Multiple myeloma is a cancer of the bone marrow with devastating impact on seniors. It strikes people at a median age of 71 years and can lead to fatigue and anemia, painful lesions, calcium abnormalities, kidney problems and infection caused by immune deficiency, and “bad bones” that literally fall apart as the cancer “tells” cells to eat bone.

The disease is considered incurable, and conventional therapy results in complete remission in only 5% of patients with overall median survival only about 36 months. Recent clinical trials are offering new hope, though, indicating complete remission rates of 25-30% with median survival exceeding 5 years achieved with a more aggressive approach utilizing higher doses of drugs and stem cell transplants.

“Standard therapies for multiple myeloma really hadn’t improved up until a few years ago, when thalidomide became available,” said David H. Vesole, MD, PhD, FACP, Medical College of Wisconsin Professor of Medicine. “Now we’ve got a couple of targeted chemotherapies that can improve the outcome of the disease and increase survival.

“Increasing survival translates into better quality of life for most of these patients. The usual treatment is to start off with some initial therapy that’s up to the individual doctor. There are a couple of different ‘recipes’ for initial therapy. The one that’s gotten a lot of favor lately, even though it hasn’t yet been proved to be superior in randomized trials, is the use of the drug thalidomide and some kind of steroid. We’ve already done one study with thalidomide and the steroid dexamethasone, and there are other studies going on.”

There are more than 14,600 current cases of multiple myeloma in the US, Dr. Vesole said, representing 1% of all malignancies and 10% of all blood-borne malignancies. For unknown reasons, the incidence of this cancer is twice as high among African-Americans.

High Protein Levels an Indicator

“The myeloma cancer cells themselves don’t actually eat up bone,” said Dr. Vesole. “Cells in our bones form bone and break down bone. We all have that. The way I explain it to patients is that there’s a ‘phone system’ in the myeloma cells that tells the ‘Pac-Man’ cells to eat bone uncontrollably.

“These ‘Pac-Man’ cells, which are called osteoclasts, have voracious appetites. They just hold on and chomp up bone and make holes. It’s as if you can sneeze on someone with this and break all their bones. So, you get bad bone lesions. Most commonly it’s in the back that you get pressure fractures, because of gravity. Patients can get holes in the skull from this disease.”

The most common signs of multiple myeloma, Dr. Vesole said, are anemia or fatigue and painful bone lesions because the bones are already broken or about to be broken. (The “multiple” in multiple myeloma refers to the fact that multiple bones in different parts of the body are involved).

“In some patients the condition gets picked up during routine blood tests,” Dr. Vesole said. “Normal plasma cells make antibodies to infections. Another thing associated with this disease is that these people make antibody-like proteins but there’s no infection, so the levels of the proteins go up. Sometimes incidentally they’ll go to the doctor’s office and find out their proteins are sky-high. Another test can discover a big spike of protein that the patient shouldn’t have, and that’s the monochromal or myeloma protein.”

A Highly Resistant Disease

Multiple myeloma has been very resistant to treatment since the major clinical features of the disease were first described in England around 1850. But recently, as one of several articles on the topic authored or co-authored by Dr. Vesole stated, “tremendous advances have been made in understanding the biology and developing treatments of multiple myeloma.”

“This is a very slow-growing disease,” Dr. Vesole said. “We think that the initial event happens ten to fifteen years before there’s any clinical evidence of it in a patient. These cells often have very complex chromosome abnormalities that evolve over time. They continue to become more and more malignant over time. Many cancers eventually become resistant. In myeloma cells, they’re resistant from the day they walk in the door even though they haven’t been exposed to any chemotherapy.

“The best way I can explain that to a patient is to say ‘if you have an individual who has acute leukemia, and they walk in the door at age 55 and we give them leukemia drugs, the chance of getting complete remission is probably 75-80%. If you walk in the door with myeloma, and we give you myeloma drugs, the chance of remission is only 5% because the cells are already resistant to the drugs.’”

It wasn’t until the mid-1980s that studies showed stronger doses could help overcome multiple myeloma’s inherent resistance to drug therapy, Dr. Vesole said. “We asked if more drugs could pulverize more of these cells, and the answer was ‘yes.’

And we have drugs that we didn’t have then. Thalidomide is now available (although it is not yet formally approved and is in effect used “off label” for multiple myeloma treatment). A new drug that was just approved, called Velcade, has a completely different mechanism from any other drug - it’s an entirely new drug class.”

Stem Cell Transplants Could Lead to Cure

The relative ineffectiveness of older drug therapies helped spur research into stem cell transplants for multiple myeloma, which are now regularly performed, Dr. Vesole said. He is one of the principal investigators in an ongoing National Institutes of Health national trial looking at new “tandem” stem cell transplants.

Instead of a single bone marrow cell transplant to obliterate cancerous cells, the tandem approach uses two transplants in sequence. The first transplant is designed to destroy most of the cancer. The second, performed three to six months later, is directed at “straggling” cancer cells.

The NIH trial is comparing outcomes between two “autologous” transplants, both using the patient’s own cells, and another tandem method using the patient’s cells first followed by a transplant of cells from another donor. A third approach being studied at the Medical College uses high doses of drugs first, followed by one stem cell transplant from a donor other than the patient so that the donor’s immune system can be a source of immune therapy to get rid of any remaining cancer.

“By doing donor transplants, multiple myeloma might be curable,” said Dr. Vesole. “The first reason why we don’t cure it using just the patient’s own cells is that we know we give them back myeloma cells and there’s no way they’re going to clean up the cells they collect. We’ve tried and it doesn’t work.

“The second thing is that some of their cells, even if you give them two different transplants, are either resistant or they’re ‘asleep’ and you don’t kill them and they eventually grow. So if you use a donor you don’t have to worry about giving back cancer cells and a donor immune system can perceive resistant or sleeping cells and still kill them.”

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