Treating Multiple Myeloma From Every Angle

In November 2008, entertainment producer Sean Murray, of Kimberling City, Mo., developed a backache that went "from annoying to excruciating" in a matter of days. After examining X-rays of his back and right shoulder, Murray’s doctor immediately suspected cancer. A full-body imaging scan revealed an 8.5-centimeter lesion on Murray's right shoulder as well as lesions on his ribs, spine and pelvis. A blood test confirmed that Murray, then 49, had multiple myeloma, a blood cancer that often causes painful bone lesions.

"I have a high threshold for pain," says Murray, explaining that he'd coped with pain in his right shoulder for more than a year before receiving his diagnosis. "But soon the house of cards started to fall."

By the time Murray started treatments, three of his vertebrae had collapsed, and he had a tumor pressing dangerously on his spinal cord. His doctors recommended that he start treatment immediately, but first Murray wanted to see his two young daughters. "At this point, we didn’t know if I was going to live," he says, "so I wanted to go home for Thanksgiving and surprise my daughters."

After the holiday, Murray embarked on a treatment journey that included a procedure to repair his vertebrae, aggressive combination chemotherapy, two autologous stem cell transplantations and three years of lower dose “maintenance” chemotherapy. By November of last year, Murray went off all his myeloma medications. To date, his disease is stable.

Although most oncologists consider multiple myeloma incurable, the survival rate has doubled in the past two decades, thanks to the development of more effective therapies. And with new drugs recently approved for multiple myeloma and others in the clinical trials pipeline, the outlook for these patients is getting even brighter.

About 22,000 Americans receive a diagnosis of multiple myeloma each year. It is more common in people over age 65, men and African-Americans. The disease arises in immune cells called plasma cells—specialized types of white blood cells that normally produce infection-fighting antibodies. The cancerous plasma cells produce abnormally high levels of a nonfunctional antibody, called M (monoclonal) protein, which can be detected in the blood or urine. Some people have elevated M protein in their blood but no other symptoms of multiple myeloma, such as bone pain, fatigue and anemia. These individuals have a pre-cancerous condition known as monoclonal gammopathy of undetermined significance (MGUS) and are not treated, although roughly 12 to 30 percent of these individuals will eventually develop multiple myeloma (most commonly), amyloidosis (a buildup of protein in multiple organs), lymphoma or chronic lymphocytic leukemia.

Patrick Killingsworth, a former real estate agent from Weeki Wachee, Fla., was told he had stage 3 multiple myeloma in 2007 at age 51. Killingsworth had always been physically active but noticed more aches and pains over the years, eventually developing severe hip pain that affected his ability to walk. "I sneezed in the shower one morning and the [back] pain was so bad I couldn't move," Killingsworth recalls. An imaging scan revealed lesions in his hips and spine.

I sneezed in the shower one morning and the [back] pain was so bad I couldn't move.

The International Staging System for multiple myeloma is based on blood levels of two proteins called beta-2 microglobulin and serum albumin, with high levels of the former indicative of more advanced disease regardless of serum albumin levels. Certain genetic abnormalities, including amplifications, deletions and rearrangements of specific chromosomes, are also associated with higher-risk disease. Although both Murray and Killingsworth received a diagnosis of stage 3 disease, neither had any of the genetic risk factors associated with a poor outcome.

Disease stage and risk factors play into prognosis, as well as treatment sequencing. After determining a patient's transplantation eligibility, the first step for virtually all patients is high-dose "induction" chemotherapy, the goal of which is to induce remission. For transplantation-eligible patients, this usually involves treatment with two types of anticancer drugs—immunomodulatory drugs and proteasome inhibitors—in combination with the steroid dexamethasone. Patients too old or sick to tolerate transplantation are still treated with combination therapy, often the same combinations as used for induction chemotherapy.

The immunomodulatory drugs include Thalomid (thalidomide), Revlimid (lenalidomide) and the newly approved Pomalyst (pomalidomide), which work in a variety of ways to block cancer cell survival. The proteasome inhibitors include Velcade (bortezomib) and the recently approved Kyprolis (carfilzomib), which block a structure that degrades unneeded proteins, thereby protecting proteins that inhibit cell division. Distinct side effects accompany each of these drugs. The immunomodulatory agents can all cause blood clots, fatigue, gastrointestinal problems and lowered white and red blood cell counts. Side effects of Velcade include peripheral neuropathy, low blood cell and platelet counts and gastrointestinal problems. Kyprolis can cause fatigue and low blood counts. Many of these drugs have rare but serious side effects, and nearly all of them require a risk evaluation and management strategy program approved by the Food and Drug Administration.

Killingsworth's induction regimen consisted of Revlimid and dexamethasone, the former of which may have contributed to a blood clot in his lung that developed early in his treatment. Murray's initial treatment was less conventional. He was treated at the Myeloma Institute for Research and Therapy (MIRT) in Little Rock, Ark., where the approach was to attack the disease from all possible angles to maximize the odds of achieving complete remission. As part of an ongoing phase 3 clinical trial (Total Therapy 4), Murray received a combination of eight drugs, including melphalan, Velcade and Thalomid, plus dexamethasone and four other chemotherapy agents followed by a transplantation and then more chemotherapy.

