Bortezomib was recently approved by the FDA for the treatment of multiple myeloma in patients who have received at least two prior treatments and have had disease progression on the most recent treatment. Approval was based on response rates; although thus far, no benefit on survival has been reported in a clinical trial, a randomized Phase III study is ongoing and should be completed later this year.
FDA approval of the drug, marketed as Velcade by Millennium Pharmaceuticals, was granted on an accelerated approval basis and was based primarily on results of a Phase II open-label, single-arm study (SUMMIT) showing that the drug was safe and achieved significant response rates in approximately 27% of 202 patients with relapsed and refractory multiple myeloma and who had received at least two prior therapies (median number of six).
Velcade, the first proteasome inhibitor to be approved, is the first new treatment for multiple myeloma in more than a decade. The drug's development was made possible by improved understanding of the molecular biology of multiple myeloma. The proteasome is an enzyme complex body that plays an important role in degrading proteins that control the cell cycle and cellular processes. Inhibition of the proteasome disrupts numerous biological pathways, including those related to the growth and survival of cancer cells.
Two clinical investigators involved in the development of bortezomib were asked what clinicians should know as they begin using the drug. Both are at the Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute—Kenneth Anderson, MD, the Center's Director, and the Kraft Family Professor of Medicine at Harvard Medical School; and Paul G. Richardson, MD, Clinical Director of the Myeloma Center and an instructor in medicine at Harvard Medical School.
Velcade is the first proteasome inhibitor to be approved by the FDA. Are there others in development?
Dr. Paul G. Richardson: Velcade is the only proteasome inhibitor that has been found to be clinically useful. In contrast with Velcade, other proteasome inhibitors used in the laboratory setting are not selective or reversible and thus have not been brought forward to the clinical setting.
How does Velcade exert its action?
Dr. Richardson: Proteasome inhibition blocks the breakdown of key proteins that control various aspects of cell behavior. Specifically, if not blocked, degradation of certain proteins would allow the cell to resist stress and proliferate. If these pathways are disrupted, then the cancer cell is less able to survive injury and apoptosis follows. Velcade also directly promotes apoptosis, but it is not clear at this time whether this occurs via proteasome inhibition alone or through other pathways.
What can patients expect to gain from Velcade?
Dr. Kenneth Anderson: The Phase II trial showed that about one third of patients with relapsed/refractory multiple myeloma responded, including a fraction of patients with complete response. These responses can be durable. Overall survival was 16 months, instead of six to nine months as predicted. Patients can also expect to gain clinical benefit, including improved quality of life, increased hemoglobin, decreased need for transfusion, normalization of the serum immunoglobulin level, and stabilization of renal function.
Dr. Richardson: In the clinical trial, a meaningful response was seen in about one third of heavily pretreated patients in whom other treatments had failed. It is important to point out that medical jargon often uses the terminology of patients failing treatments, whereas in reality it is treatments that fail patients; patients don't fail treatment.
How is the drug administered?
Dr. Richardson: Velcade is given over three to five seconds by IV push in four injections every two weeks, followed by a 10-day rest, and then another cycle of treatment ensues; this is continued for six months. It is important that the injections be given 72 hours apart.
Patients in our study were on concurrent bisphosphonates but not on other chemotherapy, with the option to add dexamethasone permitted for patients who did respond satisfactorily to Velcade alone. This was based upon the preclinical observation that steroids were at least additive with Velcade in work led by my colleague Teru Hideshima, MD, PhD.
In both the SUMMIT trial and the smaller CREST trial of Velcade in patients with relapsed, refractory, and relapsed disease, respectively, steroids were used successfully in some patients who had not experienced optimal response to Velcade alone. Significant benefit was seen in approximately 20% of patients in the SUMMIT study and in one third of patients in the CREST study (who were less heavily pretreated than their SUMMIT counterparts).
What are the side effects?
Dr. Anderson: The most common side effects were thrombocytopenia and neuropathy in the large Phase II trial, but most of the patients had these as preexisting conditions. Our hope is that as we begin to use the drug earlier in the course of disease, we will see a lower incidence of these effects.
In the Phase II trial, of 39 patients with no neuropathy at entry, only one developed Grade 3 neuropathy on Velcade. There will always be side effects with a drug, but the true incidence won't be known until we use the drug earlier in the course of the disease.
Dr. Richardson:More common side effects that occurred in the SUMMIT trial were nausea, constipation, loose stool, fatigue, peripheral neuropathy, anorexia, transient thrombocytopenia, and skin rash. Less common side effects included transient but mild drops in blood pressure, skin rash, and low serum sodium.
As symptoms dictate, we give ondansetron for nausea, normal saline to optimize hydration, laxatives for constipation, antidiarrheals for loose stool, and G-CSF for neutropenia. If significant neuropathy occurs, dose reduction is indicated, and it is important to initiate this promptly.
Dr. Richardson: Velcade needs to be given with careful monitoring, as side effects do occur, but they are usually manageable with prompt intervention. Provided the patient is tolerating the drug, my experience is that therapy should be planned for up to six months in the first instance.
Most responding patients show clinical evidence of response within six to eight weeks, but some patients have a later response. In fact, I have seen patients stabilize and then have a meaningful response a few months later to Velcade alone. The addition of dexamethasone can also help in this regard, as shown in the results of both the SUMMIT and CREST studies.
What are some future uses of bortezomib?
Dr. Anderson: Future studies will explore how to combine it with both old and new drugs. Also, we will study efficacy of the drug earlier in the course of disease.
Dr. Richardson: Preliminary results for combination therapy with Velcade are encouraging. Phase I trials of the combinations of Velcade/Doxil, melphalan/Velcade, and Velcade/thalidomide in relapsed patients have been promising so far. Also, combinations of Velcade with thalidomide derivatives look especially provocative in the preclinical setting.