Arlene Weintraub

In 2017, Michael Padjen was on the job at his exterior cleaning company in Greensboro, South Carolina, when he jumped off the bed of his truck and felt pain in his back. A course of steroids didn’t help, so he went for an MRI, which showed not only a severe compression fracture in one of his vertebrae but also abnormalities in his bone density.

A blood test then uncovered the reason behind Padjen’s back pain: multiple myeloma. “Within the next seven weeks, I (developed) seven severe compression fractures, all in my back,” Padjen says.

However, Padjen’s story is not uncommon.

Kenny Capps was struggling with bone pain because of multiple myeloma but found some relief in treatments and exercise.

For Kenny Capps, a lifelong runner and all-around endurance athlete who lives in Black Mountain, North Carolina, the first sign that something was off came in 2014. “I started having issues with fatigue after long events. I thought I was getting the flu,” Capps says. “I had serious back pain, but I assumed I had just pulled something.” After Capps received a diagnosis of multiple myeloma, positron emission tomography (PET) scans revealed two compression fractures in his spine,a lesion in his hip bone, and bone loss in his collarbone, sternum and skull.

Bone pain is a main symptom of multiple myeloma because the cancerous plasma cells that cause the disease can also weaken bones. The result is not only pain but also an increased risk of weakness and bone fractures. A 2020 study of more than 800 patients with multiple myeloma found that bone pain led to the diagnosis in 63% of patients, and that 74% of patients had two or more bone lesions by the time they started their multiple myeloma treatments.

The good news is that the entry of new multiple myeloma drugs to the market — 12 in the past 15 years, according to the Multiple Myeloma Research Foundation — has raised the probability that patients with new diagnoses will achieve remission and, by extension, relief from their bone pain.

“Most people who present with multiple myeloma have bone pain. It’s the most common symptom,” says Dr. Shagun Arora, a hematologist-oncologist at the University of California, San Francisco. “Our first goal is to control the cancer as fast as possible. Typically, if the myeloma is responding well, pain starts improving and we know the bone disease is getting better.”

Multiple myeloma weakens bones by disrupting the normal balance between osteoblasts, which are bone-making cells, and osteoclasts, which break down bone. “The myeloma cells release signals that affect the bone marrow microenvironment in a way that increases the breakdown of bone,” says Dr. Carlyn Tan, a hematologist-oncologist at Memorial Sloan Kettering Cancer Center in New York City.

The result can be pain that spans a wide spectrum, from a dull ache that’s set off by certain movements to severe pain caused by a fracture. Sometimes multiple myeloma forms tumors called plasmacytomas, which can appear in bone or surrounding soft tissues, causing pain. Some patients develop pinched nerves or spinal cord compression due to involvement of the vertebral bodies, which are the bones that support the body and protect the spinal cord. That can cause shooting pain down the legs, paralysis, incontinence and other problems.

Finding the source of bone pain is an important step in diagnosing multiple myeloma, Arora says. That’s because some bone issues need to be treated immediately to reduce the risk of breakages or compression fractures. For example, weakened bone segments, referred to as osteolytic lesions, are common in multiple myeloma, but when they occur at locations such as the top of the femur, they can be dangerous. “Myeloma involvement can lead to fragile bones, and simple movements like walking can lead to painful fractures,” she explains.

Oncologists typically start with “head to toe” imaging, Arora says, which can include low-dose CT scans, PET/CT scans or MRIs. Surgery and radiation can alleviate osteolytic lesions as well as plasmacytomas that could otherwise endanger the spinal cord, Arora adds.

Once patients start their drug treatments for multiple myeloma, they’re typically prescribed bone-strengthening treatments simultaneously. One option is Zometa (zoledronic acid), which is in a class of medicines known as bisphospho- nates, also used for osteoporosis (thinning of the bones). They work by inhibiting bone resorption, or breakdown. Zometa is given by infusion once every one to three months. Bisphosphonates sometimes cause mild side effects such as flu-like symptoms, flare in bone pain, itching and numbness, but the advantages often outweigh the risks, Tan says.

“Using (Zometa) prevents future fractures and has been shown to help with bone pain also,” Tan notes. A 2017 analysis of four studies involving 601 patients with multiple myeloma concluded that patients who took bisphosphonates faced a lower risk of nonvertebral fractures than did those who were not prescribed bone-directed drugs.

Michael Padjen now enjoys a daily four-mile walk and leans on his service dog, Flynn, to help with everyday tasks and mobility.

Padjen, now 64, was treated with the standard multiple myeloma triple-drug regimen of Velcade (bortezomib), Revlimid (lenalidomide) and dexamethasone. He also was treated with Zometa. Then he received a stem cell transplant. But his back was in such bad shape he had to undergo threeoperations prior to the transplant and one after, including kyphoplasty.

