Commentary (Kaufman/Lonial): New Treatments for Multiple Myeloma

Treatment options for patients with myeloma have moved from the relatively ineffective combinations of cytotoxic agents and corticosteroids, to the widespread use of high-dose therapy and autologous bone marrow or peripheral blood stem cell transplant. Through this transition, the overall survival for patients has nearly doubled from a previous median survival of 2 to 2.5 years, up to 4 to 5 years based on the transplant arms of several large randomized clinical trials.[1-3] In this issue of ONCOLOGY, Dr. Richardson and colleagues extensively detail the recent advances in myeloma therapy that involve the use of more "modern" or novel agents such as thalidomide (Thalomid), lenalidomide (Revlimid), and bortezomib (Velcade). These agents are of monumental importance in the assault on myeloma as they have provided much needed advances for patients with relapsed and refractory myeloma and, in doing so, have set the stage for the next major revolution in myeloma therapy. Questions Remain
While bortezomib is clearly an effective agent for patients with myeloma, many questions remain. What is the optimal timing for the use of bortezomib? As described, bortezomib was developed in patients with relapsed and refractory disease, but it clearly has significant activity among newly diagnosed patients who require treatment.[4-6] While single-agent response rates using bortezomib monotherapy are modest, bortezomib in combination with dexamethasone, doxorubicin, and melphalan (Alkeran) have yielded high response rates with impressive complete response (CR)/near- complete response (nCR) rates.[7-9] From these observations, a whole new set of questions develops. Are these impressive induction responses durable? Previously there was no correlation noted between response to induction therapy and outcomes following transplant. This paradoxic result could be addressed with one of two potential explanations. First, responses using older induction regimens such as VAD (vincristine, doxorubicin [Adriamyin], dexamethasone) or the newer approach of thalidomide with dexamethasone have not typically yielded response rates higher than 60%, with very low CR rates. In an era of higher responses to induction, will we see that patients achieving VGPR (very good partial remission; 90% reduction in serum paraprotein) or better prior to transplant achieve longer durations of remission with high-dose therapy? Logically this makes sense, but limited data support this. The second explanation is that transplant is the great equalizer, achieving more benefit for those with suboptimal responses to induction, than those who achieve CR or nCR following induction. The randomized PETHEMA trial supports this hypothesis. While the PETHEMA trial failed to demonstrate a survival benefit for high-dose therapy, only patients who achieved a partial response or better following induction therapy were eligible for randomization between standard therapy and high-dose therapy. Thus, by excluding those with < 50% paraprotein response following induction, one could argue that the real benefit of high-dose therapy was seen among those with suboptimal responses to induction therapy.[10] Once again we are left with the question: Does a patient who achieves a CR by European Group for Blood and Marrow Transplantation (EBMT) criteria require high-dose therapy? If not, what is the optimal combination to be used for induction therapy? Should we administer induction therapy with the goal of achieving a CR, or only for a fixed period of time in order to minimize toxicity? Is a CR from novel agents equivalent to a CR from highdose therapy? Non-Transplant-Based Approaches
The use of thalidomide in combination with dexamethasone has become an increasingly popular treatment for patients with newly diagnosed myeloma. As discussed in the article, the combination of thalidomide and dexamethasone is superior to dexamethasone alone in terms of improved response rates, and stem cell collection is not impaired with the thalidomide induction. However, many physicians and patients are opting for thalidomide/ dexamethasone induction without transplant or stem cell collection. Recently, the Mayo Clinic group reported progression- free survival for patients treated with thalidomide and dexamethasone who did not proceed with high-dose melphalan and autologous transplant. The median age of these 24 patients was 65 years, and 11 patients had stage I disease by the International Staging System. Progression-free survival was 19 months, and overall survival was 30 months for the group.[11] These numbers are comparable to the progression-free and overall survival rates associated with non-transplantbased approaches using conventional therapy.[1,2] Thus, it would appear that such an induction strategy requires subsequent transplant for most patients in order to improve progression-free and overall survival. For patients not deemed to be acceptable transplant candidates, the data from Palumbo and colleagues clearly support MPT (melphalan, prednisone, thalidomide) as the new standard, presuming appropriate deep vein thrombosis and anti-infection prophylaxis is instituted.[ 12] However, the side-effect profile must be emphasized and discussed with patients. Lenalidomide
The thalidomide analog lenalidomide represents an exciting new addition for clinicians. Based upon data presented by Weber and colleagues at the International Myeloma Workshop, lenalidomide in combination with dexamethasone is superior to dexamethasone alone in terms of improved responses and improved time to progression, but the addition of dexamethasone to lenalidomide is required for the very high response rate reported in that study.[13] Preliminary data using lenalidomide and dexamethasone as induction therapy looks quite promising with very high initial response rates, and 6% achieving CR, and 32% achieving VGPR or better.[ 14] Additionally, peripheral blood stem cell mobilization following lenalidomide induction did not appear to be problematic though the number of mobilized patients was quite low. More date from an ongoing Eastern Cooperative Oncology Group trial are needed to assess toxicity and tolerability of this regimen in a larger patient population. Further Considerations
Finally, it remains unclear how these agents should be sequenced. Should all of these highly active agents be given sequentially in order to maximize the response duration of each, or should we try to obtain the maximal benefit from these agents in combinations? Given that myeloma remains an incurable malignancy, many would argue that sequential singleagent administration is wisest, but if we are to learn a lesson from highdose therapy and transplant, the achievement of a CR is the major benefit resulting from a transplant. Thus, strategies that result in high CR rates-such as combinations of novel agents-should be employed to achieve this result. Conclusions
With the promise of multiple other new targets and agents on the horizon, including small molecules and antibodies, it is clear that we have entered a new era for therapeutics development in myeloma. Much of the credit for this biology-based approach to therapy should be given to Drs. Anderson and Richardson and their group. This paper is an extension of their work, and represents but a small glimpse of the forthcoming data on many other new agents. The challenge to clinicians in this field is to rapidly assimilate and constantly challenge the paradigm of "standard therapy" in myeloma. Only through rigorous biology, rapid translation, and effective clinical trials can we achieve our goal of rendering myeloma a chronic illness or, dare we say, curing it altogether.

