Continued Progress in Treatment Options for Multiple Myeloma: From Past to Present and Future

This article is a review of Liposomal Doxorubicin in Combination With Bortezomib for Relapsed or Refractory Multiple Myeloma

Following an era when a limited number of effective treatment options conferred poor outcome for almost all those diagnosed with multiple myeloma, the past 10 years have seen a dramatic improvement in prognosis following the introduction of a range of novel therapies.[1] On the one hand, the underlying genomic complexity of multiple myeloma has become increasingly understood,[2,3] and on the other, studies of the interaction of multiple myeloma cells in the bone marrow microenvironment have provided vital insights into disease biology.[4,5] Stromal cells, extracellular matrix proteins, and multiple cytokine pathways provide key mechanisms that support multiple myeloma tumor survival, proliferation, and drug resistance,[5,6] and in turn represent intriguing targets for novel therapies.

New Agents

The advent of thalidomide (Thalomid) as an effective treatment for relapsed and refractory multiple myeloma,[7] followed by its rapid incorporation into combination strategies,[8] ultimately led to its approval with high-dose dexamethasone in the front-line setting.[9-11] Then, investigations with bortezomib (Velcade)[12] as a paradigm of new drug development in multiple myeloma resulted in its accelerated approval in 2003 for relapsed, refractory disease[13] and full approval in first relapse in 2005.[14,15] With these agents, the number of drugs available to clinicians to treat multiple myeloma effectively doubled. The approval of lenalidomide (Revlimid) in combination with dexamethasone for relapsed disease followed shortly thereafter,[16,17] and now the approval of liposomal doxorubicin (Doxil) in combination with bortezomib for relapsed or refractory multiple myeloma[18] constitutes the fourth approval in as many years.

This progress reflects a remarkable series of events that have collectively led to a dramatic improvement in outlook for our patients. First, the paradigm of bench-to-bedside development of novel agents has become clearly established, and second, the extraordinary partnership between academia, pharma, patient advocacy, the National Institutes of Health/National Cancer Institute, and the US Food and Drug Administration has resulted in the rapid approval of new drugs for the treatment of an incurable malignancy for which there has been an urgent unmet medical need.[19]

Large Body of Research

Under the leadership of Dr. Richard Pazdur, Dr. Yang-Min Ning and colleagues present in their approval summary a highly concise and informative paper that encompasses a large body of work. First, the observation that bortezomib in preclinical in vitro models could potently sensitize myeloma cells to anthracyclines (doxorubicin) or alkylating agents-even in cases of myeloma cells resistant to either of these drug classes given alone[20,21]-led to the rapid translation through phase I/II clinical studies of the combination, showing its ability to overcome resistance in patients with manageable toxicity, and establishing an appropriate dose and schedule for the two agents.[22]

This was followed by the pivotal phase III international study described herein and led by Dr. Robert Orlowski and colleagues, which compared the efficacy and safety of a combination of pegylated liposomal doxorubicin plus bortezomib with bortezomib monotherapy in patients with relapsed and refractory multiple myeloma.[18] A total of 646 patients were randomly assigned to receive bortezomib (1.3 mg/m²) on days 1, 4, 8, and 11 per 21-day cycle or the same bortezomib regimen with pegylated liposomal doxorubicin given at 30 mg/m² on day 4. The median time to progression (the primary endpoint of this study) was increased from 6.5 months for bortezomib alone to 9.3 months with the pegylated liposomal doxorubicin plus bortezomib combination (P = .00004). Moreover, the 15-month survival rate for the combination was also significantly superior to that for bortezomib alone.

At the time of submission of this study at interim analysis, the complete-plus-partial response rate for monotherapy vs the combination was not significantly different. However, further analysis has confirmed superiority,[18] an observation supported in the initial analysis, where responding patients were shown to have a longer median duration of response with the combination at 10.2 months, compared to 7 months with bortezomib alone.

It is important to note that adverse reactions occurred more frequently with the combination therapy. As compared to bortezomib alone, more frequent grade 3/4 adverse reactions with the combination included neutropenia and thrombocytopenia. Additional frequent all-grade adverse reactions also included anemia, fatigue, pyrexia, nausea, vomiting, diarrhea, mucositis, and hand-foot syndrome. However, there was no significant increase in the rate of heart failure, which remained low at 3% in both groups. Furthermore, rates of peripheral neuropathy were not significantly different and remained manageable in both arms. The absence of any thrombosis and the ability of a steroid-sparing regimen to prove highly active were observations especially relevant to current practice.[18]

Important Therapeutic Option

On the basis of these findings, this combination approach received FDA approval and thus provides clinicians with another important therapeutic option for the management of relapsed and relapsed and refractory multiple myeloma. As we go forward, additional combinations are rapidly being translated from preclinical and early-phase clinical development to large phase III clinical trials, including the combination of the novel heat shock protein (HSP)-90 inhibitor tanespimycin with bortezomib in a similar design.

