Have a Cocktail: Using Multiple Drugs to Treat Myeloma

Ron Malinowski, a retired engineer living outside Ann Arbor, Michigan, was diagnosed with multiple myeloma in December 2014. He underwent a stem cell transplant in August 2015, followed by a year of chemotherapy.

Still, the myeloma came back. In a two-week period in early September of this year, Malinowski’s myeloma seemed to explode.

“It just went crazy in one week,” Malinowski, 70, remembers. “It spread from my bones to my whole torso: my lungs, my intestines. We were afraid I wasn’t going to make it much longer.”

After trying just about everything else, Malinowski’s medical team put him on a “triplet” combination colloquially called “Elo-Rev-Dex.” One of the drugs in the combination, Empliciti (elotuzumab), was not yet approved for the treatment of myeloma when Malinowski was diagnosed; now, it’s approved as part of this combination, which includes: Empliciti, a monoclonal antibody, to enlist his own immune system to fight the cancer. An immune modulator, Revlimid (lenalidomide), that targets cancerous plasma cells while also boosting the immune system. Dexamethasone, a corticosteroid, which reduces cancer-induced inflammation and can kill some cancer cells.

Each of those agents works in a slightly different way to fight cancer; side effects can include blood clots, fatigue and lowered red and white blood cell counts. The combination worked for Malinowski. Within a month and a half, his blood tests indicated that he was experiencing a major remission.

“It’s ‘minimal residual disease’ now,” Malinowski says. “It’s amazing to be part of this cutting-edge change.”

A multiple myeloma diagnosis used to mean that a patient could only expect to survive three to five years. Today, that landscape has changed so much that it’s almost unrecognizable. Multiple myeloma remains incurable, but it is becoming more manageable. Doctors are beginning to talk of it as a “chronic disease.” Some are becoming optimistic enough to say that a cure might be possible within a decade.

“Twenty years ago, when I was in training, multiple myeloma was awful,” says Craig Cole, M.D., Malinowski’s doctor and an assistant professor in the Division of Hematology/Oncology at the University of Michigan. “Everyone was dying in three years or less. Now, people are surviving and surviving. And with the new drugs, they’re surviving with quality of life.” Progress has been steady over the last decade, with eight new drugs making their way into the myeloma toolbox between 2004 and 2014.

Then, in 2015, four additional treatments were approved by the FDA and one was given a new indication, demonstrating that progress had made a quantum leap. Among the treatments approved last year is the Elo-Rev-Dex triplet. Empliciti hones in on a protein called SLAMF7, which sits on the surface of myeloma cells, and then stimulates the body’s immune system to attack those cells. The recently approved Darzalex (daratumumab) is also a monoclonal antibody, but it targets a different protein on the surface of myeloma cells, CD38.

Also approved was Ninlaro (ixazomib), the first oral proteasome inhibitor, in combination with Rev-Dex; proteasome inhibitors cause degraded proteins to build up in cells — including cancer cells — ultimately choking them. Another proteasome inhibitor, Kyprolis (carfilzomib), was approved as a monotherapy in 2012 and then, in 2015, got a new indication for use in combination with Rev-Dex. Finally, Farydak (panobinostat) works by inhibiting the activity of enzymes called histone deacetylases (HDACs). Given with the proteasome inhibitor Velcade (bortezomib) and with dexamethasone, this drug may slow the over-development of plasma cells in multiple myeloma patients, or cause these dangerous cells to die.

So much has changed that, in the spring of 2016, the National Comprehensive Cancer Network (NCCN) published a new set of myeloma treatment guidelines, and many trials now vie to clarify how best to use these new treatments and in what combination and time frame.

Doctors are trying established drugs in new combinations of three, and even four or five, different agents. They’re tweaking doses and formulations in order to cut down on the side effects of treatment, and also to lengthen stretches of progression-free survival (PFS).

Drugs in the clinical trial pipeline enlist the body’s own immune system to fight the disease while others target cells with specific genetic mutations, or target systems that control cell processes. One of the treatments just approved may be taken orally, like others in development. So that means that some patients don’t have to travel to an infusion center every few weeks to keep their cancer under control.

HOW DID WE GET HERE?

To understand why all this is such a big deal, it helps to remember how grim the outlook was just a few years ago.

The standard treatment used to be a course of chemotherapy with drugs like Cytoxan (cyclophosphamide) and Adriamycin (doxorubicin), “induction” chemotherapy meant to “induce” remission of the cancer. Next, the patient would receive high-dose melphelan, also a chemotherapy drug, followed by a stem cell transplant. This grueling, months-long procedure would replace the diseased bone marrow, typically with cleansed marrow from the patient. The side effects of these myeloma treatments could be harrowing: drops in blood counts, crushing fatigue, diarrhea, severe bone pain, relentless infections, nausea and heart damage.

After a transplant, doctors have traditionally checked the patient’s blood and urine for levels of monoclonal protein (protein secreted by the tumor cells), prescribing various drugs and combinations to keep the myeloma at bay for as long as possible.