For patients such as Padjen who have significant back pain and fractured vertebrae, kyphoplasty can stabilize the back- bone and offer significant relief. During this procedure, a balloon is inserted into the collapsed vertebra and inflated, creating a space. Then bone cement is injected into the space.

Capps, now 50, also received the same regimen of Velcade, Revlimid and dexamethasone, followed by a bone marrow transplant. This put him into partial remission, and he remains on a maintenance therapy. He also was prescribed Zometa for his bones, and he undergoes PET scans to monitor his bone health twice a year.

Another option for preventing bone issues in multiple myeloma is Xgeva (denosumab), an antibody drug that decreases bone resorption by inhibiting a protein that controls the survival and functioning of bone-destroying osteoclasts. Results of a 2018 study, published in 

, comparing Zometa with Xgeva in patients with newly diagnosed multiple myeloma with at least one lytic lesion found that Xgeva matched Zometa’s effectiveness in preventing skeletal-related events.

Zometa, however, can exacerbate kidney issues, with some patients experiencing renal injuries or failure while on the drug, so Xgeva may be a better choice for patients with chronic kidney disease. Xgeva is also more convenient, in that it can be given as a subcutaneous injection every four weeks, Tan says. Both Zometa and Xgeva can cause a degeneration of the jaw known as osteonecrosis. So patients are advised to visit a dentist to check the health of their jaw bones prior to starting the medication, she adds.

Oncologists who treat patients with multiple myeloma often prescribe bone-strengthening supplements to their patients, including vitamin D and calcium. But because the breakdown of bone can cause calcium to be released into the bloodstream, physicians typically run blood tests to measure patients’ calcium levels before recommending a supplement regimen, Arora says.

“If calcium levels are high, we need to treat the cancer first and get that under control so calcium levels will start normalizing,” Arora says. “Then our next step is to help the bones restructure themselves. Then we add in the calcium and vitamin D.”

Exercise is also an important component of multiple myeloma treatment. Patients are typically advised to avoid strenuous exercise in the initial stages of  treatment. But once their bone pain and lesions are treated, patients may find that low-impact aerobic exercise, and even light weight lifting, can be beneficial.

“Patients are usually feeling better by month three of treatment, and at that point it’s good to start some strenuous physical activities,” Arora adds. “It’s important to maintain some level of physical fitness to prevent fatigue and loss of muscle mass.”

Padjen, who is now in remission, agrees. Although he still has some bone pain, and he leans on his service dog, Flynn, to help him with everyday tasks and basic mobility, he feels well enough to walk four miles a day. “I’m feeling really good,” Padjen says. “I think the exercise helps tremendously.”

Exercising also helps patients maintain a healthy weight, says Dr. Anita D’Souza, associate professor of medicine at Medical College of Wisconsin in Milwaukee. “We often see obesity and sarcopenia, a loss of healthy muscle, in (patients with) multiple myeloma, and there’s a concern that these factors may contribute to disease progression,” D’Souza says. “Getting to a healthier weight should be a goal for all patients.” 

D’Souza co-authored a recent study of 38 survivors of multiple myeloma, 76% of whom were obese. Several participants reported significant quality-of-life challenges, including fatigue, pain and a loss of physical function. The results support the need for lifestyle coaching in the treatment of multiple myeloma, she says.

“The majority of patients weren’t involved in any exercise programs, but they expressed an interest in it,” she explains.

Capps also has found that staying active helps to keep his bone pain under control. In 2020, he ran four marathons, one 50-mile race and 63 miles of a 100-mile race. He managed all of that despite undergoing surgery earlier that year to remove his adrenal glands and a tumor that was sitting on top of one of them.

Now Capps raises awareness of the benefits of exercise in the treatment of blood cancers through his nonprofit organization, Throwing Bones. The organization provides educational videos and coaching for health care providers who want to educate patients with cancer about the benefits of exercise.

Being physically fit “can optimize your quality of life and make you healthy enough to withstand treat- ments that otherwise you may be ineligible for, like bone marrow transplants,” Capps adds.

Capps knows from experience that cancer treatments can cause fatigue, which can sap the motivation to exercise. For patients who are struggling to stay active, he has one piece of advice: “Just put your shoes on,” Capps says. “Then once you have your shoes on, getting out the door and walking to the mailbox becomes a little easier. Then maybe next time you can walk around the block. Just get your shoes on and see where that goes.”

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Bone pain is a common symptom that patients with multiple myeloma face, but some may find relief with treatments and exercise.

Treating Bone Pain in Multiple Myeloma

After Jarod Roy was diagnosed with metastatic renal cell carcinoma in July 2018, he was put on a combination of two immunotherapy drugs — Opdivo (nivolumab) and Yervoy (ipilimumab) — which had recently been approved by the Food and Drug Administration (FDA) to be used together in previously untreated patients. But his tumors kept growing, so Roy decided to drive two hours from his home in Westlake, Louisiana, to The University of Texas MD Anderson Cancer Center in Houston for a second opinion.

