Despite a flurry of treatment advances in multiple myeloma over the past decade that have increased overall survival from just 2 to 3 years in the 1990s to between 5 and 7 years today—with some data suggesting an extended life expectancy of between 7 and 10 years1—the cancer remains stubbornly incurable, and for most patients with the cancer, relapse is inevitable. The reason is often due to the low number of myeloma cells (minimal residual disease) remaining in the bone marrow of patients following treatment, even in those who have achieved complete remission from either autologous stem cell transplantation or combination regimens of novel agents, such as immunomodulatory drugs and proteasome inhibitors.
For more than 2 decades, researchers at the Fred Hutchinson Cancer Research Center in Seattle have been investigating a radioimmunotherapy approach to treating radiosensitive malignancies by delivering radionuclides directly to remaining tumor cells left behind following treatment, increasing the potential for durable remissions and even cures in patients with B-cell lymphomas and acute myeloid leukemia. Earlier this year, Damian J. Green, MD, Associate Member in the Clinical Research Division at the Fred Hutchinson Cancer Research Center and Associate Professor at the University of Washington, and his colleagues received a $3.2 million grant from the National Cancer Institute to test what Dr. Green calls “the third generation of radioimmunotherapy” in patients with multiple myeloma.
The clinical trial, which is slated to launch early next year, will investigate a process that uses a boron cage developed by Dr. Green’s collaborators at the University of Washington that houses 10 boron atoms containing astatine-211, an alpha-emitting particle. The boron cage is attached to the CD38 antibody, labeled with the astatine, and injected into patients. The antibody targets the CD38 protein, which is overexpressed on myeloma cells, and fastens to the cells. Once the antibody is attached, the alpha particle radiates the targeted malignant cells, killing them.
The clinical trial is the first-in-human study investigating this type of radioimmunotherapy, with plans to enroll patients with multiple myeloma undergoing autologous stem cell transplantation. The radioimmunotherapy procedure will be performed prior to the transplant in combination with a high-dose melphalan-conditioning regimen.
The ASCO Post talked with Dr. Green about this unique approach to treating multiple myeloma and its potential for curing the disease.
Destroying Minimal Residual Disease
Please explain how using radioactive particles to deliver anti-CD38 immunotherapy to myeloma tumor sites and wiping out minimal residual disease could potentially cure the cancer.
We have spent the past 2 decades pioneering techniques to deliver potent payloads to target myeloma cells and discovered one way to do that was through a radiolabeled antibody directed against the CD38 antigen that delivers radionuclides directly to the target cells. The goal of this type of alpha-emitting radioimmunotherapy is to deliver a sufficient dose of radiation to cause a double-strand break in cancer cell DNA, killing malignant cells in a selective fashion while leaving normal cells alone.
This radioimmunotherapy strategy has the potential to eliminate every last myeloma clone within a patient. It may also turn out this approach works best in combination….— Damian J. Green, MD
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I think of targeting alpha-emitting particles to kill myeloma cells, or cancer cells in general, as third-generation radioimmunotherapy. The first generation of radioimmunotherapy used radiolabeled antibodies, such as 131iodine-tositumomab and 90yttrium-ibritumomab tiuxetan, as a conditioning regimen for transplantation in patients with B-cell lymphomas, which resulted in some impressive responses. Then, our group and others focused considerable effort on developing multistep “pretargeting” radioimmunotherapy methods, in which we separate out the delivery of the radioactive particle step from the antibody step to enhance the therapeutic efficacy of radioimmunotherapy while reducing its toxicities.2,3
This third generation involves alpha-emitting particles and is very appealing to immunologists and oncologists because the approach harnesses the unique power of alpha emitters, which deliver a huge amount of energy over a very short distance. This allows us to hone in on the target cells and not exact significant injury to normal cells.
Our colleagues and collaborators at the University of Washington developed a boron cage we call B10, because it has 10 boron atoms into which we can stably place our alpha emitter, astatine-211. We attach the boron cage to the CD38 antibody, insert the astatine, and then deliver the alpha emitters to the target sites. We think this process offers the promise of giving us an entirely new way to go after residual myeloma cells and eliminate them.
If this type of radioimmunotherapy proves efficacious, it may represent the first significant advance in a conditioning regimen for autologous bone marrow transplant in the treatment of myeloma in over 20 years.
