Background. Multiple myeloma accounts for 10% of all haematologic malignancies worldwide. In Europe, over 10 000 new cases and nearly 8000 deaths were attributed to multiple myeloma in 2000. Unlike other malignancies, in which surgery and radiation are important treatment modalities, myeloma is exclusively treated with stem cell transplantation and drug therapy, requiring pharmacists to stay abreast of new developments. The melphalan-prednisolone and vincristine-doxorubicin-dexamethasone (VAD) regimens, which have been standard treatments for multiple myeloma over the past few decades, have yielded responses without real survival benefits. Transplantation utilizing high-dose chemotherapy has produced the only meaningful survival benefits for patients with multiple myeloma, but many patients are not candidates for this aggressive treatment option. More effective therapies for multiple myeloma are needed.
Objective. To address the mechanisms of action, safety, and efficacy of novel approaches to the treatment of myeloma involving bortezomib, thalidomide and its analogues, lenalidomide and CC-4047 (ActimidTM), and arsenic trioxide as single agents or in combination regimens.
Data sources. Published preclinical and primary clinical trial results, as well as scientific or clinical meeting abstracts. The author determined the relevance and subsequent inclusion of the data.
Conclusions. Bortezomib is approved in the US and Europe as single-agent therapy for the treatment of relapsed or refractory multiple myeloma. Thalidomide, its analogues, and arsenic trioxide have demonstrated activity and are under investigation in this disease. Further clinical trials of the efficacy and toxicity of these novel agents are ongoing and will further define optimal combinations and sequencing with conventional therapies.
Salmon SE, Haut A, Bonnet JD, et al.Alternating combination chemotherapy and levamisole improves survival in multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol1983; 1: 453-461.
2.
Blade J, Samson D, Reece D, et al.Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol1998; 102: 1115-1123.
3.
Sirohi B, Powles R, Mehta J, et al.Complete remission rate and outcome after intensive treatment of 177 patients under 75 years of age with IgG myeloma defining a circumscribed disease entity with a new staging system. Br J Haematol1999; 107: 656-666.
Alexanian R, Barlogie B, Dixon D.High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med1986; 105: 8-11.
6.
Barlogie B, Smith L, Alexanian R.Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med1984; 310: 1353-1356.
7.
Oken MM, Harrington DP, Abramson N, et al.Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer1997; 79: 1561-1567.
8.
Myeloma Trialists’ Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol1998; 16: 3832-3842.
9.
Attal M, Harousseau JL, Facon T, et al.Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med2003; 349: 2495-2502.
10.
Adams J, Palombella VJ, Sausville EA, et al.Proteasome inhibitors: a novel class of potent and effective anti-tumor agents. Cancer Res1999; 59: 2615-2622.
11.
Delic J, Masdehors P, Omura S, et al.The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis. Br J Cancer1998; 77: 1103-1107.
12.
Teicher BA, Ara G, Herbst R, et al.The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res1999; 5: 2638-2645.
13.
Hideshima T, Chauhan D, Hayashi T, et al.Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene2003; 22: 8386-8393.
14.
Hideshima T, Richardson P, Chauhan D, et al.The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res2001; 61: 3071-3076.
15.
Hideshima T, Mitsiades C, Akiyama M, et al.Molecular mechanisms mediating antimyeloma activity of protea-some inhibitor PS-341. Blood2003; 101: 1530-1534.
16.
Mitsiades N, Mitsiades CS, Poulaki V, et al.Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA2002; 99: 14374-14379.
17.
Mayo MW, Baldwin AS.The transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance. Biochim Biophys Acta2000; 1470: M55-M62.
18.
Wang CY, Cusack JC, Jr., Liu R, et al.Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat Med1999; 5: 412-417.
19.
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 Res2003; 9: 1136-1144.
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. Blood2003; 101: 2377-2380.
21.
Cusack JC, Jr., Liu R, Houston M, et al.Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res2001; 61: 3535-3540.
22.
Pervan M, Pajonk F, Sun JR, et al.Molecular pathways that modify tumor radiation response. Am J Clin Oncol2001; 24: 481-485.
23.
Russo SM, Tepper JE, Baldwin AS, Jr.et al.Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB. Int J Radiat Oncol Biol Phys2001; 50: 183-193.
24.
