Multiple myeloma is still an incurable disease. However, more and more new drugs appear, giving very good therapeutic effects even in patients in whom the best available therapies have ceased to work, assess hematologists.
The 54th annual meeting of the American Society of Hematology (ASH), held in the second week of December 2012 in Atlanta, Georgia, USA, presented the results of studies on at least 20 new drugs that are being tested in patients with multiple myeloma. However, many of them concerned the very early stage of testing.
They live longer and better
Currently, there are approximately 1 million people in the world suffering from myeloma, which is the second most common type of blood cancer. In Poland, this number is estimated at over 10. Cancer originates from mature B lymphocytes formed in the bone marrow (so-called plasma cells), which produce antibodies used to defend the body, e.g. against infections.
The last decade has seen tremendous progress in treating patients with multiple myeloma, said Dr. Meletios A. Dimopoulos of the Alexander Hospital in Athens, Greece, at a press conference accompanying the annual ASH meeting. The researcher reminded that today the average patient with this cancer will live 7-8 years, while 10 years ago his survival time was estimated at 1,5 to 3 years.
This progress also brought results in Poland. “When I started working in the hematology clinic in 1991, it was reported in the literature that the average survival of patients with multiple myeloma was at most 2,5 years. Now the patients I observe live at least 5-7 years as a standard, that is 2-3 times longer “- said Prof. Piotr Rzepecki, head of the Department of Internal Diseases and Hematology of the Military Medical Institute in Warsaw.
At a media workshop organized in Atlanta, prof. Brian Durie of Cedars-Sinai Medical Center in Los Angeles, California explained that the effectiveness of myeloma treatment has improved so much because, in addition to autologous blood stem cell transplantation used since the 90s, doctors have been given a new weapon in the fight against the disease. These were new drugs from two groups: immunomodulators, which include thalidomide and lenalidomide, and a proteasome inhibitor called bortezomib.
These drugs (and especially the use of their combinations) prolonged the life of mainly elderly patients, over 65 years of age, who are not eligible for transplant (and they account for about two-thirds of all myeloma patients).
The quality of life of patients has also improved, because the new drugs have fewer troublesome side effects, thanks to which patients can take an active part in their professional, social and family life.
Stubborn disease
“However, over time, myeloma becomes resistant to today’s most effective drugs, such as bortezomib and lenalidomide. Unfortunately, the prognosis for these patients is very bad. The median of their survival (the time until half of the patients will be alive – PAP) is 8-9 months ”- explained Dr. Dimopoulos.
This is due to the fact that the disease is constantly evolving, because even after successful therapy, mutant cells that are resistant to it retain (or appear over time). And they are the cause of relapses, the researchers explained. The fight against myeloma by prof. Paul G. Richardson of the Dana Farber Cancer Institute in Boston (Massachusetts, USA) compared to trying to catch a snake in a basket. “If it succeeds, you have to sit on this basket all the time so that the snake does not come out of it. And it can be done thanks to new and better tolerated drugs and their combinations ”- emphasized the researcher during the workshop for the media.
Currently, the most advanced research is ongoing into the latest generation of an immunomodulating drug called pomalidomide. Drugs from this group inhibit the development of myeloma in several ways – not only do they directly kill cancer cells, but also stimulate the immune system to fight them and change their environment to a less friendly one.
However, pomalidomide appears to have other mechanisms of action. Phase 3 Baana presented in Atlanta by Dr. Dimopoulos, showed that the use of a combination of pomalidomide and a low-dose steroid called dexamethasone can improve the prognosis of patients with refractory and relapsed myeloma.
The study involved 455 patients who had previously undergone 5 different treatments. Pomalidomide and low doses of the steroid were administered to 302 patients, and the rest were given high doses of the steroid – dexamethasone (which is currently used as a palliative drug in patients with refractory myeloma). Due to the progression of the disease or death, it took 25% to be analyzed. patients in the group treated with high doses of steroid and 45 percent. patients in the pomalidomide low dose steroid treatment group.
