by Diana Price 2/2019
Una Wilson initially thought that the early signs of multiple myeloma (MM) were the result of a pulled muscle in her back. At the time, the software developer from Seattle, Washington and native of Ireland was in her mid fifties and traveling in Europe. She had reached for her backpack as she exited a train and felt something “pop” in her back. After a similar experience on another trip kept Una from walking any reasonable distance, she decided it was time to see a doctor.
Una’s story is not usual among patients with MM. William Bensinger, MD, director of the Autologous Marrow Transplant Program and an associate professor at Swedish Cancer Institute Center for Blood Disorders and Stem Cell Transplantation in Seattle, explains that MM causes no clear or telltale symptoms, so it tends to be diagnosed when a patient seeks care for another concern. This can include musculoskeletal pain, such as Una’s suspected pulled muscle; fatigue; anemia; blood infection; pneumonia; kidney failure; and, when there’s underlying heart disease, chest pain.
“Multiple myeloma is a cancer involving a particular type of white blood cell that resides primarily in the bone marrow,” explains Dr. Bensinger. The bone marrow is the space inside the bone, and it’s actually an organ. Bone marrow makes blood cells that “perform a variety of functions that are essential to life.” These include red cells, which transport oxygen from the lungs to muscles and other organs; platelets, which help blood to clot; and white cells, including plasma cells, which help fight infection and play a role in repairing bone and making new bone throughout life.
Plasma cells are also the blood cells on which MM has a direct impact. “For reasons we don’t entirely understand, one of these plasma cells becomes cancerous and begins to grow and reproduce in an uncontrolled fashion,” Dr. Bensinger says. As the cancerous cells fill up the bone marrow, they tend to make high levels of protein antibodies in the blood. As MM recruits plasma cells to make antibodies, fewer plasma cells are available for bone repair. This results in calcium being released into the blood as bone breaks down, which can cause disorientation, occasionally coma, and kidney failure if the tubules of the kidneys fill with excess calcium.
Though Healthy Antibodies Help Fight Infection, Those Produced by MM Have No Benefit
“Because these antibodies are derived from a cancer cell, they don’t protect you from infection,” says Dr. Bensinger. Also, as cancer cells fill up bone marrow, there is less space to grow normal cells, especially red blood cells. This leads to the symptoms of fatigue and sometimes severe anemia, leaving patients more prone to infection.
In 2016 the American Cancer Society estimated that there would be 30,330 new cases of MM and 12,430 deaths. Multiple myeloma is the third most common blood cancer in the United States, after lymphoma and leukemia.1
Treatment of Multipe Myeloma
There is currently no cure for MM. Instead the goal of treatment is remission, which means that basic analysis cannot detect abnormal cells remaining in the bone marrow, and protein, or antibody, levels in the blood have reverted to zero. Remission, however, is not a cure, as small numbers of abnormal cells remain in the blood (more-sensitive methods can detected these). “Eventually,” Dr. Bensinger says, “these cells will cause a recurrence of the disease.”
The good news is that remission can have significant benefits for patients. “Remissions are useful,” Dr. Bensinger explains, “because ample data show that remission is linked to longer duration of disease control, improved quality of life, and longer overall survival.”
Drugs for MM treatment work by reducing the population of abnormal plasma cells—those affected by MM. “When you can do that effectively,” Dr. Bensinger says, “the signs and symptoms of MM often reverse themselves.” This means that the likes of anemia, kidney problems, and bone destruction can all be halted.
Stem cell transplantation (SCT) remains an important treatment approach that can result in remission because it allows doctors to give higher doses of chemotherapy than patients would normally tolerate. These chemotherapy drugs work against MM by damaging the DNA of abnormal plasma cells and thus destroying them. Higher doses of chemotherapy tend to kill more cancer cells than smaller quantities.
The problem with chemotherapy is that it can also damage normal cells. And higher doses can mean more side effects. “The side effects can become so severe that the patient can’t tolerate them and must stop treatment,” Dr. Bensinger explains. Bone marrow—abnormal or normal—is very sensitive to the effects of chemotherapy, making the treatment potentially very effective but also hard for patients to tolerate.
By giving the patient healthy blood cells after high doses of chemotherapy, SCT helps patients avoid serious side effects and still get the treatment they need. The process starts with collection of blood stem cells from the patient (for an autologous transplant) or from a matched donor (for an allogeneic transplant). Autologous and allogeneic approaches have some different benefits and risks, so the patient and her doctor will decide which approach is right for her. These stem cells can then be frozen and stored for months to years and used when the patient receives high doses of chemotherapy. After giving an individual a high dose, Dr. Bensinger explains, the doctor waits a couple of days for the body to clear the drug and then gives the stored stems back to the patient, like a blood transfusion.
