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From OncoLog, July 2011, Vol. 56, No. 7

A New Era in Treating Patients Who Have Multiple Myeloma

By Kate Newberry

During the past decade, several novel treatments have extended the median survival time for patients with multiple myeloma from less than 3 years to more than 7 years, and researchers are working to further improve treatment.

Multiple myeloma was first discovered more than a century ago, but until about 50 years ago there were no known treatments. Each year approximately 20,000 people in the United States are diagnosed with this blood cancer, and about 11,000 die of their disease. Patients with symptomatic disease develop fractures, severe bone pain, fatigue, infections, and hypercalcemia; if left untreated, these patients typically live less than 1 year.

Therapeutic agents

The first breakthrough in treating multiple myeloma came in the 1960s with the introduction of melphalan, an alkylating agent. Melphalan combined with prednisone increased the median survival time from less than 1 year to approximately 3 years. However, it was not until the 1980s that further progress was made when high-dose chemotherapy combined with autologous stem cell transplantation was introduced.

Two more decades passed before the next breakthrough in treating multiple myeloma; in 2003 bortezomib—the first of a new generation of therapies that inhibit proteasome activity, thereby allowing cell death to occur in myeloma cells—was approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma.

Since that time, several therapies that target not only cancer cells but also the bone marrow microenvironment have been approved by the FDA for the treatment of multiple myeloma, and several more are being tested in preclinical and clinical studies. Other drugs approved between 2003 and 2008 for multiple myeloma treatment include thalidomide and lenalidomide, which are immunomodulatory agents with antiangiogenic effects; and liposome-encapsulated doxorubicin, which induces cell death by interfering with DNA replication. Although these drugs are effective individually, they have been shown to be much more effective when used in combinations. But despite the development of these more effective therapies, nearly 100% of patients eventually have disease relapse.

“The current challenge is to find new drugs that treat relapsed disease and prolong survival,” said Michael Wang, M.D., director of the myeloma tissue bank and an associate professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center. “We are right in the middle of an era of new therapies,” Dr. Wang said. “We have prolonged median survival to about 7 years with new agents.”

Current standard of care

Multiple myeloma is thought to develop over several years and generally is treated only when a patient becomes symptomatic. The current standard of care is 2–3 months of induction therapy including novel drugs such as bortezomib, lenalidomide, and dexamethasone. Muzaffar Qazilbash, M.D., an associate professor in the Department of Stem Cell Transplantation and Cellular Therapy, said, “These days, more than 80% of patients respond to induction therapy. It used to be 50%–60% or even fewer when we didn’t have that many effective agents.” This is very important, as initial disease control is necessary before collecting the patient’s stem cells for transplantation.

After induction therapy, the patient’s stem cells are collected and banked, and 1–2 days of high-dose chemotherapy with intravenous melphalan is given to destroy any resistant cells. “High-dose chemotherapy eradicates the myeloma cells, but in the process it also wipes out the normal hematopoietic system and the immune system,” said Dr. Qazilbash. Thus, to replenish the blood and immune systems, the hematopoietic stem cells that were collected from the patient are used to reconstitute the bone marrow and immune system.

The ultimate goal of therapy is to achieve complete remission, which until recently could be achieved only by stem cell transplantation. However, today combinations that include lenalidomide or bortezomib as frontline therapy are achieving durable complete remissions in some patients, enabling them to delay or even forgo stem cell transplantation. A combination of bortezomib, dexamethasone, and either thalidomide or lenalidomide appears to be emerging as the best initial treatment.

The treatment regimen given depends on whether a patient is eligible for a stem cell transplant. Most patients who are eligible eventually undergo autologous stem cell transplantation, either as part of their initial treatment regimen or after disease relapse.

Ongoing research

In an effort to improve outcomes after autologous stem cell transplantation, several clinical trials are being conducted at MD Anderson, including a large multicenter trial conducted by the Blood and Marrow Transplant Clinical Trials Network. It is a three-arm trial comparing a single transplant, two sequential (also known as tandem) transplants, and a single transplant followed by four cycles of a standard chemotherapy regimen.

Dr. Qazilbash said that some interesting research is being done as part of a Specialized Programs of Research Excellence grant for myeloma. Collaborators including Larry W. Kwak, M.D., Ph.D., chair of and a professor in the Department of Lymphoma and Myeloma at MD Anderson, and Carl June, M.D., at the University of Pennsylvania. These researchers are hoping to improve patients’ responses to chemotherapy by priming the immune system to selectively kill myeloma cells. The approach involves using a vaccine developed from patients’ own myeloma proteins combined with patients’ T lymphocytes.

