We are international
Donate
publications TEXT SIZE   
myeloma today    back

October 2003 Volume 5, Issue 8:
Early studies indicate targeted radioactive drug may expand treatment options for myeloma
By Gregory Wiseman, M.D.
Angela Dispenzieri, M.D.
The studies involve the drug Quadramet, one of a new class of drugs that target radiation directly to bone and spare the rest of the body from exposure.
11.18.03
Gregory Wiseman, M.D.
Nuclear Medicine Specialist
Mayo Clinic
Rochester, Minnesota
Angela Dispenzieri, M.D.
Hematologist
Mayo Clinic
Rochester, Minnesota

The ultimate goal of cancer treatment is to rid the body of every malignant cell so the patient has the best chance for a very good or complete remission.

For more than two years, we have been conducting phase I and II clinical studies with that goal in mind. Our focus: to learn whether combining a targeted radioactive drug with high-dose chemotherapy can enhance the prospect of wiping out all of the destructive myeloma cells without increasing risk to the patient. While it's still too early to pass final judgment, we are encouraged by the results we've seen to date.

Our studies have involved the drug Quadramet; its technical name is "153-samarium EDTMP." Quadramet belongs to a new class of drugs that target radiation directly to bone and spare the rest of the body from exposure. The drug was approved by the Food and Drug Administration (FDA) several years ago for easing pain resulting from cancer spread to bone. It consists of a radioisotope, or radioactive atom, wrapped inside a molecule that binds very tightly to bone. The radioisotope is 153-samarium – an atom whose nucleus contains a total of 153 protons and neutrons – and the wrapper is EDTMP (ethylene diamine tetramethylene phosphonic acid), which binds to bone.

We know myeloma cells are sensitive to radiation. Indeed, until about five years ago, combining chemotherapy with whole-body radiation from an external source was standard practice in myeloma patients undergoing stem-cell transplantation. But the toxicity from chemotherapy combined with whole-body radiation caused more damage to normal organs. So radiotherapy was dropped from the treatment regimen.

The current treatment for myeloma recommends chemotherapy administered intravenously to reach wherever cancer cells may be hiding. To boost the odds that no cancer cell will survive, very high doses of chemotherapy drugs are used. Side effects may result because the chemotherapy drugs target not only cancer cells, but also all fast-dividing cells. Especially vulnerable are the all-important bone marrow blood producing cells that reside in bone marrow and serve our circulatory, blood clotting and immune systems.

To prevent that destruction while still hitting cancer hard, many otherwise healthy myeloma patients undergo a procedure called bone-marrow stem-cell rescue. Stem cells are removed from the patient by a special IV, then frozen and stored. After the patient has completed the chemotherapy treatments, the stem cells are intravenously infused back into the patient to begin the process of producing healthy blood cells.

There is no question that stem-cell transplantation improves a myeloma patient's chances of survival. But unfortunately, almost every transplant patient eventually suffers a relapse. The most likely reason for the relapse is that the high-dose chemotherapy given before the stem-cell transplantation failed to kill all the myeloma cells in the patient's bone marrow.

Now a new class of radionuclide therapy drugs that targets radiation to specific sites of cancer in the body is being developed. Quadramet is one of the new targeted radiation drugs. Its availability is causing researchers to look again at the use of radiation for treatment of myeloma.

With Quadramet, molecules that do not bind to bone are rapidly excreted. This means levels of unwanted radioactivity delivered to the rest of the body remain low and do not damage organs or other parts of the body where there is no cancer. The drug has an excellent safety record when used for treating pain from other cancers spread to bone. Its chief side effect is that at high doses it tends to deplete bone marrow cells. Interestingly, this drawback could be a plus for myeloma therapy because our aim is to kill diseased bone-marrow cells before intravenously reinfusing the patient with his or her own stem cells to make new, healthy bone-marrow and blood cells.

In early 2000, we began a phase 1 clinical study to determine how much Quadramet we could give patients without further harming their bone marrow. We treated 12 myeloma patients with increasing doses of Quadramet. The regimen was basically the same for all patients: after undergoing bone-marrow stem-cell collection, each patient received a 30-minute infusion of Quadramet. Twelve days after that, each patient got an approximately 60-minute infusion of the standard dose of melphalan (the chemotherapy drug most commonly used for transplantation of myeloma). Then two days later, each patient received intravenously his or her own stem cells. This reinfusion procedure took about 15 minutes to a half-hour. Patients were monitored throughout the entire process for toxicity and to confirm that the newly transplanted cells had started functioning in the bone marrow.

We found that giving Quadramet plus standard chemotherapy before stem-cell transplantation produced no greater toxic effects than chemotherapy and transplantation done without radiotherapy. This successful outcome prompted us to proceed to our phase II study, which involved 46 patients.

Because every patient absorbs and metabolizes drugs somewhat differently, for our phase II study we gave each patient an individually measured amount of Quadramet. The dose level was based on "test dosing" to determine how much Quadramet each patient should have to safely target the same radiation to the bone marrow in each patient.

In both studies, patients were evaluated 100 days after their stem-cell transplants for evidence of residual myeloma. Our goal was to see at least 50 percent of the patients achieve either a complete response or a very good partial response. We're pleased to report that we appear to be seeing that outcome.

Both our phase I and phase II studies are now completed and all of the data will be evaluated later this year. Then we will have more statistically valid evidence about the use of Quadramet for treatment of myeloma.

At this juncture, we know that Quadramet given prior to melphalan chemotherapy does give significantly more treatment to the myeloma cells than with the chemotherapy alone and currently we have not seen any additional toxic effects. Our measurements verify that the radiation delivered by Quadramet to organs other than bone was well within safety limits.

While we're enthusiastic about the promising indications, we want to temper our enthusiasm with this caution – these are early results. More research through a randomized phase III clinical study needs to be conducted to conclusively determine the value of Quadramet for treatment of myeloma. Hopefully, future studies will substantiate these early results and take us another step forward in our efforts to combat myeloma, help patients live longer and improve the quality of their lives.

Note: Quadramet is a product of Cytogen, Inc.


 related articles