Supplement No. 3
Tailoring Treatment for Multiple Myeloma Patients With Relapsed and Refractory Disease
By Paul G. Richardson, MD1, Jacob Laubach, MD2, Constantine Mitsiades, MD, PhD3, Robert L. Schlossman, MD4, Deborah Doss, BSN, RN5, Kathleen Colson, RN5, Mary L. Mckenney, NP6, Kimberly Noonan, NP6, Diane L. Warren7, Irene M. Ghobrial, MD4, Nikhil C. Munshi, MD8, Kenneth Anderson, MD9 |
March 8, 2010
1Associate Professor of Medicine Harvard Medical School, Clinical Director, Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute
2Instructor of Medicine, Harvard Medical School Dana-Farber Cancer Institute
3Instructor of Medicine, Harvard Medical School
4Assistant Professor of Medicine, Harvard Medical School Dana-Farber Cancer Institute
5Research Nurse, Dana-Farber Cancer Institute
6Nurse Practitioner, Dana-Farber Cancer Institute
7Clinical Research Manager, Dana-Farber Cancer Institute
8Associate Professor of Medicine Harvard Medical School; Associate Director, Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute
9Professor of Medicine, Harvard Medical School; Director, Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute, Boston, Massachusetts
One approach to the treatment of progressive MM is to consider strategies that lengthen TTP, even in the face of more modest ORR. For patients who responded to a first or subsequent line of treatment and have relapsed after > 1 year, it may be worthwhile to reintroduce the same regimen. Formal investigations have documented good results with bortezomib(Drug information on bortezomib) retreatment, as discussed above, and with second ASCT when TTP was ≥ 2 years. Patients with TTP < 2 years after ASCT or < 1 year after melphalan(Drug information on melphalan) (Alkeran)/prednisone have poorer prognosis and are candidates for bortezomib- or lenalidomide-based combination therapy or clinical trials of novel agents.
Guidance for Using Newer NCCN-Recommended Salvage Therapies in Patients With Multiple Myeloma Depending on Prior Therapy
Another individualized approach is based on type of prior therapy (Table 3). [6,8-10,18,21,22,26,33,35-40]
The safety and efficacy of bortezomib and bortezomib-based regimens are similar in patients with and without renal impairment; moreover, bortezomib-based therapy rapidly reverses renal dysfunction in up to 40% of patients with relapsed and refractory MM.[41,42]
A subgroup analysis of the APEX trial confirmed that the safety and efficacy of single-agent bortezomib are maintained regardless of renal dysfunction, even with baseline creatinine clearance (CrCl) < 30 mL/min. Reflecting this, the FDA does not suggest bortezomib dosing adjustments for patients with renal insufficiency, including patients on dialysis.
According to a subgroup analysis of DOXIL-MMY-3001, both bortezomib/PLD and single-agent bortezomib can improve renal function among patients with baseline CrCl < 60 mL/min. However, patients with renal dysfunction who received bortezomib/PLD were at increased risk of drug-related serious adverse events (28% vs 19% for CrCl < 60 and ≥ 60 mL/min, respectively).
Patients with creatinine > 2.5 g/dL were excluded from the MM-009/010 trials, but those with CrCl < 50 mL/min could receive len/dex. Pooled analysis showed that patients with moderate (30 ≤ CrCl < 50 mL/min) or severe (CrCl < 30 mL/min) renal impairment responded to len/dex as well or better than to high-dose dexamethasone(Drug information on dexamethasone) alone. Of 54 patients with renal dysfunction who were treated with len/dex, 78% had improvement in renal function within 4 months.
In the expanded access program, lenalidomide ± dexamethasone or prednisone(Drug information on prednisone) was safe and effective when given to 23 patients with relapsed and refractory MM and renal impairment. Compared with 46 patients with normal renal function, however, these patients had significantly higher rates of grade 3/4 thrombocytopenia.
The NCCN guidelines on MM management recommend pamidronate (Aredia) or zoledronic acid(Drug information on zoledronic acid) (Zometa) for all myeloma patients with bone disease, including osteopenia (category 1 recommendation). These bisphosphonates are associated with several important adverse events, so patients must be monitored closely. For instance, intravenous bisphosphonates can cause tubular necrosis and focal segmental glomerulosclerosis, and patients receiving them should undergo regular monitoring of urine creatinine and protein levels. Osteonecrosis of the jaw, a more recently recognized complication, is rare and manageable; the possibility of its development should not preclude judicious use of bisphosphonates, particularly in patients with severe bone disease. The American Society of Clinical Oncology recommends limiting the duration of bisphosphonate use to 2 years in patients with responsive or stable myeloma, with drug resumption if additional skeletal-related events occur. Prior to bisphosphonate initiation, patients should obtain a comprehensive dental examination, with particular attention paid to the presence of active infections and sites at high risk for infection.
