Sixty-two-year-old Carolyn Higgins went to see her longtime primary care doctor because something just wasn’t quite right. A self-described type A personality, Higgins was a passionate and energetic saleswoman. She couldn’t wait to knock on the door and shake the hand of her next potential customer. At the end of the day, she didn’t crash on the couch; she took off on a 5-mile walk. Weekends weren’t for lying low either. Off days were about playing with her baby grandchildren and “getting a hundred million things done,” she says.
“And now I do nothing,” Higgins recalls telling her primary care doctor. “I’m lifeless.”
Higgins’ doctor reminded her that she was still mourning the loss of her brother who’d died three months earlier. She was going through menopause, too. Both were cause for fatigue, the doctor said. “’No, it’s something more,’” Higgins told her doctor. The doctor agreed to do a blood test, which revealed elevated M proteins (myeloma gamma globulin). This kind of “M-spike” can indicate the presence of abnormal plasma cells, a sign of multiple myeloma.
Higgins had MGUS (monoclonal gammopathy of undetermined significance), elevated M proteins that are not actually associated with myeloma, but may or may not lead to a diagnosis of this type of blood cancer. Her M proteins could stay stable for years, in which case the condition would never cause any problems, or they could progress to more serious levels. Higgins checked in with a doctor quarterly to monitor the protein levels, which continued to rise. Within six months, she was diagnosed with multiple myeloma.
Her doctors gave her two to five years. That was almost nine years ago. Higgins has continued to live her life – exercising, going to church and hosting sleepovers for her granddaughters – with the help of two of the four new drugs approved by the U.S. Food and Drug Administration (FDA) in 2015 for the treatment of myeloma.
Farydak (panobinostat), Empliciti (elotuzumab), Darzalex (daratumumab) and Ninlaro (ixazomib) all got the nod from the FDA last year. Each of the former three is the first in its class approved to treat multiple myeloma. The nature of myeloma treatment for many people who live with the disease is to stay on one therapy or drug combination for as long as it works and then switch to another. So while experts don’t yet consider the blood cancer curable, each new drug to hit the market has the potential to further extend the time that one can live with the condition. For many people, multiple myeloma is a chronic condition to be managed.
“More patients are living longer. The number of patients at 10 years, even in complete remission, is steadily increasing,” says Sundar Jagannath, director of the Multiple Myeloma Program at Mount Sinai Hospital in New York City. “People who are diagnosed now, because these drugs were approved in 2015, can expect that their life expectancy has been improved by yet another year, so the median life expectancy will continuously go up.”
Moreover, many patients are living not only longer, but better. Many of the newer drugs have fewer side effects, and delaying progression of the disease improves quality of life.
WHAT IS MULTIPLE MYELOMA?
Multiple myeloma, most common in people over age 65, develops when plasma cells become cancerous and multiply. Normal plasma cells play an important role in the immune system. Found mostly in bone marrow, they make antibodies that help the body kill germs. Cancerous plasma cells, which no longer help the body fight infection, produce tumors in the bone. A person who has more than one of these tumors has multiple myeloma.
Myeloma can cause low blood counts, which can lead to anemia, thrombocytopenia and leukopenia. Anemia – a shortage of red blood cells – can leave a person pale, weak and fatigued. Thrombocytopenia – low levels of platelets – can cause bleeding and bruising. Leukopenia – a low white blood cell count – makes it harder for the body to fight infection and further compromises the immune system of someone with myeloma. This can make a person more susceptible to other illnesses, such as pneumonia.
Myeloma cells produce abnormal antibodies that can harm the kidneys. The antibodies can also cause protein to build up in various organs and prevent them from working properly.
Smoldering myeloma is caused by an excess of M protein in the blood, like MGUS, but has no other symptoms. The chance that smoldering myeloma progresses to multiple myeloma is 10 percent per year, compared with 1 percent per year for MGUS. The treatment is usually close monitoring. Many people can live years without their disease progressing. For most of them, starting treatment at this early stage won’t necessarily prolong their lives. Clinical trials are currently being conducted to see if early treatment makes a difference.
Multiple myeloma is considered stage 2 or higher when cancer levels increase and a person begins to have symptoms that require treatment. These symptoms may include bone damage, kidney problems or a dangerous buildup of protein in the organs called light chain amyloidosis. The goal of first-line treatment is to eliminate the myeloma cells and lower abnormal antibodies and associated proteins completely or almost completely. About 30 to 50 percent of people achieve that goal.