Jarod Roy was treated with Keytruda and Lenvima, which significantly reduced his metastatic renal cell carcinoma.

MD Anderson enrolled Roy in a clinical trial of a different combination — the immunotherapy drug Keytruda (pembrolizumab) plus Lenvima (lenvatinib), a drug that works by inhibiting cancer-driving enzymes known as tyrosine kinases. Roy received infusions of Keytruda every three weeks and took Lenvima orally every day.

Six weeks after Roy started the regimen, imaging tests showed that the cancer had shrunk more than 20%. “Every scan I had showed a decrease, and the overall reduction of my cancer was 54%,” says Roy, 39, who completed 35 doses of Keytruda and is still taking the Lenvima as part of the trial. He continues to manage his company, which maintains exhaust systems for restaurants, and he enjoys skiing every year with his wife and two children.

Jarod Roy continues to manage his company and ski with his family because of the effectiveness of the combination treatment.

“I’m a believer in this combination treatment,” Roy says. “It definitely did the job for me.”

Several combinations of immunotherapy drugs and tyrosine kinase inhibitors (TKIs) have been approved by the FDA for patients with newly diagnosed kidney cancer. In fact, four combinations were recently approved for the first-line treatment of kidney cancer: Bavencio (avelumab) plus Inlyta (axitinib), Opdivo plus Cabometyx (cabozantinib) and Keytruda plus Inlyta. In August, the FDA approved Keytruda plus Lenvima in the first-line setting.

With many more combinations in development, the outlook is bright for patients at the beginning of their treatment journey, says Dr. Amishi Y. Shah, an assistant professor of genitourinary medical oncology at MD Anderson.

“We have a very nice armamentarium of drugs to reach for, and now there are newer agents coming down the pike that are showing some promise,” Shah says.

In the trial that led to the approval of Opdivo plus Cabometyx, for example, the overall response rate for the combination was 56% versus 27% among patients taking the TKI Sutent (sunitinib) alone. And median progression-free survival (time when a patient lives with the disease without worsening) was 16.6 months among patients taking the combination, double that of the Sutent group.

Several experimental combinations look promising too, including the treatment Roy is receiving — Keytruda plus Lenvima. In May, the FDA granted priority review for the use of the combination in previously untreated patients, setting up a potential approval this fall.

The FDA sped up its review based on a clinical trial in which 71% of patients taking the combination responded to it versus 36% of patients taking Sutent. Progression-free survival was two years in patients taking Keytruda and Lenvima versus nine months with Sutent. And 16% of patients on the combination treatment had complete responses, meaning the cancer had disappeared or was not detectable radiographically or by physical examination.

“The responses were the highest and longest of any immunotherapy-plus-TKI study we have seen,” says Dr. Toni Choueiri, director of the Lank Center for Genitourinary Oncology at Dana- Farber Cancer Institute/Brigham and Women’s Hospital in Boston and a co-lead investigator for the trial of Keytruda plus Lenvima. “(Once) this gets approved, I would argue it should be used as the first-line treatment.”

There are some caveats with new combination treatments for kidney cancer. Some patients experience onerous side effects, and oncology researchers have yet to determine whether the positive responses to immunotherapy-TKI combinations are long lasting enough to outweigh the potential risks.

Meryl Uranga controls blood pressure fluctuations with additional medicine while undergoing treatment with the TKI-immunotherapy combination.

The most common side effects are increases in blood pressure and diarrhea. Each TKI has potential side effects because of the blockade of specific kinases. Antiangiogenic drugs target pathways involved in tumor blood vessel formation, so side effects on normal vessels like constriction or impaired healing can cause hypertension, bleeding or clotting events. Immunotherapy causes inflammation in normal tissues like skin, gastrointestinal (GI) tract and endocrine glands, resulting in rash, diarrhea and hypothyroidism. In the trial that Choueiri co-led, more than 90% of the patients taking either the TKI-immunotherapy combination or Sutent alone reported side effects, but the need for investigators to drop the doses of the medicines to get those symptoms under control was greater among patients on the combination. And nearly 10% of patients taking the combination dropped out of the trial.

Meryl Uranga had some trouble controlling her blood pressure after she started taking the Keytruda-Inlyta combination in 2018 for kidney cancer. She had initially been treated with radiation and surgery to remove one kidney and part of her lung — a regimen that put her in an 18-month remission. When the cancer returned, she was put on two immunotherapy drugs but had only a partial response, and some of her tumors grew a little, so her oncologist switched her to the TKI-immunotherapy combination.

Bruce Shreffler is currently treated with Cabometyx and Opdivo, which shrank his cancer and allows him to be active despite some fatigue.

The fluctuations in blood pressure were unsettling at first, Uranga says, but her doctor adjusted the dose of a blood pressure medicine until the problem came under control. As for the cancer, “everything was shrunken down or gone,” says Uranga, 60, a retired telecommunications project manager who lives in the Atlanta area. “I take a microdose of blood pressure medication if I need to, and I have GI issues, but the impact to my quality of life is very minimal and manageable.”

