From OncoLog, July/August 2008, Vol. 53, No. 7-8
Multiple Myeloma: Increasing Response, Remission, and Survival Rates in a Complex Disease
By John LeBas
Fifty years ago, a diagnosis of multiple myeloma meant the patient could expect a short survival period plagued by pain from bone lesions, disability, and fatigue. Progress against this plasma cell cancer was slow for several decades, and the few clinical breakthroughs sometimes proved dangerous and were suitable for only a minority of patients.
Yet in recent years, novel drugs and rational combinations of therapeutic agents have yielded better response and remission rates with less toxicity, and the end result has been longer overall survival. “The median overall survival duration was less than 2 years 50 years ago, before we had any chemotherapy for multiple myeloma. Now, the median overall survival duration is about 5 years for all patients, with perhaps 20% living for more than 10 years,” said Raymond Alexanian, M.D., a professor in the Department of Lymphoma and Myeloma at The University of Texas M. D. Anderson Cancer Center. “And the longer we can control these patients’ disease, the greater chance they have of outliving it.”
Developing successful treatments has been an exercise in perseverance, and although specialists at M. D. Anderson are happy about the progress, they are quick to explain that much work remains. A cure is still elusive, and current therapies are focused on inducing partial or complete remission and sustaining that remission as long as possible.
“Just about all multiple myeloma patients who achieve remission will relapse. And the next time we give them treatment, the disease is usually a little bit more resistant to therapy,” said Robert Orlowski, M.D., Ph.D., an associate professor and chief of the Myeloma Section in the Department of Lymphoma and Myeloma at M. D. Anderson. “Also, therapy that is effective against myeloma cells must sometimes be given at doses that are somewhat damaging to healthy tissues. Therefore, our goal is always to reduce the amount of myeloma cells in the bone marrow, hopefully to undetectable levels, with a minimum overall amount of therapy. Fortunately, we have identified combinations of agents that are increasing the effectiveness of both frontline and later-line therapy.”
Better therapeutic agents
In the past 5 years, the U.S. Food and Drug Administration has approved four therapeutic agents for multiple myeloma: bortezomib (Velcade), thalidomide (Thalomid), lenalidomide (Revlimid), and a combination of doxorubicin encapsulated in a liposome (pegylated liposomal doxorubicin, Doxil) and bortezomib. These agents’ mechanisms of action vary. Bortezomib is a proteasome inhibitor that induces apoptosis (death) of myeloma cells; thalidomide and lenalidomide are immunomodulatory agents that can slow or stop myeloma reproduction; and doxorubicin inhibits the DNA functions of cancer cells and induces apoptosis.
While each of these agents has individual activity against multiple myeloma, it’s the enhanced activity gained by combining them with older, established agents, such as the glucocorticoid dexamethasone and the alkylating agents melphalan and cyclophosphamide, that has produced the most headway against the disease in recent years. “Such combinations produce more effective anti-myeloma activity with less added toxicity,” Dr. Alexanian said. Also, the newer agents can sometimes resensitize myeloma that has become refractory to previously administered drugs. And both lenalidomide and bortezomib, relatively new drugs, yielded such positive results as second-line therapies that they are rapidly becoming part of standard frontline treatment combinations.
Safer stem cell transplantation
To be most effective against multiple myeloma, some agents, especially melphalan, must be given at high doses that are likely to damage or destroy the bone marrow. In the past, the aggressive nature of this approach decreased the proportion of patients to whom it could be applied. But today, because of improvements in supportive care and a better understanding of which patients benefit most, about two-thirds of patients are candidates for intensive therapy supported by autologous stem cell transplantation, also known as stem cell rescue. Stem cells harvested from patients’ bodies before the beginning of therapy are reintroduced after therapy to generate new marrow.
When autologous stem cell transplantation was first introduced, it was very risky. Now, techniques allow stem cells to be separated from other blood components and counted to ensure an adequate number have been collected. Thus, the risk has been greatly diminished; death from autologous stem cell transplantation now occurs in less than 2%–3% of patients.