VELCADE (bortezomib) for injection. Prescribing information available at http://www.millennium.com/products/velcade/indexasp.
25.
Lightcap ES, McCormack TA, Pien CS, et al.Proteasome inhibition measurements: clinical application. Clin Chem2000; 46: 673-683.
26.
Bross PF, Kane R, Farrell AT, et al.Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res2004; 10: 3954-3964.
27.
Aghajanian C, Soignet S, Dizon DS, et al.A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res2002; 8: 2505-2511.
28.
Orlowski RZ, Stinchcombe TE, Mitchell BS, et al.Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol2002; 20: 4420-4427.
29.
Richardson PG, Barlogie B, Berenson J, et al.A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med2003; 348: 2609-2617.
30.
Jagannath S, Barlogie B, Berenson J, et al.A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol2004; 127: 165-172.
31.
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib vs high-dose dexamethasone in relapsed multiple myeloma: results of a large randomized phase 3 study. Available at http://www.abstracts2view.com/hem_sandiego2004. Abstract 336.5.
32.
Yang HH, Vescio R, Schenkein D, et al.A prospective, open-label safety and efficacy study of combination treatment with bortezomib (PS-341, velcade and melphalan in patients with relapsed or refractory multiple myeloma. Clin Lymphoma2003; 4: 119-122.
33.
Orlowski RZ, Voorhees PM, Garcia RA, et al.Phase I study of the proteasome inhibitor bortezomib in combination with pegylated liposomal doxorubicin in patients with refractory hematologic malignancies. Blood2003; 102: 449a-449a.
34.
Mazumder A, Chauvin E, Curran K, et al.Clinical synergism of bortezomib and chemotherapy in relapsed and refractory multiple myeloma. Blood2003; 102: 390b-390b.
35.
Richardson PG, Chanan-Khan AA, Schlossman RL, et al.Phase II trial of single agent bortezomib (VELCADE®)in patients with previously untreated multiple myeloma (MM). Blood2004; 104: 100a-100a.
36.
Jagannath S, Brian D, Wolf JL, et al.Bortezomib as first-line therapy in patients with multiple myeloma: a multicenter phase 2 clinical trial. Blood2004; 103: 125-125.
37.
Cavenagh J, Popat R, Curry N, et al.PAD combination therapy (PS-341/bortezomib, adriamycin and dexamethasone) for previously untreated patients with multiple myeloma. Blood2004; 103: 413a-413a.
38.
Lonial S, Waller EK, Richardson PG, et al.Evaluation of the severity and risk of thrombocytopenia with bortezomib therapy in relapsed and refractory multiple myeloma. Hematol J2004; 5 (suppl 2): S130-S130.
39.
Richardson PG, Briemberg H, Jagannath S, et al.Peripheral neuropathy following bortezomib (VELCADE, formerly PS-341) therapy in patients with advanced multiple myeloma (MM): characterization and reversibility. Blood2003; 102: 149a-149a.
40.
Stinchcombe TE, Mitchell BS, Depcik-Smith ND, et al.PS-341 is active in multiple myeloma: preliminary report of a phase I trial of the proteasome inhibitor PS-341 in patients with hematologic malignancies. Blood2000; 96: 516a-516a.
41.
Correia MA.Hepatic cytochrome P450 degradation: mechanistic diversity of the cellular sanitation brigade. Drug Metab Rev2003; 35: 107-143.
Bagust A, Haycox AR, Boland A, et al.Economic evaluation of bortezomib (Velcade) for relapsed and refractory multiple myeloma. Blood2004; 104: 80a-80a.
Sheskin J.Thalidomide in the treatment of lepra reactions. Clin Pharmacol Ther1965; 40: 303-306.
46.
Matthews SJ, McCoy C.Thalidomide: a review of approved and investigational uses. Clin Ther2003; 25: 342-395.
47.
Hideshima T, Chauhan D, Shima Y, et al.Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood2000; 96: 2943-2950.
48.
Damiano JS, Cress AE, Hazlehurst LA, et al.Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood1999; 93: 1658-1667.
49.
Geitz H, Handt S, Zwingenberger K.Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacology1996; 31: 213-221.
50.
Bellamy WT, Richter L, Frutiger Y, et al.Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res1999; 59: 728-733.
51.
D’Amato RJ, Loughnan MS, Flynn E, et al.Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA1994; 91: 4082-4085.