Choueiri expects that ongoing clinical trials will show just how durable the positive effects of these new combinations are and that physicians will grow more and more comfortable with strategies for lessening side effects. “With the TKIs especially, there are a lot of adjustments we can make to figure out the ideal dose that the patient can tolerate while getting the benefit at the same time,” he said. While surgery is generally still the first step in patients with localized kidney cancer, that is no longer the case for many patients with metastatic disease. Before the advent of TKIs and immunotherapy, surgery was often the first line of treatment, says Shah, but now “the pendulum has swung” and drug treatments are tried first in many cases, she says.

When patients respond well to the drugs, subsequent surgery might offer a good way to eradicate the disease altogether, she adds. “One of the best conversations I have is telling a patient they had an absolutely phenomenal response to therapy and there’s no evidence of disease except for the primary renal tumor,” Shah says. “I’ve sent a number of these patients to surgery to basically render them clear of disease.”

About 25% of patients with kidney cancer are diagnosed with non-clear cell renal carcinoma, which encompasses several subtypes of the disease, including papillary renal cell carcinoma. Traditionally these patients were treated similarly to those with clear cell carcinoma, although recently, some researchers have launched studies aimed at determining whether some combination treatments should be targeted specifically to patients with non-clear cell disease.

Bruce Shreffler enrolled in one of those trials in 2018, about five months after starting treatment for metastatic non-clear cell kidney cancer. He initially took a combination of two TKIs, Lenvima and Afinitor (everolimus), but only some of the tumors shrank and the GI upset and fatigue were difficult to manage.

So Shreffler traveled from his home in Albany, New York, to Memorial Sloan Kettering Cancer Center in New York City for a second opinion. He was admitted into a trial of Cabometyx plus Opdivo in non-clear cell kidney cancer. After six months, the cancer had shrunk and stopped spreading.

“A lot of the tumors were entirely resolved,” says Shreffler, 64, a computer contractor and avid outdoorsman whose pre-cancer adventures included climbing all 46 Adirondack High Peaks.

Shreffler’s treatment includes daily doses of Cabometyx and one infusion per month of Opdivo. His oncologists told him he will stay on the regimen as long as the cancer is stable, and he’s fine with that, especially since the side effects have been much easier to tolerate than they were for the combination of two TKIs. A high-fiber diet is enough to keep his digestion under control, and although he has a touch of fatigue, he’s able to ride his bicycle 15 miles in less than an hour, he says.

“I can’t climb the mountains that I used to, but I’m as active as I can be,” Shreffler says.

In June of this year, positive data from the trial of Cabometyx and Opdivo in non-clear cell renal carcinoma were released at the American Society of Clinical Oncology annual meeting. Among 32 patients with papillary carcinoma, the response rate was 47.5%, and some of the responses correlated with specific genetic mutations found in patients’ tumors.

In fact, there’s a major push underway in kidney cancer research to find biomarkers, including genetic mutations, that can help oncologists personalize treatments, says
Dr. Chung-Han Lee, a medical oncologist at Memorial Sloan Kettering Cancer Center. “We’re trying to understand how we can use genetic sequencing to predict patient outcomes,” Lee says. “Those kinds of predictive biomarkers will improve patients’ outcomes just by getting them on the best treatment earlier.”

Even though TKI-immunotherapy combinations are moving into the frontline treatment setting, for some people, starting on two immunotherapy drugs instead might still be a good idea, Lee says. For example, immunotherapy combinations can be beneficial for patients who have no other underlying illnesses and are not experiencing severe symptoms from the cancer. “In the majority of people who do get significant shrinkage of their disease from combination immunotherapies, the effects seem to be durable, meaning they last beyond three years,” he says.

It’s not yet clear how long positive responses to TKI- immunotherapy combinations will last — the clinical trials needed to determine that durability have not yet been completed. Still, starting with one of those combinations can be a good idea for patients who are very sick from the cancer “because we can see a very rapid response,” Lee says.

Now that two-drug combinations are well entrenched in the care of patients with kidney cancer, researchers are considering a new question: Could three drugs be even better than two? One ongoing phase 3 trial is combining the TKI Cabometyx with two immunotherapy drugs that stimulate the immune response in different ways, Yervoy and Opdivo. “With two different mechanisms of action, you’re able to kill more cancer cells because cancer can be sensitive to one pathway but not the other,” Choueiri explains. “The same may be true of three drugs.”

Several new TKIs are under development, and that could lead to new combination strategies for kidney cancer in the future. In March, the FDA approved Fotivda (tivozanib) for patients with advanced renal cell carcinoma who have relapsed after two or more prior therapies. The approval was based on a response rate of 18% versus 8% for another TKI, Nexavar (sorafenib).