“The transplanted stem cells circulate in the blood, hone in on bone marrow, and begin to grow,” Dr. Bensinger says. In about two weeks, the transplanted cells are producing new blood cells in the body.
While SCT remains a significant therapy for MM, newer drugs are emerging that can help improve survival, particularly for patients with disease that recurs. “Things are getting much, much better for [patients with] this disease,” says Dr. Bensinger.
These newer drugs include Kyprolis® (carfilzomib), Thalomid® (thalidomide), Revlimid® (lenalidomide), Velcade® (bortezomib), and Pomalyst® (pomalidomide). The US Food and Drug Administration has added several new drugs to the MM treatment lineup: Empliciti™ (elotuzumab), Ninlaro® (ixazomib), and Darzalex® (daratumumab).2,3,4
Particularly significant about these latest drug approvals is that they are indicated to treat patients when MM relapses, or comes back, after the initial treatment or treatments. Because there is currently no cure for MM and treatment is aimed at remission, relapses are not uncommon, and patients stand to benefit significantly from therapies that work against relapsed disease.
Una Wilson’s treatment has included some of these newer drugs. She has been on a Phase II clinical trial with Velcade and Thalidomide plus the established chemotherapy drug Cytoxan® (cyclophosphamide) and the corticosteroid (a drug used to treat inflammation) dexamethasone. Una has also had her stem cells collected in anticipation of an eventual autologous transplant. In addition, she’s been taking Revlimid since 2007.
Una has had some great results. From 2008 to 2013, she had no trace of MM in her blood. Though traces have gradually increased over the past three years, she is otherwise healthy. “Officially, I’m now considered relapsed,” she says, “but I am fortunate to have no symptoms.”
Moving forward, Una plans to keep seeking the care she needs to maintain her health and continue to work full-time and travel the globe. She’ll continue to work with Dr. Bensinger to find new drugs, as needed.
To others facing a similar diagnosis, Una encourages working with an MM specialist and getting educated about the disease and treatment options. She adds, in light of the new advances: “Live with hope and optimism—we live in amazing times!”
On The Horizon: New Therapy for Multiple Myeloam
As research continues to move forward, MM patients may soon have even more exciting treatment innovations. Dr. Bensinger notes that a study of an entirely new form of therapy is under way. This approach proposes the use of antigen receptors known as chimeric antigen receptor T-cells (CAR T-cells). Antigen receptors are chains of amino acids that recognize specific antigens, a substance that causes an immune system to produce antibodies against it. In this therapy a patient has T-cells removed from the body. Then, in a laboratory, a receptor is introduced to the T-cells, enabling it to identify and bind to a cancer cell.5
Research into CAR T-cell therapy in MM, however, is still in the very early stages. “A lot of work needs to be done to show the benefits, but it has great potential,” Dr. Bensinger explains.
CTL019 CAR T-cell Therapy-engineers a patient’s own T cells to teach them to recognize and attack myeloma cells. CTL019 is designed to attack myeloma stem cells, a cell type that can give rise to many more myeloma cells. A pilot study reported that this approach was safe and feasible a phase 2 trial evaluating this approach is ongoing.
BCMA CAR T-cell Therapy-teaches T cells to recognize myeloma cells through a protein called B-cell maturation antigen (BCMA). This approach was reported to have promise in treating myeloma in patients who had already failed other therapies. There are several ongoing trials with BCMA as a target.
Antibody-drug conjugate, GSK2857916
GSK2857916 combines an antibody that recognizes myeloma cells by attaching to the protein BCMA and the drug monomethyl auristatin F (MMAF), which kills the cells after they’re recognized. This is the first time this drug has been studied in humans, and the primary purpose of the study was to find a dose that is safe.
Second-generation CD38 antibody, MOR202
Darzalex, a CD38 antibody, has been shown to work well against myeloma. Early-phase investigations into a new antibody, MOR202, have preliminary results suggesting that the drug is effective against myeloma.
- Cancer Facts & Figures 2016. American Cancer Society website. Available at: http://www.cancer.org/acs/groups/content/@research/documents/document/acspc047079.pdf. Accessed April 16, 2016.
- FDA Approves Empliciti, a New Immune-Stimulating Therapy to Treat Multiple Myeloma [news release]. US Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm474684.htm. November 30, 2015.
- FDA Approves Ninlaro, New Oral Medication to Treat Multiple Myeloma [news release]. US Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473771.htm. November 20, 2015.
- Lokhohrst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. New England Journal of Medicine. 2015;373:1207-19. doi: 10.1056/NEJMoa1506348.
- Crafting a Better T Cell for Immunotherapy [news release]. Fred Hutchinson Cancer Research Center website. Available at: http://www.fredhutch.org/en/news/centernews/2016/02/crafting-a-better-t-cell-for-immunotherapy.html. February 22, 2016.