52.
Haslett PA, Corral LG, Albert M, et al.Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+subset. J Exp Med1998; 187: 1885-1892.
53.
Teo SK, Scheffler MR, Kook KA, et al.Thalidomide dose proportionality assessment following single doses to healthy subjects. J Clin Pharmacol2001; 41: 662-667.
54.
Teo SK, Colburn WA, Thomas SD.Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers. J Clin Pharmacol1999; 39: 1162-1168.
55.
Rajkumar SV, Fonseca R, Dispenzieri A, et al.Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clin Proc2000; 75: 897-901.
56.
Bertolini F, Mingrone W, Alietti A, et al.Thalidomide in multiple myeloma, myelodysplastic syndromes and histiocytosis. Analysis of clinical results and of surrogate angiogenesis markers. Ann Oncol2001; 12: 987-990.
57.
Kneller A, Raanani P, Hardan I, et al.Therapy with thalidomide in refractory multiple myeloma patients: the revival of an old drug. Br J Haematol2000; 108: 391-393.
58.
Richardson P, Schlossman R, Jagannath S, et al.Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin Proc2004; 79: 875-882.
59.
Hus M, Dmoszynska A, Soroka-Wojtaszko M, et al.Thalidomide treatment of resistant or relapsed multiple myeloma patients. Haematologica2001; 86: 404-408.
60.
Neben K, Moehler T, Egerer G, et al.High plasma basic fibroblast growth factor concentration is associated with response to thalidomide in progressive multiple myeloma. Clin Cancer Res2001; 7: 2675-2681.
61.
Tosi P, Zamagni E, Cellini C, et al.Rapid response and early relapse after thalidomide plus dexamethasone salvage therapy in patients with advanced relapsed and refractory multiple myeloma. Blood2001; 98: 163a-163a.
62.
Schey SA, Fields P, Bartlett JB, et al.Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol2004; 22: 3269-3276.
63.
Mileshkin L, Biagi JJ, Mitchell P, et al.Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood2003; 102: 69-77.
64.
Singhal S, Mehta J, Desikan R, et al.Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med1999; 341: 1565-1571.
65.
Yakoub-Agha I, Attal M, Dumontet C, et al.Thalidomide in patients with advanced multiple myeloma: a study of 83 patients -report of the Intergroupe Francophone du Myelome (IFM). Hematol J2002; 3: 185-192.
66.
Barlogie B, Desikan R, Eddlemon P, et al.Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood2001; 98: 492-494.
67.
Schey SA, Cavenagh J, Johnson R, et al.An UK myeloma forum phase II study of thalidomide; long term follow-up and recommendations for treatment. Leuk Res2003; 27: 909-914.
68.
Dimopoulos MA, Zervas K, Kouvatseas G, et al.Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol2001; 12: 991-995.
69.
Palumbo A, Giaccone L, Bertola A, et al.Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica2001; 86: 399-403.
70.
Weber DM, Rankin K, Gavino M, et al.Thalidomide with dexamethasone for resistant multiple myeloma. Blood2000; 96: 167a-167a.
71.
Barlogie B.Thalidomide and CC-5013 in multiple myeloma: the University of Arkansas experience. Semin Hematol2003; 40: 33-38.
72.
Offidani M, Mele A, Marconi M, et al.Thalidomide plus melphalan in relapsed-refractory multiple myeloma. Blood2001; 98: 311b-311b.
73.
Srkalovic G, Karam MA, Trebisky BM, et al.Treatment of refractory/relapsed multiple myeloma (MM) with combination of melphalan, thalidomide and Decadron (MTD). Blood2000; 96: 294b-295b.
74.
Chanan-Khan AA, Miller K, Srinivasan S, et al.Velcade (Vel), Doxil (Dox) and low-dose thalidomide (Thal) as salvage therapy for patients (pts) with relapsed/refrac-tory multiple myeloma (MM). Blood2003; 102: 389b-389b.
75.
Zangari M, Barlogie B, Jacobson J, et al.VTD regimen comprising Valecade (V)+thalidomide (T) and added Dex (D) for non-responders to V+T Effects a 57% PR rate among 56 patients with myeloma (M) relapsing after autologous transplant. Blood2003; 102: 236a-236a.
76.