Doctors choose drugs based on the stage of disease and the patient’s age and kidney function. While some drugs work alone, many drugs work best in combinations of two or more.
A study presented in December at the American Society of Hematology’s annual meeting suggests that the three-drug combination of Velcade (bortezomib), Revlimid (lenalidomide) and dexamethasone is the best option as a first treatment for multiple myeloma. The “triplet” treatment was recommended by the study’s authors as a new standard of care, as it significantly bested the doublet combination of Revlimid and dexamethasone in the trial.
Velcade is one of three proteasome inhibitors available to treat myeloma. This type of drug blocks the activity of the proteasome – a group of enzymes that aids in elimination of defective proteins in cells. When proteasome activity is blocked, the bad proteins can build up and kill cells. These drugs, then, can help kill cancer cells, though they may destroy some normal cells, too.
Velcade can cause fever, nausea, vomiting, diarrhea, constipation, loss of appetite, fatigue and lowered blood counts, which can cause bruising and bleeding and increase risk of infections. The drug can also cause nerve damage (peripheral neuropathy), which can lead to numbness, tingling and pain in the hands and feet. Doctors may recommend an antiviral medication to prevent patients from developing shingles (a reactivation of the varicella-zoster virus that causes chicken pox) while taking this drug.
Two of the three proteasome inhibitors, Velcade and Kyprolis (carfilzomib), are IV drugs that patients must receive at an infusion center once or twice a week. Late last year, the FDA approved the first-ever oral drug in this class, Ninlaro, to be taken in combination with Revlimid and dexamethasone. The oral drug, which is approved for use in people who have already tried another medication, could improve quality of life for those who take it.
“The incidence of neuropathy is significantly lower when you give an oral proteasome inhibitor,” says Sagar Lonial, chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine and chief medical officer at Emory’s Winship Cancer Institute.
Because it’s an oral drug, patients can take it on their own without weekly trips to a health care facility. This could make the drug a viable option as maintenance therapy for people at high risk for relapse. “There’s a lot of interest in using proteasome inhibitors in patients with high-risk myeloma. But you’ve got to come in the office. An oral drug that you could give once a week would be a lot easier,” says Lonial.
Revlimid is one of three immunomodulating agents, along with Thalomid (thalidomide) and Pomalyst (pomalidomide), approved for multiple myeloma. These drugs can help improve the immune system’s response to myeloma.
Immunomodulators are not safe for pregnant women. Thalomid can cause irreversible nerve damage and serious blood clots. Revlimid can cause low blood counts, nerve damage and blood clots. Pomalyst can cause low blood counts and blood clots.
Dexamethasone is a corticosteroid that can reduce inflammation, swelling and pain in places where myeloma is causing damage. Corticosteroids can enhance the effects of chemotherapy and immunomodulatory drugs. Alone, in high doses, they can fight myeloma directly.
Corticosteroids can increase appetite, raise blood sugar and cause weight gain, sleep disturbance, irritability and hyperactivity.
While Velcade with Revlimid and dexamethasone is what many now consider the best first-line treatment for multiple myeloma, it doesn’t make stem cell transplant obsolete. “We’ve seen in clinical trials that remission duration is clearly better for patients who go on to have the transplant early after this medication regimen than for those who wait until relapse,” says Lonial.
Stem cell transplant introduces healthy new stem cells to replace the myeloma cells that get wiped out along with normal stem and other marrow cells by high-dose chemotherapy, which is given before a transplant. Stem cells produce red blood cells, white blood cells and platelets. Without them, the immune system can’t function. Doctors can replace the lost stem cells with the patient’s own stem cells or donor cells.
Side effects of stem cell transplant may be similar to, but more severe than, those from chemotherapy, such as hair loss, mouth sores, loss of appetite, nausea, vomiting and low blood counts. When stem cells come from a donor, the recipient runs the risk of graft-versus-host disease, in which the new stem cells recognize the host tissue as foreign and attack it. This complication can be life-threatening, but fortunately, a donor transplant is not commonly performed for myeloma patients.
SECOND-LINE AND BEYOND
When first-line treatments don’t work or stop working, doctors try other drugs. Three first-in-class drugs approved last year are among those treatments.