Now a new clinical trial has started comparing Fotivda plus Opdivo to Fotivda alone. Lee says he’s looking forward to seeing the results of that trial, particularly because Fotivda seems to produce fewer side effects than other TKIs. “It’s very well tolerated,” he says, “and that can certainly be a benefit for our patients.”

MD Anderson’s Shah adds that even though there’s still a lot to learn about how combination therapies can best be matched to patients, the rapidly growing selection of treatments for kidney cancer is exciting.

“It has changed the outlook in the field,” she says, “and led to great improvements in survival.”

Immunotherapy and tyrosine kinase inhibitors may potentially change the treatment paradigm for patients with renal cell carcinoma, the most common type of kidney cancer in adults.

Novel Combinations Offer New Hope in Kidney Cancer

After Michael Herman received a diagnosis of high-risk multiple myeloma in 2013, he started a treatment journey that included several years of chemotherapy and the targeted drug Venclexta (venetoclax tablets), which is investigational for the disease and was designed for patients whose cancers have certain genetic abnormalities. The medicines worked well, but as is often the case with multiple myeloma, Herman’s cancer eventually returned.

In July 2019, Herman qualified for a clinical trial of teclistamab, an investigational drug that’s part of an emerging class of immunotherapy medicines known as bispecific antibodies. He traveled from his home in Galena, Maryland, to the University of Pennsylvania in Philadelphia to get the treatment: a weekly shot in the abdomen.

After just one dose of teclistamab, Herman’s cancer load dropped 99%. His disease is no longer detectable, and the study investigators have told him he can stay on the drug as long as it continues to be effective. In terms of side effects, Herman experiences some aches and pains, but says that it doesn’t affect him from getting around.

“When I was diagnosed, I was told my life expectancy was four years,” says Herman, 59, a retired corporate real estate manager. “This drug doubled that. It’s a wonderful thing.”

Teclistamab is one of several bispecific antibodies being developed to treat a range of cancers. Bispecific antibodies are designed to simultaneously bind two targets — a target on immune cells and another on tumor cells — pulling them together to unleash an immune attack against the cancerous cells. In the case of teclistamab, the two targets are an antigen called CD3 in the immune system’s T cells, and BCMA, which is an antigen that’s overexpressed in multiple myeloma.

Several other bispecific antibodies are under development to treat blood cancers and a wide range of solid tumor types, including cervical, gastric, brain and liver.

“The idea behind combination immune therapies, which include bispecific antibodies, is to find ways to better target the immune system from the get-go, to minimize the chance of resistance or improve the chance of getting a good response,” says Dr. Deborah Wong, an oncologist at UCLA.

The first, and so far only, bispecific antibody on the market, Blincyto (blinatumomab), is approved by the Food and Drug Administration (FDA) to treat some patients with acute lymphoblastic leukemia (ALL). The drug, referred to as a bispecific T-cell engager (also referred to as BiTE), has one arm that attaches to CD3 and a second that binds to the antigen CD19 on the surface of cancerous B cells.

In a trial of patients with relapsed or resistant B-cell precursor ALL, Blincyto increased the rate of complete remissions from 20% among patients on standard-of-care chemotherapy to 42%. In a pediatric study released in March 2021, 69% of children treated with Blincyto were still alive after nearly two years, and 93% showed no sign of disease. In a phase 2 study released in May 2021, there was a 95% response rate among patients with Philadelphia chromosome-positive ALL who received Blincyto plus the targeted drug Iclusig (ponatinib), showing the potential of treating patients without the need for chemotherapy, the researchers said.

Bispecific antibodies can cause side effects, including cytokine release syndrome, a severe inflammatory response marked by high fever, body aches and other symptoms. Although Herman experienced cytokine release after his first shot of teclistamab, he has had minimal side effects since then.

Bispecific antibodies could bring immunotherapy options to patients who aren’t eligible for treatments like CAR T cells, which are personalized therapies that entail removing immune cells from patients and engineering them to recognize and attack their cancer. Although these T-cell therapies can be lifesaving, they present challenges that could be avoided with bispecific antibodies, says Dr. Joshua Richter, assistant professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York.

“CAR-Ts are not off-the-shelf products, so they take time for manufacturing, whereas bispecifics are off the shelf,” Richter says. And even though there is a risk of side effects with bispecific antibodies, they are titratable, meaning they can be given in small doses to start and then in larger doses after the immune system is given a chance to adapt. “We are concerned about giving CAR-Ts to older people because some can get quite sick (from cytokine release),” Richter says. “It’s nice to have a more titratable alternative.”

Several bispecific antibodies aimed at multiple myeloma are in clinical trials now, some of which are showing early promise. In a phase 1 dose-ranging study of an intravenous formulation of teclistamab, for example, 58% of patients on the recommended dose for phase 2 trials showed a partial response and 30% had a complete response. Although 70% of participants experienced cytokine release, none had symptoms severe enough to prompt them to pull out of the trial. Other side effects included anemia, a drop in white blood cells and fatigue. A phase 2 study of the drug in multiple myeloma is ongoing and recruiting patients.