The novel agents themselves are important components of the management of bone disease. According to in vivo and correlative clinical studies, bortezomib both inhibits osteoclasts (ie, bone-resorbing cells) and activates osteoblasts (ie, bone-forming cells).[48-52] There is also promising in vitro evidence that lenalidomide inhibits osteoclast differentiation.[53,54]
As patients live longer with improved control of their disease, extramedullary myeloma has become an increasingly important challenge. Involvement is usually multifocal, response to conventional chemotherapy is generally poor, and resistance to treatment is frequent. Response of extramedullary disease to thalidomide(Drug information on thalidomide) may be limited,[55-57] but thalidomide can be used successfully in combination with other agents. Bortezomib seems to be active in extramedullary disease, although the numbers of patients formally studied to date has been small and there is preliminary evidence that lenalidomide is active in extramedullary disease when combined with bortezomib and dexamethasone.
Extramedullary disease thus remains particularly difficult to treat in the context of advanced myeloma, and clearly more so than extramedullary disease seen at diagnosis. Patients with relapsed and refractory MM who have extramedullary disease should also be strongly encouraged to participate in clinical trials when appropriate, and off protocol typically need combination approaches including both novel agents and chemotherapy when feasible.
The potential to improve responses and survival in patients with relapsed and refractory MM has increased with the introduction of novel therapies. The NCCN-recommended approaches for treating relapsed and refractory MM with bortezomib and/or lenalidomide are single-agent bortezomib, single-agent lenalidomide, bortezomib/dexamethasone, bortezomib/PLD, len/dex, and RVD.
Synergistic Anti-MM Activity
Ongoing research into drug resistance, side-effect management, and optimal sequencing of available therapies should inform decisions about future treatment choices for individual patients with relapsed and refractory MM. Participation in clinical trials remains a key priority in accomplishing these goals and provides patients with options that may be especially effective in the face of resistant disease. In this context, a number of new approaches—such as inhibiting heat shock protein 90, histone deacetylase, AkT, and mammalian target of rapamycin (Figure 1), as well as using monoclonal antibodies—show great promise. The need for continuing research on this patient population — and the continued development of new agents—including second-generation proteasome inhibitors, new immunomodulatory agents, and other small molecules—remain paramount.
Financial Disclosure: Dr. Richardson has served on advisory boards for Celgene and Millennium. Dr. Laubach has no potential conflicts of interest to disclose. Dr. Mitsiades has received research support from Amgen, AVEO, EMD Serono, OSI, and Sunesis, and has received honoraria from Bristol-Myers Squibb, Merck, Millennium, and Novartis. Dr. Schlossman has served on speakers' bureaus for Celgene and Millennium. Ms. Doss has served on speakers' bureaus for Celgene and Millennium. Ms. Colson has served on advisory boards for Millennium. Ms. McKenney, Ms. Noonan, and Ms. Warren have no potential conflicts of interest to disclose. Dr. Ghobrial has served on advisory boards for Celgene; has served on speakers' bureaus for Celgene, Millennium, and Novartis; and has received honoraria from Celgene, Millennium, and Novartis. Dr. Munshi has served on advisory boards for Celgene, Millennium, and Novartis. Dr. Anderson has served on advisory boards for, and has received research support and honoraria from, Celgene, Millennium, and Novartis.
Acknowledgements: The authors gratefully thank Katie Redman for administrative assistance and Faith Reidenbach for assistance with drafting the manuscript.
Address all correspondence to: Paul G. Richardson, MD, Associate Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute 44 Binney St Dana 1B02 Boston, MA 02115 e-mail: email@example.com
Multiple Myeloma Therapy Supplement
1. Brenner H, Gondos A, Pulte D: Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 111:2521-2526, 2008.
2. Richardson P, Mitsiades C, Schlossman R, et al: The treatment of relapsed and refractory multiple myeloma. Am Soc Hematol Educ Program 317-323, 2007.
3. National Comprehensive Cancer Network: NCCN Practice Guidelines in Oncology: Multiple Myeloma. Version 2.2010. July 1, 2009. Available at: http://www.nccn.org. Accessed January 20, 2010.
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, Sonneveld P, Schuster MW, et al: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2005.
7. 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 110:3557-3560, 2007.
8. 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.
9. Weber DM, Chen C, Niesvizky R, et al: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133-2142, 2007.
10. Dimopoulos M, Spencer A, Attal M, et al: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 357:2123-2132, 2007.
11. Anderson KC, Jagannath S, Jakubowiak A, et al: Lenalidomide, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma: encouraging outcomes and tolerability in a phase II study (abstract 8436). J Clin Oncol 27(15S), 2009.
