In the current issue of Nature Reviews Clinical Oncology, Dr. James R. Berenson from the Institute for Myeloma and Bone Cancer Research discusses the history of Velcade (bortezomib) and the drug’s current role in treating newly diagnosed multiple myeloma in patients who are not candidates for high dose therapy.

Until recent years, the only treatment options available for patients unable to receive high dose therapy were standard chemotherapy and steroid regimens used in the conventional treatment of tumors. The most common regimen, a combination of the chemotherapy agent melphalan (Alkeran) and the steroid prednisone, led to response rates of only 50 percent.

The development of new agents specifically for the treatment of myeloma, such as Velcade and Revlimid (lenalidomide), and the new use of the older drug thalidomide (Thalomid) have now given patients new options that generally yield better responses.

For instance, early preclinical studies in 2003 showed that Velcade alone not only killed myeloma cells but actually enhanced the effectiveness of standard chemotherapy and steroid agents. Also, a Phase 1/2 study in 2006 that combined Velcade with the chemotherapy agent melphalan led to higher response rates in patients with relapsed or refractory myeloma than treatment with either Velcade or melphalan alone.

Velcade, which works by inhibiting proteasome functions to stop the growth and survival of cancer cells, was first approved by the FDA in 2003 for the treatment of relapsed or refractory patients who had received two prior treatments. Only in June of 2008 was Velcade approved for use in newly diagnosed patients.

The recent approval followed the results of the large Phase 3 VISTA trial that compared newly diagnosed patients treated with melphalan and prednisone (MP) either alone or with Velcade. Results from the randomized trial showed that adding Velcade to the MP regimen increased the time to disease progression, increased the time a patient remained disease-free, and improved complete response rates and overall survival.

Specifically, a marked increase in complete response was observed for patients with Velcade added to the regimen (33 percent) versus patients treated with MP therapy alone (4 percent.) There was also a 36 percent decrease in risk of death at three years when Velcade was added.

In addition, clinical trials in the past few years have shown that Velcade, in combination with alkylating agents alone, also leads to improved survival in relapsed or refractory myeloma patients. Alkylating agents, such as commonly used prednisone as well as cyclophosphamide (Cytoxan) and Treanda (bendamustine), bind to a tumor cell’s DNA and prevent the cell from replicating. A similar synergistic effect such as the one observed between Velcade and melphalan was seen with Velcade and these agents.

While the overall clinical data support the use of Velcade, the author goes on to discuss the issue of toxicity and studies that are examining new combinations to minimize toxic effects. Because myeloma is incurable, with many patients experiencing multiple relapses, long-term toxicity is an issue. Observed high-response rates that are only brief in time have less meaning when coupled to toxic effects, risk of death, and quality of life issues.

Because of the enhancement of activity that Velcade has demonstrated with various chemotherapy agents, lower doses are being studied. As Velcade is paired in clinical trials with other novel drugs such as thalidomide and Revlimid, the author warns that toxicity issues will have to be addressed in these studies as well.

For example, in radiation therapy Velcade shows radio-sensitizing effects which could cause increased adverse effects and organ damage. However, if radiotherapy is targeted to the tumor site only, Velcade could enhance the effects of radiation due to increased radio wave sensitivity without possible organ risk. Preclinical and clinical studies using the radioactive drug Quadramet (samarium-153 lexidronam) have shown this effect.

Overall, the author sees the large VISTA trial as only the beginning for newly diagnosed and current myeloma patients. With the number of treatment options increasing just in the past year, patients will live “longer, and more fulfilled, lives.”

For more information, please see the full article in the May issue of Nature Reviews Clinical Oncology (subscription required).