Another trial of a BCMA-CD3-targeted bispecific antibody, elranatamab, was paused in May because of cases of peripheral neuropathy reported by some patients. The drug’s developer, Pfizer, was asked to investigate the cases and report what it finds to the FDA. Patients in the trial who were benefiting from the drug were able to stay on it, but no new patients will be accepted until the investigation is complete.

There are other promising approaches to multiple myeloma in early-stage testing, Richter says, including a bispecific antibody called cevostamab, which targets CD3 and FcRH5, an antigen expressed on the surface of almost all multiple myeloma cells. Interim results from an ongoing phase 1 study that were reported in December showed an overall response rate of 53%. Responses were even seen in patients who had failed five previous treatments.

Another prospect in multiple myeloma is a bispecific antibody called GBR1342, which targets CD3 and CD38, an antigen implicated in the disease and other blood cancers. The drug, now in phase 1 testing, received orphan drug designation from the FDA in 2019, which could expedite its development path.

There are several bispecific antibodies in development to treat other blood cancers, including acute myeloid leukemia (AML). For example, a drug called flotetuzumab targets CD3 and CD123, a molecule called an interleukin-3 receptor that’s prevalent on malignant cells in AML. In a trial of the drug in patients who had relapsed after other therapies, 32% of participants achieved a response, and more than half of those were able to go on to receive stem cell transplants, which put them in remission.

The flotetuzumab trial results highlighted another potential advantage of bispecific antibodies, which is that they may offer patients a bridge to other treatments that could result in more durable remissions, such as stem cell transplants. The ALL treatment Blincyto has also been shown to offer some patients a good lead-in to stem cell transplants. In a trial comparing the drug to standard-of-care chemotherapy, the overall response rate to Blincyto was 44%, and 24% of the patients receiving the drug went on to have stem cell transplants.

Oncologists at The University of Texas MD Anderson Cancer Center in Houston are now testing Blincyto in patients with newly diagnosed ALL, and there are encouraging early results. Last year, researchers reported results from a small trial in which patients with ALL started with four cycles of chemotherapy and then were placed on maintenance treatments that included Blincyto. There was a 100% response rate, and 79% of patients stayed in remission for two years.

“Historically, we can cure about 40% to 50% of elderly patients with ALL, so if this response rate holds over time, it will be a tremendous improvement, essentially doubling survival rates,” said Dr. Marina Konopleva, a professor and physician-scientist in the department of leukemia and stem cell transplantation at MD Anderson.

Phil Briggs, who received a diagnosis of ALL in January 2018, was treated with Blincyto in the fall of 2020, after his cancer stopped responding to standard-of-care chemotherapy. He found the drug to be far more tolerable than chemotherapy, which had caused him to lose his appetite and drop more than 50 pounds, in addition to developing peripheral nerve damage. Aside from a slight skin irritation, “I felt fantastic,” says Briggs, 62, who is being treated at MD Anderson.

Briggs’ courses of Blincyto came in a portable pump, allowing him to receive the agent on an outpatient basis without having to go to the hospital. After four months on the drug, he was able to undergo a stem cell transplant and is now in remission. “I felt so much better that I was able to go straight from (Blincyto) to the stem cell trans- plant without any side effects,” says Briggs, who is now planning to go back to work as an insurance salesman.

Targeting solid tumors with immunotherapy has been difficult because they lack a single target for immune cells to latch on to, and the environment that surrounds them may not be conducible for immune cells to readily attack the cancer cells. The two-pronged design of bispecific antibodies could help overcome those hurdles.

Several bispecific antibodies being developed to treat solid tumors include one treatment group that targets an immune checkpoint like PD-L1 or CTLA-4, inhibiting it so the immune system can launch an attack.

For example, a bispecific antibody called FS118, which is now being tested in a phase 1 trial in solid tumors, has one treatment group that inhibits PD-L1 and another that blocks another immune checkpoint called LAG-3. Initial results from a trial released last year showed that patients who had been treated with PD-1 or PD-L1 blockers and became resistant to them had durable stabilization of their disease on FS118.

A bispecific antibody called XmAb20717 blocks PD-1 and CTLA-4 and is being tested in patients with a number of solid tumor types. The response rate in a trial reported last November was 19% and included a complete remission in one patient with melanoma. Partial responses were seen in patients with ovarian cancer, non-small cell lung cancer (NSCLC) and castration-resistant prostate cancer.

Other bispecific antibodies in development to treat solid tumors target disease-promoting genetic mutations. One of these agents was recently approved by the FDA. Called Rybrevant (amivantamab-vmjw), it targets EGFR and MET in NSCLC with abnormalities in those genes. It is the first fully human, bispecific antibody approved in lung cancer. The approval was based on results from the phase 1 study, where the response rate to the drug was 40% in patients who had previously been treated with platinum chemotherapy, and 74% of patients saw their disease stabilize.

