When Linda Tedone sought medical advice for pain in her back, knees and shoulders, her primary care physician attributed her discomfort to the typical aches and pains of aging. Tedone’s condition worsened significantly over the course of a year, however — at one appointment in 2015, she screamed in pain during an exam. Her doctor ordered an MRI, which revealed three lesions on her spine. Biopsies confirmed Tedone’s worst fear: She had multiple myeloma, a type of blood cancer that cannot be cured.
“I was terrified,” says Tedone, 63, of Belchertown, Massachusetts. “When I heard the word ‘cancer,’ I thought I was going to die.” After her husband and children searched online to learn more about the disease, it quickly became clear that the field of multiple myeloma research was burgeoning with innovative biotechnology and new treatments. Her oncologist at Baystate Medical Center in Springfield, Massachusetts, suggested that she enroll in a clinical trial that would allow her to start treatment with Kyprolis (carfilzomib), a drug that had been approved by the Food and Drug Administration (FDA) only for relapsed patients who had tried other therapies. Kyprolis, a proteasome inhibitor, stops enzyme complexes in cancer cells from breaking down excessive proteins generated by cell division, thereby choking cellular function.
Tedone started taking Kyprolis in combination with Revlimid (lenalidomide), an immunomodulatory agent, and dexamethasone, a corticosteroid. “I responded well and had no side effects,” Tedone says. “But the cancer was aggressive, and the treatment stopped working after six months.” She underwent a stem cell transplant, and the disease was in remission for almost a year. When it returned, she started a combination that included a different proteasome inhibitor and immunomodulatory agent, but after eight months, her body started aching and a lesion on top of her head grew to the size of a baseball.
Tedone was losing hope in fall 2018, when her doctor recommended she see an oncologist at Dana-Farber Cancer Institute in Boston. Nikhil Munshi, M.D., director of basic and correlative science at the Jerome Lipper Multiple Myeloma Center, introduced an option that was showing promise in clinical trials: chimeric antigen receptor (CAR)-T cell therapy. The treatment involved engineering Tedone’s T cells to target a protein on the myeloma cells called B-cell maturation antigen (BCMA). A week after treatment, the tumor on her head had shrunk to the size of a raisin and a tumor in her jaw was gone. “They saw no cancer in my blood or bone marrow,” she says. “It really was a miracle.”
In the past, patients with aggressive multiple myeloma — like Tedone — would have quickly run out of treatment options, but that has changed in recent years. “I’ve actually been amazed by the number of advances we’ve had,” says Jeffrey Zonder, M.D., a myeloma specialist at the Barbara Ann Karmanos Cancer Institute at Wayne State University in Detroit. “It’s easy to argue that there are no areas of cancer that have seen more progress than multiple myeloma in the last 10 years.”
Adding Monocolonal Antibodies to the Combination
Multiple myeloma is relatively uncommon, with a lifetime risk of 0.76 percent and about 30,000 new cases diagnosed each year in the United States. This form of cancer, which is usually found in people over 65, starts in the plasma cells in the bone marrow. When these cells grow out of control, people with the disease may experience weakness from anemia and pain related to fractures in the bones as myeloma cells release substances that lead to the breakdown of bone and crowd out other substances that form new bone. Symptoms may also include acute and worsening kidney function, which can result in fatigue, discomfort or swelling of the legs.
Vicki Watkins received a multiple myeloma diagnosis in 2014 after a urine test showed high levels of protein.
To diagnose the disease, a physician may order a complete blood count to measure levels of red cells, white cells and platelets. Low levels of these blood cells can be a sign that myeloma cells are growing out of control. Blood chemistry labs test for creatinine, calcium and albumin to find other indicators of myeloma. A physician may also order blood or urine tests to look for excess production of certain antibodies produced by malignant cells. The cancer is then assigned a stage using the Revised International Staging System, which is based on four factors: the amount of albumin, beta-2-microglobulin and lactate dehydrogenase in the blood, as well as the specific gene abnormalities of the cancer.
After staging, the physician addresses the possibility of a stem cell transplant. Factors such as age and heart and lung function help determine a patient’s eligibility for the procedure, says Kenneth Shain, M.D., Ph.D., a myeloma specialist in the departments of malignant hematology and tumor biology at Moffitt Cancer Center in Florida. Before undergoing a transplant, patients in the U.S. typically receive a combination known as VRd — the proteasome inhibitor Velcade (bortezomib), Revlimid and dexamethasone — in four to six cycles, according to Shain. “VRd and other induction therapies for myeloma are much more effective and less toxic than the chemotherapies we used in the past,” he says. “It is the combination of these drugs that makes them so successful.”
Most patients experience minimal side effects, but physicians and patients still need to be aware of potential issues. Velcade can cause peripheral neuropathy and injection site reactions; it can also increase the risk of shingles, which might be avoided by taking antiviral medications prophylactically, Shain says. Revlimid can sometimes cause fatigue, rash and gastrointestinal side effects, and dexamethasone can cause symptoms such as insomnia, agitation, weight gain and gastritis.
More recently, studies have shown the benefits of adding monoclonal antibody drugs to these combination treatments. Darzalex (daratumumab), for example, targets the CD38 protein in myeloma cells, flagging them for destruction by the immune system. In May 2018, the FDA approved Darzalex in combination with Velcade; prednisone, a corticosteroid; and melphalan, a type of chemotherapy, for patients who recently received a diagnosis of multiple myeloma and are ineligible for a stem cell transplant. The approval was based on findings that showed that adding Darzalex to the combination reduced the risk of progression or death by 50 percent. A recent study also showed that combining Darzalex with Revlimid and dexamethasone reduced the risk of disease progression or death by 45 percent compared with Revlimid and dexamethasone in patients with new diagnoses and who are not eligible for a stem cell transplant.
