First of new class of drugs treats multiple myeloma


Millennium Pharmaceuticals' Velcade is approved to treat multiple myeloma.



First of new class of drugs treats multiple myeloma

Most of us know that multiple myeloma is a disease of the blood, but unless your specialty is oncology, you may not have given the disease much more thought than that. Specifically, multiple myeloma is a malignancy that affects a specific set of white blood cells called plasma cells. The primary job of plasma cells is to produce immunoglobulin (antibody) molecules; immunoglobulins, of course, are necessary to fight infection and disease. In multiple myeloma, plasma cells produce an abnormal form of immunoglobulin, called M protein.

Like all malignancies, multiple myeloma is characterized by both uncontrolled cell growth and the ability to metastasize. Eventually, malignant plasma cells overgrow and replace normal white blood cells within the immune system. Since malignant cells are unable to fight pathogens, patients with multiple myeloma are susceptible to a variety of infections, including those of the lung and urinary tract. Additionally, malignant cells can metastasize by attaching to organs within the body. Secondary bone tumors are particularly common. About 70% of patients with multiple myeloma have bone pain caused by multiple bone lesions.

Although a variety of chemotherapeutic and radiation treatments can be tried in the fight against multiple myeloma (see the National Comprehensive Cancer Network at for a complete listing of clinical practice guidelines for multiple myeloma as of 2002), the unfortunate reality is that only 30% of patients with the disease survive for more than five years. Even though only 15,000 new cases are diagnosed each year, 2% of all cancer-related deaths are attributed to multiple myeloma. Clearly, with such a bleak prognosis, any new therapeutic advance offers a ray of hope to patients suffering from this malignancy.

One hopeful candidate in the fight against malignant myeloma has just arrived. Last month, the Food & Drug Administration gave approval to Millennium Pharmaceuticals for its drug bortezomib (Velcade). This is the first new drug approved for multiple myeloma in more than a decade. Granted priority review by the FDA, bortezomib was rushed through the approval process in just over two months.

Bortezomib is the first drug in a new class of compounds called proteosome inhibitors. The 26S proteosome, a large enzyme complex found in every cell of the body, is involved with numerous cellular processes, including those that play a role in degrading proteins that control the cell cycle. By inhibiting the proteosome, bortezomib interrupts pathways related to growth and survival of cancer cells. Although both cancer cells and noncancerous cells have proteosomes and are susceptible to the drug, bortezomib seems to have profound, preferential effects for disrupting the survival of multiple myeloma cells, compared with most normal cells.

Bortezomib is currently approved for patients with multiple myeloma who have failed at least two therapies and whose disease has progressed while using the last therapy. In clinical trials, 1.3 mg/m2 was given intravenously twice weekly for two weeks followed by a 10-day rest period. Per protocol, this cycle was continued for a maximum of eight treatment cycles, although patients who responded were permitted to continue therapy in extension trials.

The drug received FDA approval on the basis of a multicenter phase II open-label single-arm trial in patients who had previously failed at least two prior therapies (median of six therapies). Additionally, 91% of study participants were refractory to their most recent therapy. Overwhelmingly, the response rate to bortezomib was 27.7% for complete responders and 17% for partial responders. Nearly one out of every five patients experienced a clinical remission. According to Fabio Benedetti, VP of global medical affairs at Millennium, "Velcade is a completely new approach to treating multiple myeloma and is very exciting for patients who really need it." It is important to note that, in trials, effectiveness of bortezomib was based upon response rates; it isn't yet known if bortezomib improves survival.

Timothy Tyler, Pharm.D., director of pharmacy services, Comprehensive Cancer Center at Desert Regional Medical Center, Palm Springs, Calif., has been involved with bortezomib clinical trials. He said, "Velcade looks like an incredibly effective therapy. There are compelling data for use of this product in patients who had nothing else left. It is exciting to have this drug as another tool."

Adverse events are quite common among those taking bortezomib, but, according to Benedetti, the side effects seen in trials were predictable and manageable. Adverse events included asthenia, gastrointestinal disturbances, thrombocytopenia, anemia, peripheral neuropathy, and fever.

Tyler is optimistic that some of these adverse effects, especially neuropathies and bone marrow suppression, may be less apparent when bortezomib is used in drug-naive patients. According to Tyler, "When looking at patients that have already tried everything else, it's hard to determine the exact side-effect profile."

Three things are especially exciting about the new drug: the extent and frequency of clinical responses (some complete responses), the durability of remission lasting 12 months or longer, and improved quality of life. So far, data suggest that bortezomib can either restore sensitivity or overcome resistance in cells previously resistant to chemotherapeutics. As a result, new trials are under way to determine if bortezomib can be even more effective if used earlier in treatment regimens. Additionally, the drug is currently in phase II clinical trials for treating other cancers like non-small cell lung cancer and metastatic colorectal cancer. If data from pending clinical trials are also positive, bortezomib could be added to many clinical protocols and change current chemotherapeutic paradigms.

Kelly Dowhower Karpa, R.Ph., Ph.D.

The Author is a clinical writer based in the Philadelphia area.


  • Use caution or avoid driving automobiles following the use of Velcade, due to the possibility of fatigue, dizziness, fainting, or blurred vision.

  • Drink plenty of fluids to avoid dehydration associated with gastrointestinal upset like vomiting or diarrhea.

  • Notify physician if symptoms of peripheral neuropathy occur or worsen in severity.

  • Velcade is contraindicated in those hypersensitive to boron or mannitol.

Kelly Karpa. First of new class of drugs treats multiple myeloma.

Drug Topics

Jun. 16, 2003;147:21.

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