12. Richardson PG, Sonneveld P, Schuster MW, et al: Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma. Br J Haematol 137:429-435, 2007.
13. Lonial S, Richardson PG, San Miguel J, et al: Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma. Br J Haematol 143:222-229, 2008.
14. Richardson PG, Sonneveld P, Schuster MW, et al: Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: Impact of a dose-modification guideline. Br J Haematol 144:895-903, 2009.
15. Velcade (bortezomib) [package insert]: Cambridge, MA: Millennium Pharmaceuticals, Inc; 2008.
16. Percy LA, Rabin N, Cheesman S, et al: Bortezomib in real patients: A single-center experience (abstract A230). Clin Lymphoma Myeloma 9:S38-S39, 2009.
17. Quach H, Horvath N, Cannell P, et al: Safety and efficacy results from an international expanded access programme to bortezomib for patients with relapsed and/or refractory multiple myeloma: A subset analysis of the Australian and New Zealand data of 111 patients. Intern Med J 39:290-295, 2009.
18. Berenson JR, Jagannath S, Barlogie B, et al: Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer 104:2141-2148, 2005.
19. Mikhael JR, Belch AR, Prince HM, et al: High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: Results of a global phase 3b expanded access program. Br J Haematol 144:169-175, 2009.
20. Knauf WU, Otremba B, Overkamp F, et al: Bortezomib in relapsed multiple myeloma: Results of a non-interventional study by office-based haematologists. Onkologie 32:175-180, 2009.
21. Sood R, Carloss H, Kerr R, et al: Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib. Am J Hematol 84:657-660, 2009.
22. Petrucci MT, Blau IW, Corradini P, et al: Efficacy and safety of re-treatment with bortezomib (Velcade) in patients with multiple myeloma: Results from a prospective international phase II trial (abstract 3690). Blood 112:2008.
23. Harousseau JL, Nagler A, Sonneveld P, et al: Effect of the combination of pegylated liposomal doxorubicin and bortezomib on time to progression and overall survival of patients with relapsed/refractory multiple myeloma compared with bortezomib alone (abstract 8002). J Clin Oncol 25(18S):2007.
24. Bladé J, San Miguel J, A. N, et al: The prolonged time to progression with pegylated liposomal doxorubicin + bortezomib versus bortezomib alone in relapsed or refractory multiple myeloma is unaffected by extent of prior therapy or previous anthracycline exposure (abstract 410). Blood 110:2007.
25. Sutherland HJ, Bladé J, San Miguel J, et al: Effect of disease stage and time since diagnosis on time to progression for pegylated liposomal doxorubicin + bortezomib vs bortezomib alone in relapsed or refractory multiple myeloma (abstract 2740). Blood 110:2007.
26. Kumar S, Bladé J, San Miguel J, et al: Pegylated liposomal doxorubicin in combination with bortezomib may provide therapeutic advantage for high-risk multiple myeloma patients relapsing within 12 months of stem cell transplant (abstract 2730). Blood 110:2007.
27. Chanan-Khan A, Dimopoulos MA, Weber DM, et al: Safety and efficacy outcomes with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma were not significantly different for the treatment of patients with or without high-risk disease or elderly status (abstract 3701). Blood 112:2008.
28. Chen C, Reece DE, Siegel D, et al: Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. Br J Haematol 146:164-170, 2009.
29. Dimopoulos MA, Chen C, Spencer A, et al: Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 23:1247-1252, 2009.
30. San Miguel JF, Dimopoulos M, Weber D, et al: Dexamethasone dose adjustments seem to result in better efficacy and improved tolerability in patients with relapsed/refractory multiple myeloma who are treated with lenalidomide/dexamethasone (MM009/010 sub-analysis) (abstract 2712). Blood 112:2007.
31. Richardson P, Jagannath S, Hussein M, et al: Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood 114:772-778, 2009.
32. Mitsiades N, Mitsiades CS, Poulaki V, et al: Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: Therapeutic applications. Blood 99:4079-4086, 2002.
33. Mikhael JR, Samiee S, Stewart AK, et al: Outcome after second autologous stem cell transplantation as salvage therapy in patients with relapsed multiple myeloma (abstract 943). Blood 104:2004.
34. Reece DE, Leitch HA, Atkins H, et al: Treatment of relapsed and refractory myeloma. Leuk Lymphoma 49:1470-1485, 2008.
35. Vogl DT, Stadtmauer E, Richardson PG, et al: Impact of prior autologous stem cell transplant in patients receiving bortezomib or dexamethasone for relapsed/refractory multiple myeloma in the APEX trial (abstract 7546). J Clin Oncol 24(18S):2006.
