Progress in treating multiple myeloma: New respect for a simple old treatment
December 16, 2009 07:21 by Dr. Lorne Brandes
Multiple myeloma (which means “many marrow tumours”) is a type of bone marrow cancer involving plasma cells that normally produce antibodies to protect us from infection. Because malignant plasma cells don’t function well, patients with myeloma may suffer frequent bouts of bacterial and viral illness.
Moreover, as they divide, the cancerous plasma cells form chemical-secreting tumours that literally dissolve the bone around the marrow cavity, causing painful holes that can easily fracture. Almost always a fatal disease, multiple myeloma used to kill its victims within a few months to a year.
Interestingly, in 1949, Dr. Carman Weder, a Saskatoon physician, was the first to observe that the chemical, urethane, was effective in a patient with myeloma. Ultimately, the drug was abandoned after a clinical trial in 83 patients showed it to be both toxic and ineffective as compared to a placebo.
The modern era in myeloma treatment arrived with the synthesis, in the early 1950s, of a drug, called melphalan, at London’s Chester Beatty Research Institute (now called The Institute of Cancer Research).
Melphalan was first tested in humans by my mentor at the Royal Marsden Hospital, Dr. David Galton (see my post on Dr. Galton). He found that it predictably killed malignant plasma cells in the marrow, helped affected bones to heal, and appeared to prolong life. Melphalan was even more active when given along with a steroid drug, called prednisone. That combination, given the acronym “MP”, increased survival by two to three years, on average. As a result, MP became the gold standard against which any new treatment for myeloma was, and continues to be, compared.
Yet, although still in use all these years later, melphalan has a dark side. Because it is also very toxic to normal blood cells in the bone marrow, it increases the risk of infection and bleeding. This can be a major problem, especially in older people, in whom the disease is most frequent. As fate would have it, in the early 1980s, I stumbled across a much gentler drug treatment for myeloma.
Confronted with a gentleman whose bone marrow could not tolerate melphalan, I decided to substitute another active drug, called cyclophosphamide. However, because his blood counts were already perilously low and he needed transfusions, I settled on a much smaller single intravenous (IV) dose than usual. He was also given a prednisone pill to take every other day, rather than daily, to keep side effects to a minimum.
“Come back next week so we can check your blood,” I somewhat nervously advised after his first treatment.
When he reported back seven days later, everything was fine. His blood cells were holding their own. We gave him the same small IV dose of cyclophosphamide again and continued the prednisone pill every other day. With each weekly visit and treatment came an improvement in his condition. After three months, not only was he feeling much better and continuing to tolerate the drugs well, he no longer needed transfusions. All his blood counts had gone up while the plasma cells in the bone marrow were down by over half
"Can I tell you about a patient of mine?” I asked my illustrious boss, the late Dr. Lyonel Israels. An internationally-renowned hematologist, Lyonel had also spent time with Galton, in 1955, helping him develop another new cancer drug, CB1348, later called chlorambucil.
After listening to my story, Lyonel was eager to try the treatment on one of his own elderly patients who had stopped MP because of the side effects. A few months later, she too had improved significantly, and without appreciable toxicity.
Over the next four years, the two of us treated 20 patients with this simple regimen of weekly low-dose IV cyclophosphamide and alternate day oral prednisone; 10 had a major response while an additional five stabilized or improved.
"In myeloma, less is more," Lyonel quipped.
A country-wide trial followed, carried out by the National Cancer Institute of Canada. In confirming our findings, the researchers concluded that “the regimen of weekly cyclophosphamide and alternate-day prednisone may be as effective as more aggressive regimens in the treatment of patients with myeloma who have failed MP therapy.”
Yet, aside from a few Canadians, and David Galton and his colleagues in the U.K., nobody else seemed to be paying attention. The “zeitgeist” in the late 1980s, especially among American oncologists was that, where myeloma treatment was concerned, the more aggressive the better.
“Since it gets no respect, we should call it the ‘Rodney Dangerfield regimen’,” I lamented to Lyonel and my other Winnipeg colleagues.
And so it remained for the next 20 years, as stronger and stronger drugs were tried with much toxicity but little improvement in the outcome. Bone marrow transplants were pursued with modest success, but the mortality rate from the procedure remains considerable and most patients ultimately relapse.
Then, in 2005, came vindication… suddenly and without warning (at least to me). A study, published in the Mayo Clinic Proceedings, found that weekly cyclophosphamide and alternate-day prednisone (CP) “first introduced by Brandes and Israels” was “an effective, well-tolerated and convenient regimen” in patients with multiple myeloma who had failed a bone marrow transplant! Thirty-six of 66 patients responded to CP with a median survival of 28.6 months.
Subsequently, a 2008 study combining the CP regimen with bortezomib (Velcade) found “an unprecedented response rate [more than 50% complete remissions] and encouraging one-year survival [83%] in relapsed/refractory patients with [multiple myeloma].”
Now, as we head into 2010, myeloma patients have increasing reason to be optimistic, according to a statement just issued by the International Myeloma Foundation. Among the promising treatments cited by the foundation: a variation of the CP regimen, combined with bortezomib and another promising drug, called lenalidomide (Revlimid).
Respect has come late for our simple CP regimen. But come it has. How do I feel? To quote Jackie Gleason, “How sweet it is!”