With so many bispecific antibodies in development across a range of cancer types, many patients could benefit from enrolling in clinical trials of these new therapies, says Wong. “Clinical trials are a good option to consider, especially if you’ve already been on standard therapies,” she says. “It may be that patients who responded well to their initial therapy and then developed resistance could be good candidates for bispecific antibodies.”

And because bispecifics target the immune system, they could improve the prognosis for many patients, Wong says: “The beauty of immunotherapy is that the immune system has a long memory, so there’s a potential for patients to have long-lasting responses to these drugs.”

Bispecific antibodies, such as teclistamab, are emerging as promising immunotherapy treatments for various cancers, including multiple myeloma. These antibodies bind to two targets, facilitating an immune response against cancer cells. Teclistamab has shown significant efficacy in reducing cancer load in patients with multiple myeloma. Other bispecific antibodies, like Blincyto, have demonstrated success in treating acute lymphoblastic leukemia (ALL) and are being explored for solid tumors. Despite potential side effects, bispecific antibodies offer a more accessible and titratable alternative to CAR T-cell therapies, potentially improving patient outcomes.

BiTE therapy could lead to better ways to target the immune system, while minimizing the chance of resistance.

Bispecific Antibodies Wage a Two-Pronged Attack on Tumors

In 2019, after Jason Pike received a diagnosis of a rare sarcoma that had spread across his abdominal cavity, his doctors in San Diego told him it would be too risky to operate. Four rounds of chemotherapy didn’t make a dent in the tumor, and Pike’s doctors said they could only offer him palliative care.

So Pike sought a second opinion from an oncologist at the University of Southern California in Los Angeles who specializes in treating rare sarcomas and is known for performing delicate, complex surgeries. Pike found him by researching his particular type of tumor online and networking with other patients, some of whom he met in Facebook groups for sarcoma survivors. He ultimately switched his care, and in July 2019, Pike underwent an 18-hour surgery that involved removing his 20-pound tumor, one kidney, as well as portions of his pancreas, spleen, stomach, diaphragm, colon and surrounding muscle.

There were some complications, and Pike had to file appeals to his insurance company to have the treatment reimbursed, but his disease is now stable. He’s currently in a “holding pattern,” and he will soon meet with his team to determine his future treatment plan.

Pike’s message for other patients: Get a second opinion. “These are trained professionals, but they’re not always right,” says Pike, 48, an operations director for a medical devices distributor. “Do your research. Be your own advocate. It’s your life.”

Cancer experts have long preached the value of second opinions. And getting a second opinion is much easier now. Advances in telehealth and other virtual technologies — the adoption of which exploded during the COVID-19 pandemic — are allowing patients, physicians and pathologists to meet online and share medical records, pathology samples and other information to improve treatment plans.

A 2017 study by the Mayo Clinic found that 88% of patients who received second opinions ended up with a different or refined diagnosis. Experts from The University of Texas MD Anderson Cancer Center in Houston have previously noted that even in cases where the second opinion doesn’t change the treatment plan, patients come away from the process feeling reassured they’re on the right path.

The insights from second opinions can make a huge difference throughout the course of care, says Dr. Anees Chagpar, a professor in the department of surgery at the Yale School of Medicine in New Haven, Connecticut.

“Patients are often uneasy about how their doctor will feel about them getting a second opinion, but your doctor cares about you,” Chagpar says. “They should have no objection to getting a second pair of eyes on your case, and often doctors will collaborate with each other so they can provide the best care.”

In fact, your first step should be to ask your primary oncologist for a recommendation of where to go for a second opinion, suggests Dr. Efrat Dotan, associate professor of hematology and oncology at Fox Chase Cancer Center in Philadelphia. That’s because you should seek the second opinion from an oncologist who specializes in your particular tumor type, Dotan says, and the physician who made your diagnosis is likely to know where to find such a specialist. Other good sources of referrals are online patient groups and nonprofits that are focused on specific cancers, such as the Sarcoma Foundation of America.

Knowing that patients may be anxious to start their treatments as soon as possible, several cancer centers will offer a second opinion within a day of receiving a request. These centers include Fox Chase, which takes requests for second opinions either online or by phone. Each case is handed to a nurse navigator who coordinates all appointments, secures copies of the patients’ test results and other medical records, and shares the information with the team that will be providing the second opinion. Some centers will also offer reviews of the pathology and imaging tests, in some cases changing the diagnoses and recommended treatment course.

“The navigators make sure patients are scheduled in a timely manner with all the right doctors, and they shepherd patients through the whole process,” Dotan says. The entire process often can be done online, she adds. “I have had multiple visits on Zoom or other virtual platforms to give second opinions to patients who live quite far (away),” she says.

