Deb Graff poses for a portrait near her home on May 21, 2018, in South Dennis, Massachusetts. Graff was diagnosed with an aggressive form of multiple myeloma 9 years ago and has fought it off with the help of the drug Velcade. (Kayana Szymczak for STAT)
If you can call someone who gets a rare form of cancer lucky, then Deb Graff says she fits the bill.
At age 72, Graff has survived nine years with multiple myeloma, a blood cancer whose life expectancy used to be measured in months.
“I wasn’t ready to go anywhere,” said Graff, who lives in South Dennis, Mass., on Cape Cod. “I wanted to see my grandkids grow up and still be an aggravation to my husband.”
She was lucky enough to get multiple myeloma after the 2003 release of a drug called Velcade (bortezomib), one of the first therapies to directly target multiple myeloma. Velcade, plus more than 20 other approvals since then, have transformed multiple myeloma care. For three-quarters of patients, a disease that once brought a three-year life expectancy has become a long-term, chronic illness.
Now, multiple myeloma is poised for another inflection point.
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There are 89 experimental drugs currently being tested in people, according to Biomedtracker, a research unit of Informa. Some are improvements on existing drugs, others have found new ways to target the cancer cells; a few engage the body’s immune system in the fight.
Not all the drugs will make it through the trial process, of course.
But on the roster, there may be effective treatments for the one-quarter of patients who haven’t yet been helped by existing drugs. There may be regimens that are less challenging than the daily pills, regular infusions, and frequent doctor’s appointments that Graff and others have to manage. And there may be the long-sought cure.
“There’s no question it’s a golden age in multiple myeloma drug development,” said Dr. David Reese, a senior vice president at Amgen, which developed the drug Kyprolis (carfilzomib), and is testing five others.
“It’s possible that we already are at the juncture where patients diagnosed with this disease could live with this disease for the rest of their lives,” added Dr. Ola Landgren, chief of the Multiple Myeloma Service at Memorial Sloan Kettering Cancer Center in New York.
Despite all the advances and optimism, though, most patients with multiple myeloma will still die of multiple myeloma.
“It is incurable. I think it is a mistake to suggest otherwise,” said Dr. Paul Richardson, Graff’s physician at the Dana-Farber Cancer Institute in Boston. “I think that this disease is forever humbling.”
Every multiple myeloma patient’s disease takes a different path. That makes it hard to understand and even harder to predict.
The cancer starts in a subgroup of white blood cells called plasma cells that normally make antibodies to fight infection. When cancerous, these plasma cells produce abnormal proteins that damage organs. But where they wreak havoc can vary from person to person.
Many patients suffer crushing fatigue, aching joints, and broken bones. Some get bounced around from one doctor to the next before finally getting a diagnosis.
Graff, though, never had a symptom. In late 2009, she went in for a routine physical. She and her husband had just retired, sold their house, and were headed to North Carolina. Ten days after the move, Graff’s primary care doctor back in Massachusetts called and said she’d like to run another blood test.
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After her diagnosis and a genetic screen, Graff got more bad news. Her cancer included a genetic mutation called a 17p deletion “that was kind of the kiss of death,” Graff said. Every drug trial she looked at showed positive results for all patients, Graff said, except for those with 17p deletions.
Graff’s younger daughter moved up her wedding to Memorial Day 2010 to make sure her mother could attend. Graff was scheduled for a stem cell transplant six weeks later.
Unfortunately, like many people with a 17p deletion, the transplant didn’t stick. Instead of staying in remission, by November 2010, she was put on a cocktail of three powerful drugs.
With so many approved therapies, doctors like Graff’s can keep switching their patients’ regimens. If one combination stops working, there’s another one to try.
“My feeling, and I think it was the right feeling, was that it was my job to stay alive and Paul’s job was to find the next best thing,” she said, referring to her doctor.
But still, the disease is tenacious.
“It will come back even after remission of five to 10 years,” said Dr. Elisabet Manasanch, an assistant professor in the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.
There’s no such thing as too many treatment options with a disease as wily as multiple myeloma.
“Maybe 1,000 drugs is not enough,” said Martina Sersch, Amgen’s head of global development oncology. “It’s a very clever disease.”
And now that patients are living longer, the quality of that extra time matters more, Landgren of Memorial Sloan Kettering said, adding that he expects the next wave of therapies will improve the patient experience.
Amgen’s drug Kyprolis, for instance, is currently given twice a week via infusion, but is being tested at a higher, once-a-week dose. Trial results for this regimen will be presented at the American Society for Clinical Oncology annual meeting, which starts Friday.
“We may have to attack it from different sides and different pathways to achieve what we ultimately want to achieve, which is a functional cure,” Sersch said.
Most patients today start with a combination of treatments: a “veritable Army, Navy, and Air Force,” as Richardson puts it.
