Multiple myeloma has long been a killer. Therapies are changing that.

(The Washington Post) – Audrey Greene, a retired sales agent from Long Neck, Del., celebrated her 80th birthday in March. Diagnosed in 2010 at age 68 with multiple myeloma, a cancer that attacks the white blood cells and has always had a dire prognosis, she didn’t expect to live past her early 70s. She was wrong.

Fortunately, her illness was discovered at a pivotal time when an array of new drugs and other treatments — including those that harness the body’s immune system — were starting to transform a once-deadly cancer into a chronic manageable disease for many patients. These approaches for myeloma are among many in the growing field of precision medicine, which uses information from a patient’s tumors and genetics to design novel therapies for other cancers as well.

“Thirty years ago, multiple myeloma was a death sentence,” says Kathy Giusti, founder of the Multiple Myeloma Research Foundation and a myeloma survivor diagnosed in 1996 who benefited from these early drug advances and a stem cell transplant. “Today it’s one of the most treatable cancers out there. People are living longer lives with tremendous hope. I was supposed to live three years and I’ve lived almost 30.”

Along with new therapies, there are more than a dozen new drugs, both approved and in clinical trials, available to myeloma patients now, experts say. “The outlook used to be really poor … because myeloma doesn’t respond well to typical chemotherapy,” says Elizabeth M. Hill, assistant research physician in the lymphoid malignancies branch of the National Cancer Institute.

The advances began in the early 2000s “when we started getting treatments specific to the biology of myeloma,” Hill says. “The field has exploded ever since. Now, at diagnosis, [statistics suggest] most people live eight to 10 years, which is probably an underestimate, since the data lag behind where we are.” If advances continue, “we might be able to control multiple myeloma in a way that people can live a normal life span,” she adds.

Ivan Borrello, a myeloma expert at the Cancer Institute at Tampa General Hospital, says some may be close to doing that already. “I have patients I have been following for 20 years,” he says.

Multiple myeloma is a cancer of the plasma cells, the white cells in the blood that produce antibodies against infection. In myeloma, the cells grow too much, crowding out normal cells in the bone marrow that make red blood cells, platelets and other white blood cells and causing pain in the affected bones. Multiple myeloma develops in the bone marrow and can spread throughout the body

The most significant risk factor for developing multiple myeloma is age. The cancer is rare in people younger than 45. It afflicts men more than women and is more than twice as common among Black people than White, according to the Centers for Disease Control and Prevention. The American Cancer Society estimates there will be 35,730 new cases diagnosed this year, and about 12,590 deaths.

For more than 50 years, the mainstay of myeloma treatment was the chemotherapy drug melphalan and steroids. A trial in the late 1990s found that the drug thalidomide was “remarkably effective” at combating myeloma among patients with no other therapy options, according to S. Vincent Rajkumar, a myeloma expert at the Mayo Clinic. In 2006, the Food and Drug Administration approved it for use in combination with the steroid dexamethasone for newly diagnosed myeloma.

(Thalidomide is the same drug marketed abroad as a sedative in the late 1950s that caused birth defects in babies born to women who had taken it during pregnancy. It was not licensed in the United States at that time, although in the 1990s it was “repurposed” and approved to treat certain cancers, advanced leprosy and other conditions.)

After thalidomide, more drugs followed, including new versions of thalidomide that were more effective and had fewer side effects. Most significantly, in 2003 new drugs called proteasome inhibitors were used, which prevent cancer cells from getting rid of old proteins in order to replace them with newer versions; as old proteins pile up, cancer cells die. Initially, proteasome inhibitors were given to myeloma patients who relapsed after drug therapy, but now they are among the drugs given as first-line therapy in newly diagnosed patients.

In 2015, an even newer type of drug, the first monoclonal antibody — daratumumab — was approved for myeloma. It directly targets myeloma cells by binding to a specific target on the cancer cell (in this case, an antigen known a CD38) and renders it harmless.

“Together, these changes transformed myeloma into a more chronic malignancy where the median survival has more than doubled,” Rajkumar says.

Robert Orlowski, professor of medicine in the departments of lymphoma/myeloma and experimental therapeutics at MD Anderson Cancer Center at the University of Texas, says that in his experience, longevity now is about 10 to 15 years. He acknowledges this might not seem very encouraging to patients in their 60s or younger. “But I tell folks that we have so many new drugs and therapies under development that their prognosis will improve with the passage of time as we replace less effective therapies with more effectives ones,” he says.