These days, transplant is safer and swifter, with a two-week timeframe possible, and many completing the process as outpatients, points out Amrita Krishnan, M.D., director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope in Duarte, California. However it’s done, the goal of this sometimes exhausting protocol has been to create stretches of time when the disease did not progress. Unfortunately, since there has been no curative therapy, those periods of PFS eventually become shorter and shorter, until finally, all of the drugs become ineffective.

Today, newer drugs have so improved the prognosis and quality of life for myeloma patients that there’s a robust debate among myeloma specialists about whether to do a stem cell transplant after diagnosis, or to wait until relapse. Stem cells transplants can be harsh, and not all patients are even strong enough to endure one. Some doctors even suggest that stem cell transplants may not be indicated in myeloma.

Whether to do stem cell/bone marrow transplants remains a controversy, however. A recent longitudinal study — that is, one that follows patients over a long period of time — shows that myeloma patients who do receive transplants early in treatment tend to have longer remissions.

What’s certain, experts say, is that transplants will exist in a landscape where there are many, many more options. The new NCCN guidelines incorporate several changes that will be important to patients:

They adjust what “active” disease means. Your disease may be classified “active,” even if you don’t have some of the defining features of hypercalcemia, kidney dysfunction, anemia or bone disease. That means that some patients may qualify for earlier intervention with treatments.

The Revised International Staging System is now included, adding new diagnostic tests (for lactate dehydrogenase levels in the blood and for high-risk chromosomal abnormalities, as defined by FISH) to the standard serum albumin and beta 2 micro globulin tests.

The guidelines now recommend several triple regimens, based on recent studies.

“The NCCN guidelines used to be a laundry list of drugs; it was up to the lay hematologist to put it all together. Now, multiple approaches are reflected in the guidelines. The progress is going to affect everybody, but I think it will be biggest in the newly diagnosed,” says Cole. “With the ongoing clinical trials, new immune therapies — and “Dara-Rev-Dex” — those are the results that will really change the landscape, because the responses are better, are faster and deeper. The deeper we can put people in responses (leaving fewer myeloma cells), the better they do long-term.”

“I like to say that it’s not about more, it’s about being more specific,” says James Berenson, M.D., a West Hollywood,California oncologist who specializes in myeloma. He is president, and medical and scientific director, of the Institute for Myeloma and Bone Cancer Research in West Hollywood.

The breakthrough class of drugs that led to a public statement like that even being possible was the proteasome inhibitors. The first of these medicines, Velcade (bortezomib), came on the market in 2003. It attacks myeloma cells by interfering with proteins that regulate various cycles within cells, such as DNA repair.

Then doctors began to use immune-modulating therapies (IMiDs) to treat myeloma. These drugs — Thalomid (thalidomide), Revlimid (lenalidomide) and Pomalyst (pomalidomide) — interfere with the blood supply to cancer cells, while at the same time stimulating the action of the body’s disease-fighting T-cells. Side effects can include gastrointestinal discomfort, fatigue, low red or white blood cell counts, swelling in the arms and legs or dizziness, with severe side effects including blood clots. The third generation of these drugs, Pomalyst, is more potent but has a somewhat different side effect profile, so that it can be used in patients who are older, or whose disease has relapsed on other medications, even including other immunomodulatory agents.

With the development of the proteasome inhibitors and immune-modulating drugs, several large international studies (FIRST, UPFRONT, MOVE) proved that two-drug combinations could be effective against myeloma. That, in turn, led to “triplet” therapies, using two or three agents of various kinds and in various doses and patient populations.

WHERE MYELOMA TREATMENT IS HEADED

Researchers are now investigating whether certain combinations work better when myeloma is first diagnosed, or might be better for very old patients. They are also beginning to combine four different agents, and sometimes even five. And they are trying to develop better tests to detect “minimal residual disease” (MRD) in patients.

In the near term, doctors express hope about studies involving Darzalex, approved as a single agent, in combination with other agents. Two phase 3 studies, recently published in The New England Journal of Medicine, have shown encouraging results:

The POLLUX trial focused on patients who’d had at least one prior therapy, comparing those who took the Dara-Rev-Dex triplet with those who took only the last two agents. Phase 3 results showed that this triplet reduced the risk of progression or relapse by 63 percent. The CASTOR trial made a comparison between Dara-Velcade-Dex in patients who had relapsed after one or more therapies, and phase 3 results showed a 61 percent reduction in the risk of progression or relapse. The FDA in October granted priority review to these therapies, making it likely they may be approved more quickly and made available to more patients.

“Both CASTOR and POLLUX have shown very encouraging early results,” says Joan Levy, Ph.D., vice president for research at the Multiple Myeloma Research Foundation.

These combinations seem to work better because they strive to cover all the bases: A doctor might use one proteasome inhibitor, one IMiD and one steroid. That way, experts explain, the drugs hit as many viable targets as possible, attacking the disease from all angles.

