Injectable forms of medication may benefit patients with blood cancers.
MARIEBETH HEROFF, who is living with multiple myeloma, continued working full time thanks to few side effects. - PHOTO BY ALY WILLIS
When Mariebeth Heroff couldn’t stay awake during her nursing shifts in late November 2017, she thought she simply needed more sleep. She slept as soon as she returned home, at 5 p.m., waking briefly to eat dinner and help her 8-year-old daughter get ready for bed. Then she began experiencing back pain and nausea.
Heroff, 43, had a history of high cholesterol, and she worried that these were symptoms of a heart attack.
Heroff, of Oak Harbor, Washington, made an appointment to see her primary care doctor. Blood tests revealed that her protein levels were slightly elevated, but the physician was not concerned, and he suggested retesting in a week. When the second round of results also showed elevated protein levels, Heroff was desperate to gather more information, so she turned to the internet. Suspecting that she could have multiple myeloma, a cancer of plasma cells, Heroff was overcome with fear — especially about the implications for her daughter. In March 2018, further testing confirmed her diagnosis: stage 1 multiple myeloma.
Heroff was eager to begin treatment, which included subcutaneous injections of Velcade (bortezomib), a targeted chemotherapy that was offered only intravenously before 2012. Her oncologist explained that injections of the medication were preferable because she would have a lower chance of developing peripheral neuropathy, or tingling, numbness, burning or weakness in the hands or feet. Heroff had witnessed the effects of neuropathy in her husband, who has diabetes.
Although Velcade is the only chemotherapy drug offered subcutaneously for patients with multiple myeloma, studies are underway to evaluate whether subcutaneous injections could be also be an option for an intravenous (IV) monoclonal antibody therapy known as Darzalex (daratumumab).
This drug works by attaching itself to multiple myeloma cells and killing them directly or by allowing the immune system to destroy them. Patients with certain forms of lymphoma and leukemia — relapsed or refractory follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia — also started reaping the benefits of the trend toward injections in June 2017, when the Food and Drug Administration (FDA) approved subcutaneous Rituxan Hycela (rituximab), a drug that has been given intravenously in the United States since the late 1990s.
“The fact that we can administer these drugs subcutaneously is a very big deal,” says Jason Valent, M.D., the director of plasma cell disorders at Cleveland Clinic in Ohio. “Infusions of rituximab used to take hours, and now patients can be done in a matter of minutes. And reducing the rate of peripheral neuropathy with subcutaneous bortezomib allows more patients to stay on the drug longer.”
THE SUBCUTANEOUS JOURNEY
Researchers started exploring the possibility of reformulating IV medications as subcutaneous injections to reduce the toxicity of the drugs and to improve convenience for patients, says Stephen Ansell, M.D., Ph.D., a hematologist at Mayo Clinic in Minnesota. With the subcutaneous method, a drug is injected with a needle into the tissue under the skin in the abdomen or other area typically known to have ample subcutaneous tissue, and nurses are trained to give these injections, says Kathleen Wiley, RN, MSN, AOCNS, an oncology clinical specialist with the Oncology Nursing Society. In contrast, IV medications travel through the vein directly into the circulatory system, and they act more quickly than injections under the skin, Wiley says.
When medication is absorbed by tissue under the skin, usually there is a lower level of the drug in the body sustained for a longer period of time than with IV administration, Ansell explains. “The peak levels of the drug may be higher with an IV infusion. This may be good for killing cancer, but this can also cause more toxicity,” he says. Although the peak levels may vary with these two forms of administration, studies suggest that both methods are equally effective.
Researchers compared the effectiveness of these two forms of administration in a 2011 study of 222 patients with relapsed multiple myeloma who were assigned to receive subcutaneous or IV Velcade. The results showed that patients in both groups had an equal overall response rate to the medication, but 38 percent in the subcutaneous group experienced peripheral neuropathy, compared with 53 percent in the IV group. Velcade works by blocking or slowing down the action of proteasomes in cells, which break down proteins in healthy and cancerous cells. The buildup of protein can cause cancer cells to stop growing, dividing and multiplying.
Heroff and her doctor have been encouraged by her response to Velcade in combination with the oral chemotherapy Revlimid (lenalidomide) and a steroid called dexamethasone, which increases the response to Velcade.
After two months, her myeloma protein, sometimes called the M protein or M spike, dropped from 3.1 to 0.6 g/dL — the goal is to get that number as close to zero as possible.
Her low albumin/globulin ratio jumped from 0.7 to 1.2, which meant her body’s overproduction of the globulin protein was slowing. She noticed a red, itchy skin reaction at the injection site, but the reaction has not been painful. She’s grateful to have minimal side effects from treatment and the ability to continue working full time.