When Higgins was diagnosed, her doctor started her on the chemotherapy drug Doxil (liposomal doxorubicin) and Velcade. Besides giving her neuropathy so severe it turned her hands and feet black, a bone marrow biopsy revealed that the drugs did nothing else for her. So her doctor pushed for a stem cell transplant, but Higgins refused.
“I had already made my decision when I got diagnosed and did my research. I did not want a stem cell transplant,” she says. “I didn’t want to be out of commission that long and away from my baby grandchildren. And, as far as I could tell, they only offered temporary remission.” True to her relentless, type A personality, she added, “I wanted a cure.”
Higgins was referred to Lonial at Emory, who helped her enroll in a phase 1 clinical trial of Empliciti. In a class of drugs called monoclonal antibodies, Empliciti and Darzalex were the first of these drugs approved to treat multiple myeloma. The approvals came 14 days apart in November of last year.
Monoclonal antibodies are man-made antibodies designed to attack a specific target, such as a particular substance on the surface of a cancer cell. Empliciti targets a protein called SLAMF7, found on the surface of myeloma cells and “natural killer” cells. Natural killer cells are immune cells that can kill cancer cells or virus-infected cells. When Empliciti interacts with SLAMF7 on myeloma cells, it tags the cells and makes them easy for natural killer cells to find. When the drug interacts with SLAMF7 on natural killer cells, it activates the cells to destroy the cancer cells.
“Elotuzumab doesn’t really kill myeloma cells by itself, but when you combine it with an immune-stimulating drug like Revlimid, you get one plus one equals five,” says Lonial.
The drug was approved for use in combination with Revlimid and dexamethasone for people who have already received one to three previous therapies. In clinical trials, Empliciti gave study participants more than 19 months of progression-free survival compared with just under 15 months with Revlimid and dexamethasone alone. The percentage of patients who responded to the drug combination at all was also better, at 78.5 versus 65.5 percent.
Empliciti kept Higgins’ myeloma at bay for five years. “I was so thrilled with the results. I had no setbacks. It was the perfect match,” she says.
But Higgins’ M-proteins began to creep back up in 2014. Lonial then helped her enroll in a phase 2 clinical trial for the other drug in the same class, Darzalex.
Darzalex is for people who have already had three previous therapies, including a proteasome inhibitor and an immunomodulator. This drug attaches to a protein called CD38 found on the surface of myeloma cells. Researchers believe that when the drug attaches to this protein, it both helps kill the cancer cell and tags the cell for immune cells to recognize and destroy.
When Higgins started this trial, she received Darzalex, Pomalyst and dexamethasone, but within four months, the side effects of the immunomodulator were too much to take.
“I had all the symptoms of someone with heart disease,” Higgins recalls. “I had swollen limbs. I retained fluid. My blood pressure went up. And headaches.” The doctors took Higgins off the Pomalyst. Now, almost two years later, she remains stable on Darzalex.
“I’m all for clinical trials. I’ll stay on this one as long as they’ll let me, and then I’ll be on another if I have to,” she says.
Monoclonal antibodies may have a better side-effect profile than other drugs already in use. “They don’t lower blood counts, and they don’t have many side effects,” says Jagganath. The drugs do run the risk, however, of causing an injection reaction on the first dose or shortly after. This can result in fever, chills, lightheadedness, rash, wheezing, trouble breathing, tightness in the throat, a runny or stuffy nose, rash or nausea.
Others like Higgins, who have already tried Velcade and an immunomodulatory drug, have yet another option as of 2015. Farydak, a histone deacetylase (HDAC) inhibitor, was approved early last year for use in combination with Velcade and dexamethasone. Blocking HDACs are another way to stop protein breakdown in the cell, similar to Velcade, but in a different pathway. For some patients, this is an important process to block.
In a clinical trial, people who received Farydak, Velcade and dexamethasone — after they had already been treated with Velcade — got almost five more months of progression-free survival than those who were treated with Velcade and dexamethasone alone.
Experts in the field of multiple myeloma are not calling the newest drugs to get FDA’s green light a “cure,” but the drugs are moving treatment forward and extending life.
“We still haven’t found the answer for myeloma,” says Jagganath. “But every drug that is added is improving quantity and/or quality of life, giving multiple choices and improving life expectancy.”