The model of enhancing clinical benefit and confirming this in the context of the phase III randomized trial presented above now constitutes a paradigm of clinical drug development in multiple myeloma. As a strategy, it builds on the success of first the APEX study using bortezomib as monotherapy-now a comparator of choice[14,23,24]-then the large lenalidomide and dexamethasone combination trials,[16,17] in which especially durable disease control has been seen.[18]

Based on this remarkable collaborative work between academic cancer centers, pharmaceutical sponsors, regulatory authorities, and patient advocacy, the future for our patients is indeed brighter. While many challenges remain, researchers are better informed by newer laboratory tools and increasingly robust preclinical models, with consortium efforts to expedite clinical translation growing continuously. Thus, ongoing collective efforts to generate more effective and less toxic combinations promise to further improve patient outcome, and this study and its approval reflects yet another important milestone on that busy road.

-Paul G. Richardson, MD
-Constantine S. Mitsiades, PhD
-Kenneth C. Anderson, MD

References:

1. Richardson PG, Hideshima T, Mitsiades C, et al: The emerging role of novel therapies for the treatment of relapsed myeloma. J Natl Compr Canc Netw 5:149-162, 2007.

2. Bergsagel PL, Kuehl WM: Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 23:6333-6338, 2005.

3. Hideshima T, Bergsagel PL, Kuehl WM, et al: Advances in biology of multiple myeloma: Clinical applications. Blood 104:607-618, 2004.

4. Hideshima T, Mitsiades C, Tonon G, et al: Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer 7:585-598, 2007.

5. Mitsiades CS, Mitsiades NS, Munshi NC, et al: The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: Interplay of growth factors, their receptors and stromal interactions. Eur J Cancer 42:1564-1573, 2006.

6. Mitsiades CS, Mitsiades N, Munshi NC, et al: Focus on multiple myeloma. Cancer Cell 6:439-444, 2004.

7. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999.

8. Palumbo A, Giaccone L, Bertola A, et al: Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 86:399-403, 2001.

9. Rajkumar SV, Hayman S, Gertz MA, et al: Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 20:4319-4323, 2002.

10. Weber D, Rankin K, Gavino M, et al: Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21:16-19, 2003.

11. Rajkumar SV, Blood E, Vesole D, et al: Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 24:431-436, 2006.

12. 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.

13. Kane RC, Bross PF, Farrell AT, et al: Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8:508-513, 2003.

14. Richardson PG, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005.

15. Kane RC, Farrell AT, Sridhara R, et al: United States Food and Drug Administration approval summary: Bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res 12:2955-2960, 2006.

16. Weber D, Wang M, Chen C, et al: Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): Results of 2 phase III studies (MM-009, MM-010) and subgroup analysis of patients with impaired renal function. Blood 108:1012A-1013A, 2006.

17. Dimopoulos MA, Spencer A, Attal M, et al: Study of lenalidomide plus dexamethasone versus dexamethasone alone in relapsed or refractory multiple myeloma (MM): Results of a phase 3 study (MM-010). Blood 106:6A-7A, 2005.

18. Orlowski RZ, Nagler A, Sonneveld P, et al: Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: Combination therapy improves time to progression. J Clin Oncol 25:3892-3901, 2007.

19. Anderson KC, Hannah AL, Pazdur R, et al: A strategic framework for novel drug development in multiple myeloma. Br J Haematol 138:153-159, 2007.

20. Mitsiades N, Mitsiades CS, Richardson PG, et al: The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: Therapeutic applications. Blood 101:2377-2380, 2003.

21. Ma MH, Yang HH, Parker K, et al: The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136-1144, 2003.

22. Orlowski RZ, Voorhees PM, Garcia RA, et al: Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 105:3058-3065, 2005.

23. Richardson P, Sonneveld P, Schuster M, et al: Bortezomib continues to demonstrate superior efficacy compared with high-dose dexamethasone in relapsed multiple myeloma: Updated results of the APEX trial. Blood 106:715A-716A, 2005.

24. Richardson PG, Sonneveld P, Schuster M, et al: Extended follow-up of a phase 3 trial in relapsed multiple myeloma: Final time-to-event results of the APEX trial. Blood August 9, 2007 [epub ahead of print].