While reducing the incidence of neuropathy is the main advantage of injecting Velcade subcutaneously rather than intravenously, studies are showing different benefits of this route of administration for Darzalex. The drug can be used to treat patients with relapsed or refractory multiple myeloma and also in combination with Velcade in newly diagnosed patients with multiple myeloma who are ineligible for autologous stem cell transplant.
“When the drug is administered intravenously, one of the big problems is that many patients experience an infusion reaction,” Valent says. “It is almost like an allergy, with symptoms such as shortness of breath, cough, scratchy throat, itchy skin or wheezing. With the subcutaneous administration, the risk of such infusion reactions seems to be much less.”
In December 2016, Saad Usmani, M.D., presented study results at the American Society of Hematology annual meeting in San Diego, showing that only 22 percent of patients who received the drug subcutaneously experienced infusion reactions, compared with 46 percent for those who received the drug intravenously. The efficacy of the drug is equal with both forms of administration, and the subcutaneous method is far more efficient, says Usmani, the director of plasma cell disorders and clinical research at Carolinas Healthcare System in North Carolina.
“The weekly infusions can take seven hours the first day, then more than four hours the second and third days, and then three and a half hours after that,” he says. “The injection is given within five minutes.”
Now there is a large randomized phase 3 trial underway comparing IV and subcutaneous Darzalex, and the results will ideally lead to FDA approval of subcutaneous Darzalex, Usmani says.
Long IV infusion times have also been one of the disadvantages of taking Rituxan. Studies have shown comparable clinical efficacy between the two forms of administration, and one study showed that 81 percent of patients preferred subcutaneous over IV administration because it required less time in the clinic. Rituxan binds to the CD20 protein on the surface of normal and malignant B cells and recruits the body’s immune and other defenses to attack and kill the marked B cells.
A phase 3 trial of 410 patients with previously untreated follicular lymphoma who received the drug either intravenously or subcutaneously showed that the overall response rate at the end of treatment was 84.9 percent with the IV group and 84.4 percent with the subcutaneous group. The study also showed that the frequency of severe side effects was similar between the groups, with 34 percent in the IV participants and 37 percent in the subcutaneous participants.
Before starting subcutaneous injections, patients must receive one full dose of IV Rituxan to give nurses an opportunity to watch for any reactions, including headache, rigors (sudden feeling of cold), fever, chills, stomach pain, nausea and diarrhea. If the patient is cleared to start injections, the volume of medication in the syringe will be larger than nurses are accustomed to giving subcutaneously, Wiley says. Fortunately, the addition of hyaluronidase to Rituxan increases the permeability of the tissue and helps the body absorb and distribute the high volume of medication, she says.
CRAIG NATZKE and his wife, MORGAN, drove two hours for monthly infusions to treat his follicular lymphoma. - PHOTO BY CHRISTA REED
Craig Natzke, 37, was relieved when his doctor said he could switch from IV to subcutaneous administration. For the past year, Natzke and his wife had been driving two hours from their home in Savage, Minnesota, to Mayo Clinic for monthly infusions. Natzke was diagnosed with stage 4 follicular lymphoma in December 2015 after he noticed a bump increasing in size on the left side of his neck. During the previous six months, the bump had become as large as a Ping-Pong ball, and family members suggested that he see a doctor. His physician noticed swelling under his left armpit and on the left side of his chest and immediately ordered a series of tests.
“My body was lit up like a Christmas tree on the first PET scan because there was so much cancer,” Natzke says. “I was shocked because I had gotten physicals every year and had been completely healthy.”
Natzke started on a combination of Rituxan and Treanda (bendamustine), and his first infusion appointment lasted eight hours. Eventually the appointment times decreased to two hours, and he was thrilled when his second PET scan showed no cancer in his body after three months of treatment. After six months on the drug combination, Natzke started going to his doctor every other month for infusions of Rituxan as maintenance therapy. A year later, the drug was available subcutaneously.
“I’m really happy that the appointments take 20 minutes now instead of two hours,” Natzke says. “I’ve been in remission for two years, and that is a major milestone.”
Natzke, who sells software to law firms, continued working full time throughout his treatment. He and his wife have rekindled their love of travel, and they’ve visited New York City, Costa Rica, Iceland, London and Jamaica in the last two years. Now they’re eyeing Machu Picchu, in Peru, and a few other places in South America.
Doctors like Valent are pleased to see that subcutaneous options for medications are giving patients more time to enjoy their lives with fewer side effects. “There is excitement about the very good response rates patients are having with these drugs in combination with other drugs,” Valent says. “They are very well tolerated for the most part, which is good news for patients.”