Monoclonal antibodies often have fewer side effects compared with conventional chemotherapy drugs because they target proteins on myeloma cells that are not expressed extensively on other tissues of the body, which is one reason researchers are testing whether adding these medications to existing three-drug combinations can benefit patients, says Peter Voorhees, M.D., a myeloma specialist at Levine Cancer Institute-Morehead in North Carolina. In December 2018, Voorhees presented findings of a safety study that tested a combination of Darzalex, Velcade, Revlimid and dexamethasone in patients with new diagnoses who are eligible for stem cell transplants. Researchers found that all the patients achieved a very good partial response — a 90 percent reduction of the disease burden (measuring myelomasecreted proteins in the blood or urine) — to the fourmedication therapy. Fifteen of 16 patients achieved a complete response, meaning there is no evidence of disease, as their best response, and the side effects were manageable.
Signaling Cancer Cell Death
Selinexor, an oral drug not yet approved by the FDA, is also generating excitement: Study findings show that it can extend life for patients who cannot tolerate or have progressed after five other FDA-approved medications, which is known as penta-refractory multiple myeloma. One way cancer cells proliferate is by escaping mechanisms that normally control cell growth, and this drug traps tumor suppressor proteins within the nucleus of cancer cells, forcing them to stop growing or die. Recent study results showed that the drug had an overall response rate of 26.2 percent in penta-refractory patients, and the median response time was 3.7 months. The results led the FDA to expedite the approval process for the drug, which is now under review.
Venclexta (venetoclax) also shows promise for patients with relapsed/refractory multiple myeloma. Researchers discovered that patients with the disease who test positive for a particular chromosomal rearrangement often respond well to Venclexta, which works by inhibiting the BCL-2 protein in myeloma cells. “Cancer cells take advantage of a mechanism that signals the cells to keep them from dying, but this drug blocks that signal,” says Andrew Kin, M.D., an assistant professor of oncology at Karmanos Cancer Institute. Clinical trials are underway to test the potential benefits of combining Venclexta or Selinexor with other approved therapies.
Weaponizing the Body's Immune System
Patients are also increasingly taking advantage of clinical trials that are testing other monoclonal antibody-based approaches for the treatment of multiple myeloma, such as antibody-drug conjugates. “These monoclonal antibodies have a warhead, or chemotherapy, attached to them,” Voorhees says. “When they bind to myeloma cells, not only do they engage the immune system to go after the cancer, but (also) the antibody is taken up by the myeloma cell. This allows the chemotherapy drug to be directly released inside the cell, maximizing tumor cell kill and minimizing side effects. It is like a Trojan horse-based approach to therapy.”
Clinicians and patients have also been impressed with the success of CAR-T cell therapy in recent clinical trials. “I’ve been an oncologist for 30 years, and I have never seen something that works so well, so quickly,” says Munshi, who is involved in a clinical trial for this therapy. “Patients are having an amazing response rate within weeks, and these are people who had no hope.”
In this form of therapy, patients’ T cells are separated from their blood and sent to a lab, where they are genetically modified and multiplied. The altered cells, which can better recognize and kill cancer cells, are then re-infused into the patient’s bloodstream.
“One potential benefit of this therapy is that we don’t have to keep redosing patients like other treatments,” Zonder says. “In some cases, the cells can persist in the patient’s system for an extended period of time.” However, he cautions, the cell therapy is associated with inflammatory reactions, such as potentially lifethreatening cytokine release syndrome and neurological complications.
Vicki Watkins, 62, experienced severe side effects from CAR-T cell therapy, but she says the benefit of a longer life has outweighed the disadvantages. Watkins, of Orlando, Florida, discovered she had multiple myeloma in 2014 after a urine test during a routine physical exam showed high levels of protein. At the time, she was working as a bus driver for Walt Disney World and felt no symptoms, but her primary care physician referred her to a specialist. Results from blood tests and a bone marrow biopsy made it clear that she had multiple myeloma.
Under the care of Shain, she tried four drug combinations but relapsed after six to eight months on each regimen. “My biggest prayer during that time was that I would not have nausea and could work,” she says. “The only symptom I experienced was fatigue, and I learned to listen to my body and get more rest.”
In early 2018, Shain told her that a slot was available in a clinical trial for CAR-T cell therapy. Watkins was aware of the potential side effects and benefits, and in February 2018 she started the treatment process. Watkins recalls that three days after the infusion of engineered T cells, she heard the medical team explain that she was cancer-free, but soon after that, she started losing her balance and her thyroid stimulating hormone levels skyrocketed. She went into a coma for two months, and when she woke up in April 2018, her muscles had atrophied to the point that she could not walk, and she struggled to vocalize her thoughts.
After months of physical therapy, Watkins relearned how to walk and her speech improved; recently, she felt strong enough to walk through Disney World with her husband and friends for the first time in months. Although she still struggles to maintain her balance and speak as quickly as before, Watkins has no regrets about her decision to enroll in the clinical trial. “I was in the right place at the right time,” she says. “I would not be here without CAR-T therapy. It saved my life.”