36. Nagler A, Hajek R, Sonneveld P, et al: Doxil + Velcade in previously treated myeloma with prior SCT (abstract PO-625). Haematologica 92(S2):161, 2007.
37. Sonneveld P, Hajek R, Nagler A, et al: Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy. Cancer 112:1529-1537, 2008.
38. Wang M, Dimopoulos MA, Chen C, et al: Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 112:4445-4451, 2008.
39. San Miguel JF, Schlag R, Khuageva NK, et al: Updated follow-up and results of subsequent therapy in the phase III VISTA trial: Bortezomib plus melphalan-prednisone versus melphalan-prednisone in newly diagnosed multiple myeloma (abstract 650). Blood 112:2008.
40. Trieu Y, Xu W, Masih-Khan E, et al: Bortezomib-based therapy following prior lenalidomide + dexamethasone in relapsed multiple myeloma (abstract A334). Clin Lymphoma Myeloma 9:S53-S54, 2009.
41. Chanan-Khan AA, Kaufman JL, Mehta J, et al: Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: A multicenter retrospective study. Blood 109:2604-2606, 2007.
42. Roussou M, Kastritis E, Migkou M, et al: Treatment of patients with multiple myeloma complicated by renal failure with bortezomib-based regimens. Leuk Lymphoma 49:890-895, 2008.
43. San Miguel JF, Richardson PG, Sonneveld P, et al: Efficacy and safety of bortezomib in patients with renal impairment: Results from the APEX phase 3 study. Leukemia 22:842-849, 2008.
44. Bladé J, Sonneveld P, San Miguel JF, et al: Pegylated liposomal doxorubicin plus bortezomib in relapsed or refractory multiple myeloma: Efficacy and safety in patients with renal function impairment. Clin Lymphoma Myeloma 8:352-355, 2008.
45. Weber DM, Spencer A, Wang M, et al; for the MM-009 and MM-010 Investigators: The efficacy and safety of lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma patients with impaired renal function (abstract 8542). Blood 112:2008.
46. Reece DE, Masih-Khan E, Chen C, et al: Use of lenalidomide (Revlimid) +/- corticosteroids in relapsed/refractory multiple myeloma patients with elevated baseline serum creatinine levels (abstract 3548). Blood 108:2006.
47. Kyle RA, Yee GC, Somerfield MR, et al: American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 25:2464-2472, 2007.
48. Heider U, Kaiser M, Muller C, et al: Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Eur J Haematol 77:233-238, 2006.
49. Giuliani N, Morandi F, Tagliaferri S, et al: The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood 110:334-338, 2007.
50. Uy GL, Trivedi R, Peles S, et al: Bortezomib inhibits osteoclast activity in patients with multiple myeloma. Clin Lymphoma Myeloma 7:587-589, 2007.
51. Boissy P, Andersen TL, Lund T, et al: Pulse treatment with the proteasome inhibitor bortezomib inhibits osteoclast resorptive activity in clinically relevant conditions. Leuk Res 32:1661-1668, 2008.
52. Pennisi A, Li X, Ling W, et al: The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo. Am J Hematol 84:6-14, 2009.
53. Breitkreutz I, Raab MS, Vallet S, et al: Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia 22:1925-1932, 2008.
54. Munemasa S, Sakai A, Kuroda Y, et al: Osteoprogenitor differentiation is not affected by immunomodulatory thalidomide analogs but is promoted by low bortezomib concentration, while both agents suppress osteoclast differentiation. Int J Oncol 33:129-136, 2008.
55. Damaj G, Mohty M, Vey N, et al: Features of extramedullary and extraosseous multiple myeloma: A report of 19 patients from a single center. Eur J Haematol 73:402-406, 2004.
56. Bladé J, Perales M, Rosiñol L, et al: Thalidomide in multiple myeloma: Lack of response of soft-tissue plasmacytomas. Br J Haematol 113:422-424, 2001.
57. Rosiñol L, Cibeira MT, Bladé J, et al: Extramedullary multiple myeloma escapes the effect of thalidomide. Haematologica 89:832-836, 2004.
58. Laura R, Cibeira MT, Uriburu C, et al: Bortezomib: An effective agent in extramedullary disease in multiple myeloma. Eur J Haematol 76:405-408, 2006.
59. Richardson PG, Jagannath S, Avigan DE, et al: Lenalidomide plus bortezomib (Rev-Vel) in relapsed and/or refractory multiple myeloma: Final results of a multicenter phase 1 trial (abstract 405). Blood 108:405, 2006.
60. Richardson PG, Mitsiades C, Schlossman R, et al: New drugs for multiple myeloma. Oncologist 12:664-689, 2007.
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