As calculated by the scientists, the median survival in the group treated with high doses of dexamethasone was about 8 months, and in the group treated with the combination of two drugs, it has not been determined yet, because the patients are still alive. Scientists estimate, however, that it should last 11-12 months. “This means that pomalidomide in combination with low doses of dexamethasone is a better combination than the current therapy. Therefore, we believe that it may become the new standard of treatment for these patients, ”assessed Dr. Dimopoulos.
Based on these results, the study’s independent oversight committee recommended that patients treated with high doses of dexamethasone be switched to the two-drug combination. The most common side effect in people taking pomalidomide was neutropenia (i.e. a shortage of important body defense cells, granulocytes). However, scientists know how to deal with it, because other drugs in this group also have similar effects.
Paula van Riper from New Jersey, who has had myeloma for 13 years, is now using pomalidomide with dexamethasone as her disease has become resistant to the latest drugs available. As she confessed during a workshop for journalists, this is the most gentle therapy she has ever used. He only feels a little tired and some gastric ailments. However, he goes to work every day and can function normally. “In therapy, it is important not only to live longer, but also to live well, and new drugs allow you to enjoy your life” – she emphasized.
According to prof. Robert Orlowski of the University of Texas MD Anderson Cancer Center in Houston (Texas, USA), the US Food and Drug Administration (FDA) is likely to register pomalidomide in February 2013.
Quick registration
The haematologist recalled that in July 2012, the FDA approved a new myeloma drug called carfilzomib. This medicine, like bortezomib, works by blocking a structure in cells called the proteasome that deals with the digestion of proteins that they don’t need. Inhibiting this process leads to the accumulation of various proteins in myeloma cells, which causes “these cells to become very stressed and commit suicide,” explained Prof. Orlowski.
One of the advantages of carfilzomib is that, compared to bortezomib, it causes polyneuropathy in a much smaller percentage of patients, i.e. damage to the peripheral nerves, which in extreme cases can even cause disability.
The drug was approved on the basis of phase 2 trials only, as it gave good results in patients with myeloma resistant to the latest drugs used, i.e. bortezomib and lenalidomide or thalidomide. And it is indicated for this group of patients. “Replacing bortezomib with its newer equivalent improves the length and quality of life of patients” – explained Prof. Orlowski.
According to him, the results of the study in a group of patients with refractory and relapsed myeloma, in whom carfilzomib was used together with pomalidomide and dexamethasone, are also very promising. As many as 56 percent. patients who had previously undergone at least 6 treatments have responded to this treatment. “These new drugs allow long-term benefits even in high-risk patients” – emphasized the expert.
Necessary new drugs
“The fact that myeloma continues to relapse is a big challenge for doctors, but the good news is that each new drug helps to better cope with the disease,” said Prof. Richardson. Hence, scientists continue to develop medications for myeloma. Currently, preparations with completely new mechanisms of action are also being tested. Among the most important of them, prof. Richardson listed two monoclonal antibodies – elotuzumab and daratumumab. The first one acts on the CS1 glycoprotein, which is present in very large amounts on myeloma cells. It is found in small amounts on immune cells known as natural killer (NK) cells and hardly ever on other healthy cells in the body.
According to the expert, the addition of this antibody to lenalidomide and dexamethasone turns out to be a very effective combination in patients with refractory myeloma. The second monoclonal antibody, daratumumab, destroys myeloma cells by binding to the CD38 protein on their surface. Good results have also been obtained in studies where a drug called vorinostat was added to bortezomib, lenalidomide and dexamethasone. Research is also underway on the first oral proteasome inhibitor, so far referred to as MLN9708. The existing inhibitors are administered by injections (intravenously or subcutaneously). Dr. Shaji K. Kumar from the Mayo Clinic in Rochester (Minnesota) emphasized at a press conference that the drug in an oral form can further improve the quality of life of patients.
Joanna Morga (PAP)
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