Others have yet to be convinced of this approach. "Giving all the agents together certainly increases the toxicity," says Ravi Vij, an oncologist and transplantation specialist at the Siteman Cancer Center in St. Louis, "and there is the feeling that when you get [drug] resistance, you may have nothing left to turn to." But MIRT director Bart Barlogie argues that this is the most promising way to kill the cancer completely. "There are so many [survival] pathways that the myeloma cells can activate, that using one or two drugs at a time will never work in a curative way," he says, referring to the cells’ genetically mixed nature.

Once remission is achieved, most patients undergo years of maintenance chemotherapy with the aim of maximizing the length of remission. This approach has proven successful in some trials but is also associated with a slight risk of developing secondary cancers, particularly with Revlimid. The optimal timing and drug doses used for maintenance therapy are being studied in clinical trials. Murray was treated for three additional years with Velcade, Revlimid and dexamethasone, which he says made him feel wired and a bit manic. "The family joke was that on Thursdays, I was no longer Dad, I was Tyrannosaurus Dex," he says.

For Murray, recovering from his first transplantation has been the most challenging part of his experience with multiple myeloma thus far. At his lowest point, he recalls thinking, "God, I don't know what you have in mind for me, but if your plan is to take me, today is OK." Killingsworth, who was also eligible for a transplantation, was fearful of the process, and after having a complete response to his initial treatment, he and his oncologist decided to hold off on transplantation for the short term.

Indeed, given the efficacy of the current drug combinations, some oncologists question whether stem cell transplantation is needed at all. Until there are data available to answer that question, autologous stem cell transplantations will remain the standard of care for eligible patients.

Whether transplantation should be delayed until the disease relapses is more hotly debated, particularly as responses to newer drug combinations can last years. Furthermore, some studies have suggested that there's no harm in waiting. However, some myeloma drugs that can have permanent effects on the marrow should be avoided if future transplantation is being considered. Killingsworth's disease relapsed after four years. After another round of induction chemotherapy with Velcade, Revlimid and dexamethasone, he finally had a transplantation. "It was no picnic, but it was easier than I'd feared," he says.

Despite substantial advances in treating multiple myeloma, most patients eventually relapse, often because their cancer cells develop drug resistance. Patients may respond a second time to the same chemotherapy if their relapse occurs more than six months after initial treatment. Yet with each relapse, the cancer cells grow faster and remission times usually get shorter.

The good news is that new drugs and different drug combinations are still effective, even in patients whose cancer cells develop resistance to related drugs. In patients who have relapsed on Thalomid, around half have a response to Revlimid, even though the drugs are almost identical, adds David H. Vesole, co-chief and director of research for the multiple myeloma division of the John Theurer Cancer Center in Hackensack, N.J.

How this works is not entirely clear; one reason may be that the newer drugs tend to attack their targets from different angles. The efficacy may be partially explained by the mixed nature of the cancer cells, some of which might be naturally resistant to individual drugs.

"Our current philosophy is to make this a chronic disease akin to diabetes or hypertension," Vesole says. "But you have to have enough drugs in the [arsenal] to do sequential therapies."

Barlogie disagrees with this sentiment and feels that the goal should be a cure. "If you choose to keep [certain drugs] in reserve that are important, you take away from the curability potential," he says.

Whether the goal is chronicity or cure, the new drugs Pomalyst and Kyprolis give additional options to patients whose disease has relapsed. In one study, Pomalyst, in combination with low-dose dexamethasone, partially or completely wiped out myeloma cells in 29.2 percent of patients who had relapsed or recurrent disease after approximately five different therapies, including those who had already taken Velcade and Revlimid. A recent phase 3 trial found that this combination also improved survival when compared with high-dose dexamethasone alone. Side effects included fatigue and decreased white cell counts. Kyprolis showed promising results when used as a single agent, with an overall response rate (complete or partial disappearance of cancer cells after treatment) of up to 50 percent in patients with relapsed multiple myeloma who had never taken Velcade and 23 percent in those who had. Response rates were even better when Kyprolis was combined with Revlimid and low-dose dexamethasone, a combination currently being tested in larger phase 3 studies. Kyprolis also appears to be better tolerated than Velcade, with fewer patients developing peripheral neuropathy. However, recent studies have shown that the inclusion of Velcade in the initial chemotherapy combination results in increased response rates and progression-free survival.

New drugs are also being tested in clinical trials. Proteasome inhibitors, including oprozomib and ixazomib, have shown promise in early trials with low rates of peripheral neuropathy.

Two new monoclonal antibodies, elotuzumab and daratumumab, which bind to proteins on the surface of myeloma cells, are also being tested. Both drugs were well-tolerated in early studies in patients whose disease had relapsed or was refractory (resistant to drugs), but only daratumumab was effective on its own with some patients showing a partial response or stable disease. In a phase 2 trial, 84 percent of patients responded to elotuzumab in combination with Revlimid and dexamethasone. Ongoing phase 2 and 3 trials are testing elotuzumab in various drug combinations in both newly diagnosed and relapsed disease.

"What would be nice is if we could pick out the right targets in each patient, so we don't treat them with non-targeted therapies," Vesole says. "But we do not have a way to do that right now." To achieve this goal, many investigators are studying the genetic profile of cancer cells before and after treatment. Barlogie’s team has identified a 70-gene "signature" that pinpoints patients who may be at high-risk for recurrence or metastasis and also might predict survival post-relapse.

Murray's first blood test since ceasing all medications showed no trace of M protein, giving him hope that Barlogie’s goal of achieving a cure may become a reality.