this patient-led initiative that could very likely make a difference in YOUR own care.  For more information about the MCRI, click here. To donate to the MCRI or to create your own fundraising page and encourage family and friends to support the MCRI, click here.