Commentary (Nowakowski/Rajkumar): New Treatments for Multiple Myeloma

In the past decade there has been a rapid increase in our understanding of the biology of multiple myeloma and the development of new treatment strategies.[1] In the current issue of ONCOLOGY, Richardson et al provide an excellent overview of new agents in the treatment of multiple myeloma. Two of these agents are currently available in the United States outside of clinical trials: thalidomide (Thalomid) and bortezomib (Velcade). The thalidomide analog- lenalidomide (Revlimid)-will likely be available in the near future, while several other novel agents are being evaluated in clinical trials. Richardson and colleagues have played a major role in the development of bortezomib and lenalidomide, as well as numerous novel agents currently in clinical trials. Their review is therefore particularly enlightening, and provides a first-hand account of the clinical development of various new drugs for the treatment of myeloma. Role of Newer Agents
Thalidomide, bortezomib, and lenalidomide have demonstrated high levels of activity in relapsed and refractory myeloma in several clinical trials. Single-agent response rates are approximately 30% in relapsed myeloma with each agent; response rates are much higher when the drugs are used in combination with dexamethasone or other active agents. Given significant efficacy in advanced myeloma, the importance of studying the role of these new drugs early in the disease course is readily apparent. In fact, several studies have already demonstrated the activity of thalidomide plus dexamethasone in newly diagnosed myeloma, and the regimen is now commonly used as induction therapy for patients who are candidates for autologous stem cell transplantation (ASCT), replacing the older regimen of vincristine, doxorubicin, and dexamethasone (VAD).[2] Bortezomib and lenalidomide have also shown promising activity in the setting of newly diagnosed patients, but confirmation from larger phase III trials is needed. Such trials are under way and will define the role of bortezomib and lenalidomide as initial therapy. Although Richardson and colleagues have included arsenic trioxide (Trisenox) in their discussion of new agents, we are not impressed with the evidence so far concerning the activity or role of this agent in multiple myeloma. The drug has so far demonstrated minimal single-agent activity compared to other active drugs, and it is impossible to interpret response rates from small phase II trials in which arsenic trioxide has been combined with dexamethasone or melphalan (Alkeran). The contribution of arsenic trioxide to the responses in these combination studies cannot be determined without a control arm. We agree with Richardson and colleagues that, given the "limited efficacy data," additional studies are needed. Until then, we do not recommend the use of arsenic trioxide for myeloma outside a clinical trial. Stem Cell Transplantation
Progress in the treatment of myeloma has not been limited to the introduction of new agents. The use of single and tandem ASCT and improvements in supportive care have had a profound impact on the management of this disease.[1,3] ASCT, although not curative, is proven to prolong survival in multiple myeloma. A recent French trial showed significant prolongation of survival with a second (tandem) ASCT for patients failing to achieve a complete response or very good partial response with the first treatment.[4] Presently one of the major questions for patients and physicians alike concerns the role and, more importantly, timing of ASCT given the arrival of new active agents. Clearly, large randomized trials are needed to adequately address this issue, but it would be exceedingly difficult to conduct equivalence trials comparing ASCT to novel therapy in the United States, given the large sample sizes involved and anticipated rates of accrual. An alternative strategy would be to develop highly active combinations using novel agents in phase II trials with the goal of developing regimens that can produce complete response rates that rival, and hopefully exceed, those obtained with ASCT. Critical Issues
There are three areas in the treatment of myeloma that require urgent attention. One is the treatment of highrisk myeloma. By Mayo Clinic criteria, this is defined by the presence of any one of the following features: karyotypic deletion 13 or hypodiploidy; t4;14, t14;16 or 17p- by fluorescent in situ hybridization (FISH) or other molecular cytogenetic studies; or plasma cell labeling index of 3% or higher.[5] Patients with high-risk myeloma do not do well with current therapy including tandem ASCT and need novel approaches. The second area is the treatment of elderly patients for whom melphalan/prednisone is still the standard of care, and no combination regimen has shown superiority in terms of overall survival. Third is development of effective maintenance therapy following ASCT. In all three areas, trials incorporating novel agents are already under way. Conclusions
Any development or discovery presents us with new questions and challenges. A plethora of possible combinations of newer and older agents need to be tested. Combinations need to be developed based on an understanding of the mechanisms of resistance as well as synergy observed in preclinical studies. By the same token, ongoing trials must incorporate translational components to further explore mechanisms of action and resistance. The identification of predictors of response to a given drug is very much needed in myeloma; therapy should be ideally tailored to the individual patient based on predictors of response. Richardson and colleagues have led by example in these areas and are to be congratulated.

Disclosures:

Dr. Rajkumar receives research support for clinical trials from Celgene and Millennium.

References:

1. Kyle RA, Rajkumar SV: Multiple myeloma. N Engl J Med 351:1860-1873, 2004.
2. Dimopoulos MA, Anagnostopoulos A, Weber D: Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol 21:4444-4454, 2003.
3. Barlogie B, Shaughnessy J, Tricot G, et al: Treatment of multiple myeloma. Blood 103:20-32, 2004.
4. Attal M, Harousseau JL, Facon T, et al: Single versus double autologous stem-cell transplantation for multiple myeloma [see comment]. N Engl J Med 349:2495-502, 2003.
5. Rajkumar SV, Kyle RA: Conventional therapy and approach to management. Best Pract Res Clin Haematol 18:585-601, 2005.