Disclosures:

Dr. Lonial receives research support from and is a consultant for Millennium, and is a member of the speakers bureaus for Millennium and Celgene.

References:

1. Attal M, Harousseau J-L, Stoppa A-M, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 335:91-97, 1996.
2. Child JA, Morgan GJ, Davies FE, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875-1883, 2003.
3. Attal M, Harousseau J-L, Facon T, et al: Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 349:2495-2502, 2003.
4. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609- 2617, 2003.
5. Jagannath S, Barlogie B, Berenson J, et al: A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165-172, 2004.
6. Richardson PG, Chanan-Khan, Schlossman RL, et al: Phase II trial of single agent bortezomib (VELCADE®) in patients with previously untreated multiple myeloma (MM) (abstract 336). Blood 104:100a, 2004.
7. Harousseau J, Attal M, Leleu X, et al: Bortezomib (VELCADE®) plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: Preliminary results of an IFM phase II study (abstract 1490). Blood 104:416a, 2004.
8. Cavenagh J, Popat R, Curry N, et al: PAD combination therapy (PS341/bortezomib, Adriamycin and dexamethasone) for previously untreated patients with multiple myeloma (abstract 1478). Blood 104:413a, 2004.
9. Mateos MV, Blade J, Diaz Mediavilla J, et al: A phase I/II national, multicenter, openlabel study of bortezomib plus melphalan and prednisone (V-MP) in elderly untreated multiple myeloma patients (abstract 3462). Blood 104:943a, 2004.
10. Blade J, Sureda A, Ribers J, et al: Highdose therapy autotransplantation/intensification versus continued conventional chemotherapy in multiple myeloma patients responding to initial chemotherapy. Definitive results from PETHEMA after a median follow-up of 66 months (abstract 137). Blood 102:42a, 2003.
11. Rajkumar SV, Dingli D, Nowakowski G, et al: Thalidomide and dexamethasone in newly diagnosed multiple myeloma: Long-term results in patients not undergoing upfront autologous stem cell transplantation (abstract 6632). J Clin Oncol 23(16S):593s, 2005.
12. Palumbo A, Bertola B, Musto P et al: A prospective randomized trial of oral melphalan, prednisone, thalidomide (MPT) vs oral melphalan, prednisone (MP): An interim analysis (abstract 207). Blood 104:63a, 2004.
13. Weber DM, Chen C, Niesvizky R, et al: A multicenter, randomized, parallel-group, double-blind placebo-controlled study of lenalidomide plus dexamethasone versus dexamethasone alone in previously treated subjects with multiple myeloma. The Hematology Journal 90:155a, 2005.
14. Rajkumar SV, et al. Blood, Aug 23, 2005. (Epub ahead of print.)