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Winter 2004/2005 Volume 6, Issue 3:
The Expanding Role of Proteasome Inhibition in Multiple Myeloma
By Robert Orlowski, MD, PhD
At the 2004 ASH meeting, data from a variety of proteasome inhibitor studies was discussed. Based on these, it seems safe to conclude that more patients with relapsed or refractory disease will benefit from such therapy than previously thought.
03.22.05
Assistant Professor of Medicine
Lineberger Comprehensive Cancer Center
University of North Carolina, Chapel Hill, NC

Cells need to make new proteins to adapt to a changing environment, and also often have to replace older, damaged proteins to maintain normal function. Such new protein synthesis occurs through an organelle called the ribosome. By the same token, cells need to have a way to remove the unwanted proteins that accumulate, and this occurs through the ubiquitin-proteasome pathway. While this system is important to both normal and cancer cells, it seems to be particularly important for the growth and survival of multiple myeloma, making it an attractive therapeutic target (1, 2). One of the most exciting recent developments in this area has been the approval of the proteasome inhibitor bortezomib (VELCADE®) by the Food and Drug Administration (FDA). Currently, this agent is used to treat patients with relapsed and refractory myeloma if they have received at least two other prior treatments, and if their disease has progressed on the last of these. FDA approval of bortezomib has served to further spur interest into the potential applications of this new class of drugs. At the December 2004 meeting of the American Society of Hematology (ASH) in San Diego, data from a wide variety of proteasome inhibitor studies was reviewed and discussed. Based on these, it seems safe to conclude that more patients with relapsed and/or refractory disease will benefit from such therapy than was previously thought, and that proteasome inhibitors will also be active as part of initial therapy for myeloma.

Bortezomib initially showed clinical activity against multiple myeloma in a small phase I trial (3), and was approved by the FDA on the basis of excellent results from a larger phase II trial (4). This study of single agent bortezomib showed an overall response rate of 35%, with a complete response (CR) rate of 10%, in patients with heavily treated, relapsed and/or refractory myeloma. The next step in evaluating new drugs is usually a phase III trial, which compares the novel agent against a known therapy with established efficacy, to see which is better. Richardson and colleagues presented the final results of just such a trial, called the APEX study, which randomized patients who had relapsed or refractory disease after one to three prior treatments to receive bortezomib or the steroid dexamethasone. Myeloma was twice as likely to respond to bortezomib therapy than dexamethasone, with 38% of patients achieving a response on bortezomib versus only 18% on the steroid. In addition, the quality of the responses was better, since a CR or near-CR was seen in barely 2% of patients on dexamethasone, compared with 13% on bortezomib. An improvement was seen by 78% in the time to progression (TTP), or the time until the patients’ disease began growing again, and the best results were seen in patients that had received only one prior therapy for their myeloma*. These findings suggest that patients who receive bortezomib earlier may have a greater benefit than patients who receive it later in their disease course. Most importantly, the improved response rates and TTP translated into a survival benefit, since patients treated with bortezomib had a 41% decreased risk of dying compared to those who received dexamethasone. Toxicities of the two drugs were also compared and, perhaps not surprisingly, patients on each agent had slightly different side effects. Among those who received dexamethasone, there was a greater risk of some problems such as infections, musculoskeletal effects like weakness, and elevated blood sugars. Patients who received bortezomib had a greater likelihood of a decline in their platelet count, gastrointestinal effects like constipation or diarrhea, and also peripheral neuropathy, or numbness and tingling in their hands and/or feet. Despite these different side-effects, the proportion of patients having serious drug-related problems was similar, as was the proportion of people who had to stop their treatment because of such difficulties. Patients should speak with their health care providers in detail, since there may be other reasons why one drug or the other might be better suited for a particular individual. Overall, however, in this study patients receiving bortezomib had better outcomes compared to those on dexamethasone, and this did not come at the cost of an increased frequency of serious side effects.

Proteasome inhibitors seem likely to work well not just alone, but also in combination with other drugs by helping to overcome several pathways of drug resistance. These mechanisms are often used by myeloma cells to help them survive the effects of chemotherapy (see Myeloma Today, Volume 5, Number 10, page 7). Previous reports indicated that bortezomib seemed to co-operate well in several two-drug combinations, including with either liposomal doxorubicin (Doxil®), melphalan (Alkeran®), or thalidomide (Thalomid®), without adding side effects. At the recent ASH meeting, preliminary data was shown of results from clinical trials with several new combinations. One example was the work of Channan-Khan and colleagues, who are studying the combination of bortezomib, pegylated liposomal doxorubicin, and thalidomide. They have so far found that this three-drug regimen has been well tolerated with no unanticipated side effects, and rare low platelet or white blood cell counts as the only severe side effects. In patients with heavily pre-treated multiple myeloma, 54% have had a 50% or better reduction in their disease burden, also known as a partial response (PR). Encouraging finding were also reported by Hollmig and colleagues, who are evaluating the four-drug regimen of bortezomib, infusional doxorubicin (Adriamycin®), thalidomide, and dexamethasone. If seen, most of the more severe side effects were again manageable decreases in the platelet or neutrophil counts. A similar response rate was seen with this four-drug regimen, with 63% of patients having a CR or PR. This latter result is especially interesting since almost all of the patients had myeloma that had previously become resistant to bortezomib, but with the addition of other drugs this resistance was able to be overcome. Much data needs still to be gathered, and additional studies are needed to find out if such combinations are better than bortezomib alone. At least one such study is currently underway, a phase III randomized trial comparing bortezomib alone against bortezomib with pegylated liposomal doxorubicin. Also, additional studies are needed to determine which of these many combinations are best, or if they can be used sequentially. Nonetheless, these new results continue to reinforce the impression that combinations of bortezomib with other drugs don’t significantly increase side effects, but can overcome drug resistance and induce better response rates.

