Eliminating residual multiple myeloma with precision

From the Green Lab, Clinical Research Division

Multiple Myeloma (MM) is a form of blood cancer that arises from plasma cells in the bone marrow. Current treatments including chemotherapy and stem cell transplants can result in complete remission for some MM patients. Nonetheless, most treated patients show minimal residual disease (MRD), in which a few treatment-resistant MM cells survive and can ultimately cause relapse. As practically all MM cells are sensitive to radiation, targeted therapy using radioactive elements known as radionuclides has the potential to eliminate remaining MM cells. 

Dr. Damian Green has previously published work with his late mentor Dr. Oliver Pressdemonstrating the effectiveness of astatine-211 (211At) in lymphoma mouse models. In addition, Dr. Johnnie Orozco has been exploring 211At in leukemiaand Dr. Brenda Sandmaier has clinical trials translating discoveries made at the center into treatments for patients with acute myeloid leukemia. Now the team from Dr. Green’s laboratory (Clinical Research Division) has published a study in the journal Blood on 211At targeted to MM. 211At may be an ideal candidate for therapies targeted to blood cancers as it releases a great amount of energy with low penetration in the form of α-particles. Dr. Shyril O’Steen, a staff scientist in the Green lab, said that α-particles “blast through a cell, but then they’re done, as their short path length limits their impact to less than three cell diameters. Other types of radiation can act like a bullet that goes through the tumor cell and then carries on through all the other tissue around it. That means that α-particle therapies are much safer for clinical staff to handle and have a much better toxicity profile for patients. If we can get an α-particle where we want it, it won’t produce a lot of collateral damage. And because it’s so powerful, it’s got a high probability of actually killing the target cell.”

Figure: An α-particle from decaying Astatine-211 breaking DNA strands of a multiple myeloma cell.  Image provided by: Dr. Shyril O’Steen
Figure: An α-particle from decaying Astatine-211 breaking DNA strands of a multiple myeloma cell. Image provided by: Dr. Shyril O’Steen

In collaboration with Dr. Scott Wilbur at the University of Washington, researchers in the Green lab conjugated 211At to a CD38-targeting antibody. CD38 is a protein that is highly expressed in MM and is the target of a similar FDA-approved treatment daratumumab (trade name Darzalex). However, daratumumab treatment relies on patient immune cells to eliminate MM, which ultimately allows resistance to the therapy in virtually all patients. The authors hypothesized that the 211At-CD38 conjugated antibody would be able to travel to the bone marrow, home in on and attach to MM residing there, and directly damage MM DNA and eradicate the cancerous cells without causing widespread toxicity. Dr. O’Steen said, “Multiple myeloma tends to be highly heterogeneous, and so depending on what you’re hitting it with, there’s probably some cell hanging out there that is resistant to treatment. The other thing that MM is known for is that it comes back. What we’re excited about with 211At-CD38 treatment is that if we can get the 211At onto a multiple myeloma cell, and the daratumumab results support our longstanding contention that CD38 is a very good target, then we can potentially kill every single cell, because unlike a lot of other treatments out there, there are very few things that can rescue a MM cell from this kind of damage.”

The researchers found that 211At-CD38 was effective in mouse models of disseminated MM. These are models with similarities to MRD in humans—the cancer cells are injected intravenously and spread throughout the body as single cells or small cell clusters. When the authors treated disseminated disease bearing mice with 211At-CD38, 90% of them survived over 120 days, compared to a median survival of 23 days in untreated mice. The researchers then tested different doses of 211At-CD38 in disseminated models and compared them with mice treated with 211At conjugated to an isotype control antibody. They found that a medium dosage of 211At-CD38 resulted in no detectable disease by imaging in 70% of the mice at day 41, while 211At conjugated to the isotype control antibody showed disease in all mice at the same dose. Increasing the dose of 211At-CD38 eliminated disease in all of the mice. This treatment showed minimal toxicity effects on body weight, platelet counts, and kidney and liver function. 

What are the next steps to explore this approach? Dr. Green has an R01 grant from the National Cancer Institute to translate the findings into patients. Along with his mentee, Dr. Sherilyn Tuazon, he is planning to open a clinical trial adding 211At-CD38 into the stem cell transplant treatment regimen for multiple myeloma. “In the United States, we do more autologous stem cell transplants for myeloma each year than for any other disease, but these transplants are not curative. There has been no improvement to the transplant regimen for over 20 years. We believe that 211At-CD38 may allow us to eliminate minimal residual disease, and in so doing may offer a game changing approach to myeloma management,” Green said. The team expects to open the trial in the next few months. “There is no place like the Fred Hutch with respect to our ability to rapidly translate discovery from our laboratories into patient trials” Green said.  

This work was supported by the National Cancer Institute, The Defeat Myeloma Fund, MMORE, The Brotherton Family, The Multiple Myeloma Cure Seekers Society, and The Quest for Truth Foundation

Fred Hutch/UW Cancer Consortium members Johnnie Orozco, D. Scott Wilbur, Ted Gooley, Brian Till, Ajay Gopal, Brenda Sandmaier, and Damian Green contributed to this research

O'Steen S, Comstock ML, Orozco JJ, Hamlin DK, Wilbur DSS, Jones JC, Kenoyer A, Nartea ME, Lin Y, Miller BW, Gooley TA, Tuazon SA, Till BG, Gopal AK, Sandmaier BM, Press OW, Green DJ. The Alpha Emitter Astatine-211 Targeted to CD38 can Eradicate Multiple Myeloma in a Disseminated Disease Model. Blood. 2019 Aug 8;. doi: 10.1182/blood.2019001250. [Epub ahead of print] PubMed PMID: 31395601.


Additional citations

1.    Orozco JJ, Bäck T, Kenoyer A, Balkin ER, Hamlin DK, Wilbur DS, Fisher DR, Frayo SL, Hylarides MD, Green DJ, Gopal AK, Press OW, Pagel JM. Anti-CD45 radioimmunotherapy using (211)At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model. Blood. 2013 May 2;121(18):3759-67. doi: 10.1182/blood-2012-11-467035. Epub 2013 Mar 7. PubMed PMID: 23471305; PubMed Central PMCID: PMC3643772.

2.    Green DJ, Shadman M, Jones JC, Frayo SL, Kenoyer AL, Hylarides MD, Hamlin DK, Wilbur DS, Balkan ER, Lin Y, Miller BW, Frost SH, Gopal AK, Orozco JJ, Gooley TA, Laird KL, Till BG, Bäck T, Sandmaier BM, Pagel JM, Press OW. Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model. Blood. 2015 Mar 26;125(13):2111-9. doi: 10.1182/blood-2014-11-612770. Epub 2015 Jan 27. PubMed PMID: 25628467; PubMed Central PMCID: PMC4375108.