Ideal Timing of Radioimmunotherapy
In your clinical trial launching early in 2018, patients will receive radioimmunotherapy using astatine-211 along with melphalan as part of the conditioning regimen prior to receiving a bone marrow transplant. If the goal of the radioimmunotherapy process is to wipe out minimal residual cells, why wouldn’t the procedure be more appropriate in the post-transplant setting, when there are often persistent low levels of disease in the bone marrow?
My goal is to make transplantation for myeloma obsolete. But right now, it is still a standard of care in the treatment of this cancer.— Damian J. Green, MD
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Ultimately, that may prove to be the best time to use this approach. However, in this study, we are targeting CD38, and CD38 is expressed on other cells within the bone marrow environment. We want to demonstrate the safety of this procedure in a situation where we can rescue the marrow, so the reason we are using a 211At-labeled monoclonal antibody this way in this first clinical trial is because we know we will have stem cells in reserve to repopulate the marrow after targeting CD38 with the alpha emitter.
If we see this treatment is well tolerated and safe to administer, and I think it will be, I would be very interested in studying this procedure in a minimal residual disease setting following a transplant, as well as in patients not going to transplant. But first we have to demonstrate this type of radioimmunotherapy is well tolerated and safe.
Tracking Toxicities
What are the side effects of this type of therapy?
Because the alpha emitter travels only a very short distance, just one to two cell diameters, we anticipate the toxicities will be few. If there is significant off-target delivery of the radionuclides, that would be concerning, which is why we are starting the trial using a very low dose of the alpha emitter and plan to monitor patients closely.
New Approach to Killing Myeloma Cells
If you could eliminate minimal residual disease in myeloma would that constitute a cure?
Absolutely, as long as every myeloma cell is eliminated. The advantage of using a radioimmunotherapy approach like ours, as well as approaches like chimeric antigen receptor (CAR) T-cell therapy, in the treatment of myeloma is these treatments are potentially agnostic to the high-risk features of myeloma cells. As far as we know, the impact of using an alpha emitter to go after myeloma cells and its capacity to cause double-strand breaks in the cell DNA is entirely independent of whether a patient has a high-risk cytogenetic abnormality, such as 17p deletion or t(14;16). So, this therapy affords us a completely different way of targeting myeloma cells.
This radioimmunotherapy strategy has the potential to eliminate every last myeloma clone within a patient. It may also turn out that this approach works best in combination with melphalan, lenalidomide -(Revlimid), or bortezomib (Velcade). But radioimmunotherapy is a very different way of targeting the tumor cell.
Role of Bone Marrow Transplantation
What is the role of bone marrow transplantation in this era of so many effective, novel therapies for multiple myeloma? Is transplantation for this cancer becoming obsolete?
My goal is to make transplantation for myeloma obsolete. But right now, it is still a standard of care in the treatment of this cancer, and each year the number of transplants for myeloma increases nationwide. As a result, myeloma remains the most common indication for autologous transplant in the United States. The combination of chemotherapy and bone marrow transplantation in this setting continues to make sense. I’m not saying transplantation is the right therapy for every patient with myeloma, but for transplant-eligible patients, autologous transplantation still offers the best option to prolong overall survival.
Right now, we do not have a crystal ball to tell us which patients will benefit the most from a transplant and which ones won’t, but we are getting closer to making that determination. In fact, some patients may be less responsive to high-dose melphalan based on their genetic profile.4 In the next few years, we are going to see an era of much more tailored therapy for this cancer and, hopefully, a more effective shot at a cure. ■
Disclosure: Dr. Green reported no conflicts of interest.
References
1. Jagannath S, Richardson PG, Munshi NC: Multiple myeloma and other plasma cell dyscrasias. Physicians Practice, June 1, 2016. Available at www.physicianspractice.com/printpdf/167438. Accessed August 1, 2017.
2. Green DJ, Orgun NN, Jones JC, et al: A preclinical model of CD38-pretargeted radioimmunotherapy for plasma cell malignancies. Cancer Res 74:1179-1189, 2014.
3. Green DJ, Frayo SL, Lin Y, et al: Comparative analysis of bispecific antibody and streptavidin-targeted radioimmunotherapy for B-cell cancers. Cancer Res 76:6669-6679, 2016.
4. Walker BA, Boyle EM, Wardell CP, et al: Mutational spectrum, copy number changes, and outcome: Results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol 33:3911-3920, 2015.