These days, initial therapy for a newly diagnosed patient typically has been a three-drug regimen that includes one proteasome inhibitor, one immunomodulatory agent (a drug from the thalidomide class) and the steroid dexamethasone. However, many clinicians also add a fourth in many cases. “In the past few years, there is evidence that adding in a fourth drug, anti-CD38 monoclonal antibodies, can deepen and lengthen initial responses,” Hill says.

A stem cell transplant usually follows the initial drug regimen. It is an arduous procedure and can be risky. Clinicians harvest the patient’s own stem cells from their blood and save them while the patient undergoes high-dose chemotherapy to kill the cancer. The preserved stem cells then are returned to the body and begin to produce new cancer-free blood cells. Because the process essentially wipes out the old immune system, patients must later undergo re-immunization, including for all the diseases of childhood.

“A stem cell transplant is still the gold standard of care, especially for younger patients,” Borrello says, adding: “The cutoff is supposed to be 70, but that’s a ‘biological’ 70, meaning that older patients who are healthy can still get one.” Such stem cell transplants for myeloma are not new; a version that required extracting bone marrow from a patient and reintroducing it was used starting in the 1980s, Borrello says. Since then, new techniques allow stem cells to be harvested from blood, without having to extract them directly from bone marrow

There also are more recent options in the past several years for those who relapse four or more times. Beginning in 2021, the FDA licensed several new drugs belonging to two novel classes of therapies: CAR T-cell therapy and bi-specific antibodies.

In CAR T-cell therapy, a patient’s T cells (a type of immune system cell) are removed from their blood, then genetically altered in a laboratory to bind to specific cancer cells in the patient’s blood and kill them off.

Bi-specific antibodies are created in the lab to bind to cancer cells at the same time as to T cells, a structure that prompts the T cells to destroy the cancer. The FDA approved the use of a bi-specific antibody, teclistamab, just last fall, following encouraging results from clinical trials among patients with repeated relapses. The NCI’s Hill calls it a “game changer for patients who failed earlier therapies.”

Saad Usmani, chief of the myeloma service at Memorial Sloan Kettering Cancer Center and one of the authors of the teclistamab study, agrees. Although the CAR T and bi-specific drugs currently are approved only for relapsed patients, he is conducting clinical trials testing them in people newly diagnosed with multiple myeloma. “If these trials pan out, in the next five to 10 years, we might be able to cure a subset of myeloma patients,” he says.

Orlowski says about 80 percent of the myeloma patients he sees are nonaggressive “standard” (or lower) risk, with a good prognosis now that there are more-effective therapies than in decades past. For them, a “good prognosis” means about 15 years of survival, whereas the remaining 20 percent in the “high risk” category are likely to have about seven or eight years, he says. These high-risk patients initially respond to treatment but tend to relapse sooner than those at standard, or lower, risk, he says.

High-risk myeloma patients “are identified by molecular testing,” Orlowski says. “There are molecular irregularities and mutations seen in these patients that are not seen in standard-risk patients.”

He and his colleagues are trying to understand the biology of the more aggressive form, with the goal of designing new drugs to “bring these patients down to standard risk,” he says.

Most patients experience a relapse after treatment — “the question is when,” Borrello says. The goal of current research into drugs and other treatments is to prompt patients back into remission and continue to extend their lives, experts say.

One such experiment, still ongoing, seems to have helped Greene. She was part of a clinical trial of a second procedure that accompanied her 2011 stem cell transplant. Along with her saved stem cells, she also received an infusion of her own T cells — known as marrow-infiltrating lymphocytes, or MILs — taken earlier from her bone marrow, which were “revved up” in the lab by a combination of antibodies and growth factors, then returned to her body, the goal being to prolong remission and delay relapse.

“Myeloma originates in the bone marrow, so if we want to identify myeloma-specific T cells, what better place to find them” than in the bone marrow, says Borrello, who pioneered the approach and treated Greene. “These [disease-fighting immune cells] become exhausted by this cancer and are no longer capable of doing their job. What we do is take the cells out, activate them, then reinfuse them into the patient.”

Greene stayed in remission after her stem cell/MILs procedures until 2014, when she relapsed. She then began taking an immunomodulatory drug (one of the drugs in the thalidomide class) until 2020 and is once again in remission and not on any drugs for myeloma.

Today, “I travel the world and live a fun life,” she says. She has three children, seven grandchildren, one great-grandchild “and a wonderful man I’ve been married to for almost 59 years,” she says. “I’m thankful every day.”

Written by: Marlene Cimons