Stanford University in California launched its online second opinion program in 2018, and for some patients with cancer, it has resulted in coordinated care plans that may not have been possible in the past, says Dr. Kristen Ganjoo, an associate professor of oncology at Stanford who specializes in sarcoma.

For example, after Ganjoo met a patient from Nevada who had a rare sarcoma, she arranged for a surgeon to perform the surgery at Stanford. But she was able to do a follow-up consultation with the patient online, saving him 10 hours of driving back and forth from his home.

In other cases, Ganjoo has provided second opinions for out-of-town patients, then arranged for standard treatments such as chemotherapy to be done close to where they live. “If a community physician sends a patient to me for a second opinion, I can formulate a plan for that patient to be treated locally,” she says. When patients get CT scans to check their progress, they can follow up with her by video chat. “I can review it with them and say, ‘Your CT scan looks good, continue with the same therapy.’ It can be reassuring for them to know that someone with sarcoma expertise is watching over them.”

The National Cancer Institute has selected 71 institutions around the country as “NCI-designated” cancer centers because of their focus on research aimed at developing new cancer treatments. It may be beneficial for patients to obtain second opinions from one of these centers because oncologists who practice there may be researchers in clinical trials of innovative treatments or may know about trials happening at other institutions.

“There’s a lot of research right now, and what’s amazing is some companies are developing drugs for rare sarcomas,” Ganjoo says. “But you may need to get a second opinion from a sarcoma specialist to find the best clinical trial for you.”

Although many oncologists recommend getting a second opinion before starting treatment, some patients can benefit from getting that second set of eyes on their case after they’ve completed one therapy and are moving to a second drug regimen or maintenance therapy.

Sarah Kelly sought her second opinion after she was treated for triple-negative breast cancer at a community hospital near Boston in 2015. She was pregnant when she received her diagnosis, and her first round of chemo- therapy — along with the delivery of her daughter, induced at 38 weeks — went well. But when her oncologist treated her with a regimen of taxol and carboplatin, her blood counts dropped so low she had to skip some treatments.

Knowing that triple-negative breast cancer is aggressive, Kelly decided to get a second opinion at Dana-Farber Cancer Institute in Boston. Her oncologist there recommended three high-dose treatments of taxol alone, followed by surgery to remove her tumor and nearby lymph nodes. The treatment was more tolerable for Kelly, and it worked; she has been free of cancer for six years. And she’s confident she’s getting her care from a cancer center that’s staying on top of developments in triple-negative breast cancer.

“I took a long-term perspective in moving to Dana-Farber. I knew if there was a recurrence of my cancer, there would be clinical trials happening there and access to new types of treatments,” says Kelly, 42, who went on to co-found SaltyGirl Beauty, a company that produces cosmetics using natural and organic ingredients.

Making a decision to switch to the cancer center that provided the second opinion can be difficult, but in some cases, it makes sense, Chagpar says. “Trust your gut,” she says, and your research. “Say you have a rare cancer, and your first doctor only sees one case of it every five or 10 years. Then you go for a second opinion at a place that sees five cases a week. You may feel more comfortable at that second institution where they have more expertise in your particular condition.”

Chagpar was contacted by a patient with a rare cancer at the base of his skull, which his oncologist wanted to treat with surgery. “It would have been very risky. I found out where the national experts were and he got into a clinical trial of a chemotherapy treatment,” she says. “He avoided surgery altogether and is doing remarkably well.”

So what are the most important questions to ask during a second opinion? Dr. Charles LeVea, chair of pathology and laboratory medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York, recommends asking whether your case will be reviewed by a tumor board and, if so, who would serve on that board.

“Multidisciplinary tumor boards meet as a group, with pathologists, oncologists, surgeons and other people who would be taking care of the patients,” LeVea says. “We project pathology slides on a screen so everyone understands the diagnosis and can discuss it.” Some advanced cancer centers use new technology to convert tumor glass slides to digital images, which can then be run through algorithms that enhance details that might otherwise be missed — and that can lead to a more accurate diagnosis, LeVea says.

Dotan recommends asking what the standard of care for your cancer would be at the institution that’s providing your second opinion. Depending on the tumor type, some cancer centers may have different strategies when it comes to surgery, chemotherapy, radiation and immunotherapy. “You want to know if the standard of care fits what you’re being offered at your local site,” she says. “If you find out that the place you go for a second opinion does something differently, that may be worth exploring.”

Finally, if you’re open to participating in a clinical trial, be sure to bring that up to your doctor during your second opinion appointment. Kelly says she felt a bit guilty telling her first oncologist that she obtained a second opinion at Dana-Farber and decided to continue her treatment there. But in the end, she knew it was the right decision.

“It’s important to understand all the options and opportunities for your kind of cancer,” Kelly says. “As I always say, you’re the CEO of your own cancer journey.”

Second opinions may enhance your treatment plan or even change your course.

Arlene Weintraub

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