When new drugs are discovered that work against relapsed and/or refractory myeloma there is often interest in studying them in patients with previously untreated disease. The rationale is that chemotherapy-naïve myeloma would be less drug resistant than it becomes in the relapsed setting, resulting in a higher response rate. This would hopefully result in the ability to collect stem cells from patients for later transplant that would have fewer residual myeloma cells. For these patients, and also for those who are not transplant candidates, these higher response rates could hopefully improve overall survival. Preliminary results of one study using bortezomib alone as initial myeloma therapy were reported by Richardson and colleagues. Most of the side effects seen so far were similar to those described in other trials of this proteasome inhibitor. An overall response rate of 44% has been seen so far, similar to that reported for dexamethasone alone, which has previously been the single agent with greatest activity against myeloma. Since some patients cannot take steroids for their myeloma because of problems with steroid side effects, these results suggest that bortezomib alone may one day be a rational initial treatment option. For patients who can take steroids the data presented by Harousseau and colleagues was very encouraging. They found that the combination of bortezomib and dexamethasone had few if any serious side effects, and yet induced a response rate of 83% after four cycles of treatment. Furthermore, stem cells could be collected safely, and patients could go on to successful stem cell transplantation. These results were so encouraging that this group is planning to start a randomized comparison of bortezomib/dexamethasone versus the VAD regimen (vincristine with infusional doxorubicin and dexa-methasone), which has so far been one of the standard combinations used for myeloma therapy.

Two other regimens commonly used as initial therapy for myeloma are melphalan with prednisone (MP) and thalidomide with dexamethasone (TD). The former is often used in older patients or others that do not have transplant as an option, while the latter is more commonly used in patients prior to stem cell transplantation. Both TD and MP are now been studied in combination with bortezomib, and early results of these trials were also presented. Mateos and colleagues described their results with bortezomib and MP, which they called VMP, showing that decreased platelets or neutrophils were the only moderate side effects seen. Among the first small group of patients treated in the phase I portion of this study the response rate was 91%. This is far better than what would be expected of MP alone, which usually results in responses in only a little more than half, and a larger phase II study is planned. Alexanian and colleagues reported on their so-called VTD regimen, which was very well tolerated, and induced an overall response rate of 80%, which may be better than that of TD alone. Interestingly, they found that there was a trend for an even higher response rate of 94% when bortezomib doses greater than the 1.3mg/m2 approved for relapsed/refractory myeloma were used. Also, they noted that the vast majority of the responses were seen in just the first two monthly cycles of therapy, and further treatment led to only modest additional improvements. These results suggest the exciting possibility that shorter courses of treatment with these novel combinations may result in equivalent or even better outcomes compared to currently available therapies. Since the risk of developing a drug-related side effect is often related to its total dose and duration of exposure, such briefer treatment plans could help in reducing the toxicities of myeloma therapy, thereby also improving quality of life.

These and other studies that were presented at ASH are good examples of the many ways in which bortezomib is being used to treat patients with myeloma. Many questions need still to be answered, such as whether proteasome inhibition could be effective in a maintenance setting. If so, this would allow patients who achieve a remission to receive lower doses of bortezomib less frequently to increase their chances of staying in remission. Another important question is if patients who are treated with bortezomib, or a bortezomib-based regimen, can then be retreated with the same or a different combination later in their disease course, and once again benefit. What has been learned so far, however, is encouraging indeed. Bortezomib as a single agent has established itself as a standard of care for patients with relapsed and/or refractory myeloma. It seems to be active as early as in the second line of treatment, and may be more effective the earlier that it is used. Combination regimens based on bortezomib that may well further improve the outcome of patients with relapsed disease are poised to enter phase III testing, which will hopefully prove their enhanced efficacy. Finally, bortezomib is beginning to prove itself to be a valuable and safe drug as part of the initial therapy of myeloma in patients both prior to transplant, as well as in patients who do not have transplant as an option. This drug is therefore poised to significantly contribute to the recent trend in patients with myeloma for an increasing survival and quality of life in the short run, and hopefully to the cure of this disease in the longer term.

*45% response rate compared to 26% with dexamethasone. There was a 62% reduction in the risk of death at 1 year for these patients.

REFERENCES

1. Voorhees, P. M., Dees, E. C., O'Neil, B., and Orlowski, R. Z. The proteasome as a target for cancer therapy. Clin Cancer Res, 9: 6316-6325, 2003.

2. Yang, H. H., Ma, M. H., Vescio, R. A., and Berenson, J. R. Overcoming drug resistance in multiple myeloma: the emergence of therapeutic approaches to induce apoptosis. J. Clin. Oncol., 21: 4239-4247, 2003.

3. Orlowski, R. Z., Stinchcombe, T. E., Mitchell, B. S., Shea, T. C., Baldwin, A. S., Stahl, S., Adams, J., Esseltine, D. L., Elliott, P. J., Pien, C. S., Guerciolini, R., Anderson, J. K., Depcik-Smith, N. D., Bhagat, R., Lehman, M. J., Novick, S. C., O'Connor, O. A., and Soignet, S. L. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol, 20: 4420-4427, 2002.

4. Richardson, P. G., Barlogie, B., Berenson, J., Singhal, S., Jagannath, S., Irwin, D., Rajkumar, S. V., Srkalovic, G., Alsina, M., Alexanian, R., Siegel, D., Orlowski, R. Z., Kuter, D., Limentani, S. A., Lee, S., Hideshima, T., Esseltine, D. L., Kauffman, M., Adams, J., Schenkein, D. P., and Anderson, K. C. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med, 348: 2609-2617, 2003.


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