Treatment strategies
When pain or dangerous side effects are present, as they are in about 80%–85% of newly diagnosed patients, it is important to rapidly achieve complete remission, or as close to it as possible, Dr. Alexanian said. Not only does a quick and complete remission help the patient avoid repeated cycles of potentially toxic therapy, but remission status after initial therapy is also a predictor of how long the patient will live. Complete remission is associated with a median overall survival of 10 years, while patients who achieve partial remission or no remission have median overall survival durations of 5 years and 2.5 years, respectively.
Usually, the first step in treatment is to try to induce remission through several rounds of chemotherapy at the highest dose acceptable for the patient. If the patient is a candidate for autologous stem cell transplantation, more intensive therapy can be given. Recently, combinations of bortezomib and lenalidomide with older drugs (bortezomib plus dexamethasone, bortezomib plus thalidomide and dexamethasone, and lenalidomide plus dexamethasone) have been shown to produce the best rates of complete remission in patients who also received a stem cell transplant, Dr. Orlowski said. Complete remission can be achieved in at least 35%–40% of patients who receive both drug therapy and a transplant, and partial remission is seen in up to 95% of patients.
Unfortunately, not every patient is a candidate for stem cell transplantation. About 30% of multiple myeloma patients cannot undergo a transplant because their age or other medical problems increase the risk of the procedure beyond a safe range or because of socioeconomic factors. For this “nontransplant” population, less toxic drug combinations are available, Dr. Orlowski said. They include a melphalan-prednisone-bortezomib combination and a melphalanprednisone-thalidomide (MPT) combination. In a recent clinical trial, treatment with MPT in the nontransplant population increased overall survival by 1.5 years over the old standard, melphalan plus prednisone. Without a stem cell transplant, complete remission can be achieved in 15%–30% of patients.
For the 15%–20% of patients who are not experiencing symptoms at the time of diagnosis, no immediate treatment may be needed. Rather, these patients may be monitored closely for several years, with therapy delayed until a risk of complications from the disease arises, at which point new, more effective therapies may be available.
Future directions
Despite the recent advances against multiple myeloma, there is much room for improvement, said Dr. Orlowski, who believes more widespread clinical testing is key to identifying future standard therapies. He cites bortezomib as an example of a breakthrough agent that first was tested in patients with relapsed and treatment-refractory multiple myeloma and then was found to be effective against newly diagnosed disease. Without clinical trials, researchers would not have known whether it was worth the risk to make bortezomib a frontline therapy.
“When we move these active experimental drugs such as bortezomib into the front line, what we don’t know is whether they will still be as effective once the disease relapses,” said Dr. Orlowski. “The question is always, are we burning some bridges by using these therapies up front, in newly diagnosed multiple myeloma? I generally think it’s important to take that chance, because that’s when we have the best possibility of achieving a durable remission and a longer survival.”
Clinical trials are also needed to help validate research into multiple myeloma’s genetic signature. It is now believed that the disease comprises seven or eight distinct subtypes defined by different genetic abnormalities. For example, up to half of all cases are associated with chromosome 13 monosomy, which predicts poor outcome in multiple myeloma patients. “Even though patients with chromosome 13 monosomy and certain translocations benefit less from the current standard therapies, they might benefit from having novel therapies such as bortezomib and lenalidomide in their treatment regimens,” Dr. Orlowski said. “We want to identify appropriate therapy for patients based on the genetic subtype of their myeloma. Doing so could help us achieve greater response and remission rates with initial therapy, which will then lead to longer survival for more patients.”
Characteristics of Multiple Myeloma Multiple myeloma (plasma cell cancer) progresses slowly, with the time from first cancer cell to diagnosis typically about 20 years. However, the disease is usually considered advanced and is causing serious health problems by the time it is discovered. Diagnosis usually occurs between the ages of 55 and 80 years. As many as 65,000 patients in the United States are living with the disease, and more than 17,000 new cases are expected to be diagnosed this year. Major symptoms include:
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For more information, call Dr. Orlowski or Dr. Alexanian at 713-792-2860.
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