According to Dr. Wang, potentially better chemotherapy drugs are in the pipeline. For example, carfilzomib, a second-generation proteasome inhibitor, is being tested in a phase II clinical trial at MD Anderson and other centers in patients with relapsed or refractory multiple myeloma who have received one to three prior therapies but not bortezomib.

Initial data from this trial presented at the 51st Annual Meeting of the American Society of Hematology showed that 45% of participants responded to carfilzomib. Furthermore, carfilzomib did not cause peripheral neuropathy, a dose-limiting toxicity of the older drugs thalidomide and bortezomib. “These findings are truly an advance for patients with multiple myeloma,” said Dr. Wang. “This is a challenging disease with devastating consequences. While new agents are extending life expectancies, they often have adverse side effects, including severe neuropathy.

Carfilzomib is showing good response rates and an improved side effects profile.” Carfilzomib is now being tested in combination with lenalidomide and dexamethasone in a phase III clinical trial at MD Anderson. Furthermore, the FDA has granted fast track designation for carfilzomib, which will allow for the accelerated approval of this drug for treating multiple myeloma.

Other new drugs for myeloma being tested in clinical trials at MD Anderson include panobinostat, a nonselective histone deacetylase inhibitor; ARRY-520, a kinesin spindle protein inhibitor; and KW-2478, a heat shock protein inhibitor. All of these drugs act to induce cell death through different mechanisms.

Another burgeoning area of multiple myeloma research is genetic profiling. In the past few years, there have been many genetic profiling studies and even a recent report of sequencing the multiple myeloma genomes of 38 patients.

Although these studies are in the early stages, Dr. Wang predicted that genetic profiling will influence practice eventually. In fact, he said that gross genetic features have al ready changed treatments for some patients. For example, multiple myeloma patients whose tumor cells contain chromosome 13 monosomy, 17p deletion, or some chromosome 14 translocations are considered to have high-risk myeloma. For patients with these chromosomal abnormalities, a more aggressive course of treatment usually is recommended. However, more preclinical research and clinical trials will be necessary to determine whether certain treatments are better suited for patients whose tumors have certain genetic characteristics.

Thanks to the breakthroughs of the past decade, patients with multiple myeloma are living longer than ever with better quality of life. Furthermore, new treatments being tested preclinically and clinically—along with further analysis of the genetic profile of multiple myeloma—provide hope for even better outcomes in the future. “We are increasing the rate of complete remissions and prolonging survival,” Dr. Wang said. “But our ultimate goal is to one day cure multiple myeloma.”

Improvements in Stem Cell Transplantation

Over the past 20 years, autologous stem cell transplantation has evolved and is now considered a relatively safe procedure. Although once offered only to younger patients, the procedure is now given to patients up to 80 years old. “Autologous stem cell transplantation is an intense procedure, but it is safe,” said Muzaffar Qazilbash, M.D., an associate professor in the Department of Stem Cell Transplantation and Cellular Therapy. “Our fatal complication rate has consistently been less than 2%. Almost all of our patients fully recover.”

Numerous factors have contributed to improvements in the safety and efficacy of autologous stem cell transplantation. Over the years, oncologists have learned more about the safety of the procedure. Better diagnostic tests have become available to detect infections, and these infections can be treated with better supportive care such as new antibiotics and antifungal treatments. In addition, new antinausea and pain medications are available for managing the side effects of treatment.

Dr. Qazilbash also noted the importance of a team approach to stem cell transplantation. “Older patients may have a history of cardiac or pulmonary disease or renal failure,” he said. “But we have shown that even these patients can safely undergo transplantation as long as you identify these issues and have the patient evaluated by a cardiologist or nephrologist who treats these underlying conditions.”

As a testament to the safety of autologous stem cell transplantation, the majority of patients are treated as outpatients. Dr. Qazilbash said that the only reason for hospital admission would be the occurrence of complications such as fever, neutropenia, or nausea and dehydration.

For more information, call Drs. Muzaffar Qazilbash at 713-563-7508 or Michael Wang at 713-792-2860. For more information about clinical trials in multiple myeloma, visit clinicaltrials.org.

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