“Regarding new drugs, we are using them in combination with older drugs, as well as moving them up earlier in the course of disease,” Krishnan says. “Future plans would include studying them as maintenance therapy.”

Many experts expect that the next breakthrough will come with monoclonal antibodies, which have made such a difference in improving the prognosis of many breast and lung cancers. It’s a completely new class of drugs for this cancer type, and is showing its potential in the triplets that include Empliciti and Darzalex.

Half a dozen monoclonal antibodies are in various stages of trial for use against myeloma, or in trials for combined use with other drugs. Certain types of antibodies are of special interest because they may activate the immune system, and unlike older drugs, may have a more sustained effect because they harness the body’s own protective systems.

Even before they were added to triplets, monoclonal antibodies showed promise in myeloma. Darzalex was approved as a monotherapy. In two clinical trials that led to its approval, 29 percent and 36 percent of patients who were not responding to any other drug experienced control of their disease, in one of the studies halting progression for six months or more. This was a first for myeloma patients.

After two stem cell transplants, and two four-year periods of remission, Dana Davis, an Atlanta father and school administrator, had started to run into trouble. “My multiple myeloma started to not respond to traditional treatments,” recalls Davis, who was diagnosed more than 15 years ago. “I tried four or five different drugs. They’d be effective for a little while, and then they’d lose their effectiveness.”

Davis took Darzalex for more than two years, then Pomalyst for a few months. He’s now on Kyprolis, the newly approved proteasome inhibitor, and his myeloma has gone back into remission.

“We not only have the biologic agents, but now the immune therapies, the monoclonal antibodies,” explains Cole. “It’s been remarkable in that respect. The future will be the combined application of biology, genomics and using the patients' own immune systems.”

The next class of drugs on the horizon will target specific mutations within myeloma cells. For instance, 50 percent of metastatic myeloma contains a genetic mutation called “BRAF,” so that makes a natural drug target. This is a mutation that is also druggable with targeted medication in non-small cell lung cancer.

Other targeted therapies in trials for the treatment of myeloma aim at an alphabet soup of different mutations: MEK, PI3K/AKT, FGRF3, CDK and MDM2i/Del17p.

“Ultimately, the idea is to sequence genes that make the patient’s tumor-specific marker, the monoclonal antibody, and then to use that as a vehicle to deliver toxins or other therapy. That should be a beautiful way to concentrate treatment,” explains Berenson.

Capitalizing on this exploding understanding of the genetics of tumors, the International Myeloma Foundation has launched a “Black Swan Initiative” aimed at finding and characterizing MRD in patients, and figuring out which treatments that lingering disease may be resistant to. The idea is to learn how to eliminate MRD and ultimately cure myeloma. The IMF can scan the full genetic record of a patient’s cancer, its genome, and screen for 1,800 different genetic mutations that may be relevant in myeloma.

“We can test patients at baseline, and then see how their disease changes over time. We’re learning that multiple myeloma cells have many mutations that vary from patient to patient,” explains Brian Durie, M.D., chairman of the IMF. “We’re characterizing disease at the cellular level. We’re developing tests than can detect just a few multiple myeloma cells, one myeloma cell in a million, what we call ‘minimal residual disease.’”

STILL IN THE PIPELINE

Meanwhile, research teams around the world are looking at completely new ways to kill myeloma:

Selinexor targets nucleotide transport, what goes in and out of myeloma cells. Based on promising early results, trials of this agent are being expanded.

CB-5083, an oral drug in very early trials, inhibits p97, a protein that acts like a pump, carrying loads of unfolded proteins of each cell. In their frenzied growth, cancer cells create a lot of these botched proteins, which could interfere with the cell’s functions if not removed. By interfering with the pump, it’s hoped that the drug will kill the myeloma cells.

Filanesib (ARRY-520) interferes with “kinesin spindle proteins” which are essential when cells divide. Obviously, messing with a cancer cell’s ability to divide is a good thing.

Ibrutinib inhibits “Bruton’s tyrosine kinsase” (BTK), interfering with the cell signaling pathways of myeloma cells, hopefully accelerating their demise.

In research that experts caution is still in very early stages, some teams are focusing on CAR-T cells, essentially engineering certain immune system T-cells to attack cancer cells.

“There are a lot of good, new drugs in trials now,” Berenson says. “I used to say, ‘Don’t go on a trial until it’s time for the Hail Mary pass.’ Now, we are enrolling many new patients on trials.

“Increasingly, in our studies, we’re trying to capture patients that have really aggressive disease, designing drugs and combinations to treat those patients,” says Shaji Kumar, M.D., of the Mayo Clinic in Minnesota, who has conducted numerous studies on oral proteasome inhibitors for multiple myeloma. “For the patients, the key thing is this: We have made this a chronic disease. Having enough drugs to keep the myeloma under control is the key thing. The longer we keep someone on a drug, the closer they are to something new that might be on the horizon, something that might cure this disease. Our next goal is to start exploring the possibility of a cure for the disease. This will eventually come from the judicious combinations of the effective drugs we have been blessed with, as well as determining the right time to intervene.”