The past 12-18 months have seen the introduction of multiple new therapeutic options for patients with newly diagnosed or relapsed multiple myeloma. The annual American Society of Hematology (ASH) 2003 meeting was filled with reports of new agents and updates on recently novel combinations of existing agents for the treatment of multiple myeloma. This report contains a brief summary of some of the exciting data presented during the meeting utilizing the newly approved agent bortezomib (VelcadeTM).
Dr. Orlowski and colleagues from the University of North Carolina reported on a phase I trial combining bortezomib with the liposomal agent Doxil®. The trial was open for any relapsed hematologic malignancy and 24 patients with myeloma enrolled in the trial. Among the 22 evaluable multiple myeloma patients, 5 patients achieved a complete remission (CR), 2 patients achieved a near CR, 8 patients achieved a partial remission (PR, > 50% reduction in serum protein), and 6 patients achieved either a minor response or stable disease. The toxicities from this trial were modest, and among a subset of patients who were considered non-responsive to Doxil® or other agents of similar class, significant responses were seen. A phase II/III trial evaluating this combination with fixed doses of both the Doxil® (40mg/m2 on day 4) and bortezomib (1.3mg/m2 on days 1,4,8, and 11) trial is planned.
Dr. Yang and colleagues from Cedars-Sinai reported on their trial combining oral melphalan with bortezomib at very low doses. This trial is based upon in vitro data from Dr. Bersenson’s and Dr. Anderson’s groups showing that there was significant synergy when these agents were given together, and that very low doses of both agents could be used. Dr. Yang started with doses of bortezomib of 0.7mg/m2 (half the usual dose) given on days 1,4,8, and 11, with doses of melphalan as low as 1/10 the usual starting dose, and increasing up to higher doses of melphalan. In this dose escalation trial, 12 patients achieved a response with 10 PRs, and 4 patients who achieved minor response or stable disease. The only major toxicity was the expected suppression of blood counts seen with melphalan. Further study of this combination is also planned, and really highlights the benefit of well-designed clinical trials modeled after well-designed laboratory work.
Dr. Zangari and colleagues from Arkansas also presented data on the combination of bortezomib/thalidomide/ dexamethasone. Nearly all of the patients in this trial had received prior transplant, 81% had received prior thalidomide, and 75% of the patients in the trial had abnormal cytogenetics. Because of concerns regarding neuropathy among recipients of both bortezomib and thalidomide, the thalidomide was started at a dose of 50mg/day and increased to a maximum dose of 200mg/day. Despite starting with a low dose of thalidomide in combination with the bortezomib, 22% of patients achieved a CR or near CR, and 50% of patients achieved a PR. Along with the impressive response data, the frequency of severe neuropathy (grades 3 or 4) was only 10%; about 50% of the patients did develop some neuropathy (grade 1 or 2). Overall the regimen was quite well tolerated, and is currently being studied in a larger group of patients, but should be done with careful attention to the issue of neuropathy.
In response to the overwhelmingly positive data with either single agent or combinations of agents with bortezomib, Dr. Jagannath and his colleagues from the Salick network reported on the first 16 patients enrolled to receive bortezomib as first-line therapy for symptomatic myeloma. In this trial patients received standard bortezomib at a dose of 1.3mg/m2 on the day 1, 4, 8, 11 schedule every 21 days. Patients did not receive dexamethasone unless the response after 2 cycles was less than a PR, or the response after 4 cycles was less than a CR. Among the first 12 evaluable patients, 75% achieved either a PR or near CR, and stem cell collection and subsequent transplant have been uneventful thus far. While the authors are cautious about making predictions based upon this small cohort of patients, this preliminary analysis is promising not only from the standpoint of responses to initial therapy, but also because of the stem cell collection and transplant data that are planned as part of this trial. To date there is no reason to suspect that the collection of stem cells for a subsequent transplant is an issue for patients receiving bortezomib, but other studies will also address this issue.
Three abstracts were presented to further describe toxicities of bortezomib or its use in patients with renal insufficiency. The first was an abstract presented by Dr. Richardson from the Dana-Farber Cancer Center on behalf of the Summit and Crest studies looking at the problem of peripheral neuropathy. Among the patients entered into those two trials, 81% had neuropathy at the time of study entry, and 35% developed neuropathy during the trials. Patients who developed more severe neuropathy on study were the ones who entered with a greater degree of neuropathy at the onset of therapy. The dose of bortezomib was reduced or held in the study for 19% of the patients, and 5% required discontinuation of the drug because of neuropathy. Among the patients with neuropathy that developed on study, 74% of the neuropathy resolved back to baseline over a median of 99 days.
Dr. Lonial and colleagues from the Winship Cancer Institute and the Summit and Crest investigators, presented an analysis of the thrombocytopenia seen in the phase II trials of bortezomib in multiple myeloma. They also evaluated the impact of bortezomib on a platelet growth factor normally found in the blood known as thrombopoietin. Across all patients for which there was data, there was an average of a 60% reduction in the platelet counts during the course of therapy which rapidly recovered back to baseline during the 10 day rest period of each cycle. Additionally, the baseline platelet count at the initiation of each cycle of therapy increased over the course of 8 cycles of therapy. The response of blood thrombopoietin levels associated with the reduction in platelet counts seen in patients on bortezomib was as expected, and was not thought to be related to the etiology of the thrombocytopenia. This observation in concert with the proposed mechanism of action, support the use of bortezomib with appropriate platelet support even in the context of thrombocytopenia during therapy.
Finally, Dr. Jagannath evaluated the use of bortezomib among patients with renal insufficiency on the Summit and Crest trials. His review demonstrated that the response rates and toxicities were similar when compared against patients with normal renal function, and that therapy could be continued without dose adjustment or reduction based solely upon the renal function. The frequency of missed doses or dose reduction was similar to the larger population with normal renal function.
There were other studies presented utilizing in vitro models of myeloma growth and development that addressed the combination of bortezomib with other novel agents. From this perspective, it appears that bortezomib works well with other chemotherapies as well as with other targeted molecular agents that are in development or currently available. It is now incumbent upon physicians caring for patients with myeloma, as well as myeloma patients themselves, to enter trials designed to evaluate these novel combinations, and to help all of us improve the level of care and cure for patients with multiple myeloma.