They get a proteasome inhibitor, often Velcade, to directly attack the myeloma cells; an immunomodulatory treatment such as Revlimid (lenalidomide); and the steroid dexamethasone to tamp down an over-reactive immune system.
The Marines, Richardson said, are also coming, in the form of monoclonal antibodies, a type of engineered protein that can bind specifically to cancer cells.
The monoclonal antibodydaratumumab, sold by the Janssen unit of Johnson & Johnson under the brand name Darzalex, was first approved in 2015 for people with late-stage disease. Earlier this month, the Food and Drug Administration expanded its approval, allowing it to be used in combination with the standard, three-pronged treatment in newly diagnosed patients.
Daratumumab seeks out, binds to, and preferentially kills multiple myeloma cells. In a company-supported study published in the New England Journal of Medicine in February, 22 percent of patients who used the four-drug combination showed undetectable levels of disease after about 16.5 months. Only 6 percent of patients who used the three-drug combination saw such results.
“If you can fundamentally clear all the disease from a patient, now you start to think about, wow — maybe I can get to cure,” said Mark Wildgust, vice president for global medical affairs, oncology, at Janssen.
Today’s drugs are so effective that studies take a very long time. In one trial for Kyprolis, for instance, patients who were supposed to be near the end of life survived for 48 months on average, Amgen’s Sersch said. Drug companies will need to find strong, validated criteria other than survival, she said, to provide faster results and potentially drug approvals.
Amgen is hoping for game-changing responses to an experimental type of treatment called a BiTE — for bispecific T cell engager. BiTEs essentially are two-armed drugs, Reese said. One arm grabs the tumor cell and the other an immune cell. This activates the immune cell, which kills the cancer cell and primes the immune system to turn against others.
It’s too soon to know how long a patient would need to be on BiTE therapy, how to identify which patients might be helped, or how much improvement to expect, Reese said. But because BiTEs train the immune system to fight cancer, they might offer the possibility of a long-term remission or even a cure.
Other immune therapies under development include vaccines to amp up the immune system, and an approach called CAR-T, for chimeric antigen receptor T cell. In CAR-T, a patient’s own immune cells are removed and engineered to track down and destroy tumor cells.
Richardson, whose first multiple myeloma patient back in 1986 survived just three months, said he’s been amazed by how well CAR-Ts have worked in some of his sickest patients.
“I’ve seen the most dramatic responses in CAR-T. They’re quite remarkable,” he said. “Patients who’ve been so ill, and these therapies really made a difference for them beyond what I would expect.”
Because CAR-Ts have to be made with the patient’s own T cells, they are expensive and time-consuming; BiTEs are off the shelf and can be mass-produced, theoretically at a lower cost.
Cost, of course, is another huge issue in multiple myeloma therapy.
Lisa Stephenson, 65, of Whitefish, Mont., who was diagnosed in June 2014, said her multidrug regimen runs about $29,000 a month, plus an occasional $7,000 to boost her immune system. Luckily, nearly all of it is covered by the “incredible insurance” from the law firm where her husband worked until his recent retirement.
Stephenson didn’t end up needing a stem cell transplant because an experimental therapy she took at the beginning of her treatment worked so well. But if she had needed it — or needs one in the future — she was told it would cost a minimum of $365,000.
“I think to myself, ‘How in the world can people who don’t have good insurance — what do they do?’” she said.
It’s not yet clear how much the experimental therapies like BiTEs will cost patients, Amgen’s Reese said. But if these new treatments can produce truly life-altering results, then a one-time large payment, as seen recently with gene therapy and CAR-Ts in other types of blood cancer, might be justifiable. Or, as Wildgust from Janssen put it, “if we can eliminate disease, I’m sure we’ll be able to find a value proposition.”
Stephenson and Graff both said that they still feel like patients much of the time, and that every ache and pain can awaken cancer fears. But they are endlessly grateful for the years the treatments have given them.
“Life is good. I can’t complain,” said Stephenson, a mother of three with a strong religious faith. “As bad as myeloma is — and it hasn’t been a picnic by any means — but it has brought so many silver linings. To list them all would take all day.”
She doesn’t sweat the small stuff anymore.
“So what if you reach for a can of crushed tomatoes and you don’t have any — it’s not the end of the world. Or your stove is dirty. So? I’ll clean it tomorrow if I don’t want to do it today.”
Both she and Graff spend time sharing what they’ve learned with patients who are coming up behind them.
“I tell people how lucky they are to be diagnosed with multiple myeloma at this time,” said Graff, whose youngest granddaughters are now 4 and 6. “If you have to have it, this is the time.”
This story was originally published by STAT, an online publication of Boston Globe Media that covers health, medicine, and scientific discovery.
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