Responses to treatment of relapsed and refractory multiple myeloma are characteristically short, and median survival is as brief as 6 months. Although prognostic factors in the context of relapsed and refractory disease require further characterization, high-risk patients include those with certain cytogenetic abnormalities, high β2-microglobulin, and low serum albumin. The development of novel therapies targeting disease biology and tumor microenvironment has significantly improved the outlook for patients with relapsed and refractory disease, with bortezomib (Velcade), a first-in-class proteasome inhibitor, and the immunomodulatory agents thalidomide (Thalomid) and lenalidomide (Revlimid) constituting “backbone” agents in this setting. More recent approaches for treating relapsed and refractory myeloma that are recommended by the National Comprehensive Cancer Network include single-agent bortezomib, single-agent lenalidomide, bortezomib/dexamethasone, bortezomib plus pegylated liposomal doxorubicin, lenalidomide/dexamethasone, and lenalidomide/bortezomib/dexamethasone. Individualized treatment of progressive myeloma should take into account the time to progression and/or the type of prior therapy. Additional clinical challenges discussed in this article are renal dysfunction, extramedullary disease, and advanced bone disease. Finally, participation in clinical trials is especially encouraged in this patient population.
Supported by an educational grant from Millennium Pharmaceuticals, Inc.
Survival in multiple myeloma (MM) has improved significantly since 1990, but the disease remains incurable, with most patients responding to therapy but all eventually relapsing. Some have primary refractory disease and do not respond to initial therapy, and those with relapsed and refractory disease constitute a serious and unmet medical need. Overall, the median survival of patients with relapsed and refractory MM is as short as 6 months.
Patients who have received at least two prior therapies and have progressed on therapy or within 60 days of last treatment are usually defined as having “relapsed and refractory” MM. Clinical considerations in caring for these patients include the number of prior therapies, existing and potential toxicities related to treatment, and disease characteristics (eg, aggressiveness of relapse, relapsed disease emerging from prior remission vs disease that is truly both relapsed and refractory, and other high-risk features). Features associated with poor prognosis are t(4;14) or t(14;16), deletion of chromosomes 17 and/or 13, hypodiploidy, high β2-microglobulin, and low serum albumin. Additional challenging clinical scenarios include patients with light-chain and immunoglobulin A (IgA) isotype, renal failure, extramedullary disease, hyposecretory myeloma, and/or advanced bone disease.
There is no single standard treatment for relapsed and refractory MM; the National Comprehensive Cancer Network (NCCN) recommends a number of agents and combinations as salvage therapy (Table 1). This article reviews recent data on the efficacy and safety of NCCN-recommended therapies that make use of bortezomib and/or lenalidomide, in primarily describing the use of novel agents in the setting.
Clinical Data on NCCN-Recommended Therapies
In 2003, bortezomib (Velcade) was granted accelerated approval by the US Food and Drug Administration (FDA) for treatment of relapsed and refractory MM on the basis of results from the phase II trials SUMMIT (Study of Uncontrolled Multiple Myeloma managed with proteasome Inhibition Therapy) and CREST (Clinical Response and Efficacy Study of bortezomib in the Treatment of relapsing multiple myeloma).[4,5] Subsequently, the phase III APEX trial (Assessment of Proteasome inhibition for EXtending remissions) showed that in comparison with high-dose dexamethasone, bortezomib improved time to progression (TTP), complete response (CR) rate, and overall survival (OS) (Table 2).[3,6-11] Bortezomib received full FDA approval in 2005. With extended follow-up (median, 22 months), response rates further improved to 43% with bortezomib; moreover, 1-year survival was superior with bortezomib, even though 62% of patients in the control arm crossed over to bortezomib. On subgroup analysis of the APEX trial, bortezomib demonstrated substantial clinical activity in patients ≥ 65 years old and those with more than one prior line of therapy, stage II/III myeloma by the International Staging System, or refractoriness to immediate prior therapy.
As observed in SUMMIT and CREST, bortezomib-associated thrombocytopenia and neutropenia in APEX were transient and cyclical, with rapid recovery during the treatment-free period in each dosing cycle. Although the rate of grade 3/4 thrombocytopenia was higher with bortezomib than with dexamethasone (30% vs 6%), the incidence of significant bleeding events was comparable in the two treatment groups. Bortezomib-associated thrombocytopenia may not require treatment delays or dose reductions, except in instances of grade 4 toxicity or any situation involving bleeding. In most instances, it can be managed with platelet transfusions as needed to maximize dosing and response to therapy. Similarly, bortezomib-associated neutropenia can typically be managed with growth factor support, with dose delay reserved for patients with febrile neutropenia, which occurred in only 0.3% of bortezomib-treated patients in the APEX, SUMMIT, and CREST studies.
Bortezomib-associated peripheral neuropathy (PN) was the most important toxicity, but proved generally reversible in the APEX trial, using a dose-modification guideline that now appears in the bortezomib prescribing information. Overall, 91 of 331 (27%) patients in the bortezomib arm had treatment-emergent PN of grade ≥ 2. Of those, 64% experienced improvement or resolution to baseline at a median of 110 days, and improvement/resolution was more likely for patients who had dose modification. Grade ≥ 2 PN and dose modification did not appear to adversely affect bortezomib efficacy. Fourteen patients discontinued bortezomib due to grade ≥ 2 PN, and of these, 45% did so within the first three cycles. Close monitoring during initial treatment and, if required, prompt dose modification are necessary to prevent progressive PN and aid reversibility.
Experience outside clinical trials has confirmed the tolerability and efficacy of bortezomib in relapsed and refractory MM. At one center, among 65 patients who received bortezomib with or without a corticosteroid, the overall response rate (ORR) was 64% among patients with relapsed and refractory MM, and the response rate was even higher (82%) among those with primary refractory disease. Response was better in patients who received bortezomib at first or second relapse than in those treated at later points in the disease course. Four patients developed acute renal failure requiring dialysis, two of them following grade 3 diarrhea, and both of the latter patients subsequently died. Grade 3 PN occurred in 13% of patients, grade 3/4 thrombocytopenia in 42%, and grade 3/4 neutropenia in 31%.
In a separate study, investigators in Australia and New Zealand evaluated 111 heavily pretreated patients who received bortezomib for relapsed and refractory MM. Among them, 82% had at least three previous lines of therapy and > 40% had at least four. The most common grade 3/4 events were thrombocytopenia (26%), anemia (8%), peripheral neuropathy (7%), and diarrhea (7%). Of 106 patients evaluable for response, 22% achieved CR and 20% achieved partial response (PR), with the median time to best response being 69 days.
The combination of bortezomib and dexamethasone is at least additive. In an extension trial involving 63 patients from SUMMIT and CREST, retreatment with or continuation of bortezomib ± dexamethasone for a total of 7 to 32 cycles was documented to be safe, with no evidence of new cumulative toxicity. In total, 75% (n = 47) of patients received bortezomib plus dexamethasone, with 38% (n = 18) achieving at least PR.
A multicenter, open-label, phase IIIb trial also showed that bortezomib/dexamethasone is safe and effective for heavily pretreated patients with relapsed and refractory MM. The 638 patients (median, three prior therapies) received bortezomib ± dexamethasone for a maximum of eight 3-week cycles (median, five cycles). The ORR was 67%, including 11% CR. Among the 208 patients who received bortezomib/dexamethasone, 70% showed stable disease or improved response compared with their response to bortezomib monotherapy. The most common grade 3/4 adverse events were thrombocytopenia (39% of patients), neutropenia (16%), and anemia (12%). The most common adverse event leading to treatment discontinuation was PN (5%).
Bortezomib was also recently prospectively studied by 14 office-based hematologists. Of 46 evaluable patients with relapsed and refractory MM, 22 received concurrent dexamethasone and 1 received prednisone. The ORR was 61%, with a median time to best response of three cycles. Response rates were similar for patients ≤ 70 and > 70 years of age, those with and without renal impairment, and those who did or did not receive concurrent steroid medication. Important grade 3/4 adverse events included thrombocytopenia, PN, fatigue and bone pain, and anemia.
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.