Hussein MA.Modifications to therapy for multiple myeloma: pegylated liposomal doxorubicin in combination with vincristine, reduced-dose dexamethasone, and thalidomide. Oncologist2003; 8 (suppl 3): 39-45.
77.
Rajkumar SV, Hayman S, Gertz MA, et al.Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol2002; 20: 4319-4323.
78.
Rajkumar SV, Blood E, Vesole DH, et al.A randomised phase III trial of thalidomide plus dexamethasone versus dexamethasone in newly diagnosed multiple myeloma (E1A00): a trial coordinated by the Eastern Cooperative Oncology Group. Proc Am Soc Clin Oncol2004; 23: 558-558.
79.
Weber D, Rankin K, Gavino M, et al.Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol2003; 21: 16-19.
80.
Zangari M, Anaissie E, Barlogie B, et al.Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood2001; 98: 1614-1615.
81.
Bennet CL, Schumok GT, Kwaan HC, et al.High Incidence of thalidomide-associated deep vein thrombosis and pulmonary emboli when chemotherapy is also administered. Blood2001; 98: 863a-863a.
82.
Haslett P, Tramontana J, Burroughs M, et al.Adverse reactions to thalidomide in patients infected with human immunodeficiency virus. Clin Infect Dis1997; 24: 1223-1227.
83.
Rajkumar SV, Gertz MA, Witzig TE.Life-threatening toxic epidermal necrolysis with thalidomide therapy for myeloma. N Engl J Med2000; 343: 972-973.
84.
Richardson PG, Jagannath S, Schlossman R, et al.A multi-center, randomized, phase 2 study to evaluate the efficacy and safety of 2 CDC-5013 dose regimens when used alone or in combination with dexamethasone (Dex) for the treatment of relapsed or refractory multiple myeloma (MM). Blood2003; 102: 235a-235a.
85.
Streetly M, Macey MG, McCarthy DA, et al.Changes in neutrophil phenotype following the administration of CC-4047 (Actimid) to patients with multiple myeloma. Blood2003; 102: 687a-687a.
86.
Richardson PG, Schlossman RL, Weller E, et al.Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood2002; 100: 3063-3067.
87.
Gallagher RE.Arsenic -new life for an old potion. N Engl J Med1998; 339: 1389-1391.
88.
Park WH, Seol JG, Kim ES, et al.Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res2000; 60: 3065-3071.
89.
Rousselot P, Labaume S, Marolleau JP, et al.Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients. Cancer Res1999; 59: 1041-1048.
90.
Deaglio S, Canella D, Baj G, et al.Evidence of an immunologic mechanism behind the therapeutical effects of arsenic trioxide (As(2)O(3)) on myeloma cells. Leuk Res2001; 25: 227-235.
91.
Roboz GJ, Dias S, Lam G, et al.Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis. Blood2000; 96: 1525-1530.
92.
Rousselot P, Larghero J, Labaume S, et al.Arsenic trioxide is effective in the treatment of multiple myeloma in SCID mice. Eur J Haematol2004; 72: 166-171.
93.
Shen ZX, Chen GQ, Ni JH, et al.Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood1997; 89: 3354-3360.
Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I, et al.Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res2002; 8: 3658-3668.
96.
Borad M, Swift RA, Sadler K, et al.Melphalan, arsenic trioxide and ascorbic acid (MAC) is effective in the treatment of refractory and relapsed multiple myeloma (MM). Blood2003; 102: 235a-235a.
97.
Rousselot P, Larghero J, Arnulf B, et al.A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients. Leukemia2004; 18: 1518-1521.
98.
Berenson J, Yang H, Vescio R, et al.Preliminary findings in a phase I/II study of Trisenox® (arsenic trioxide) dosed twice weekly in patients with advanced multiple myeloma. Blood2002; 100: 394b-394b.
99.
Munshi NC, Tricot G, Desikan R, et al.Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia2002; 16: 1835-1837.
100.
Birch R, Schwartzberg L, Lawrence V, et al.A phase II study of arsenic trioxide (ATO) in combination with dexamethasone (Dex) and ascorbic acid (VITC) in patients with relapsed/refractory multiple myeloma. Blood2003; 102: 386b-386b.
101.
Hussein MA, Saleh M, Ravandi F, et al.Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol2004; 125: 470-476.
102.
Boccia R, Bessudo A, Steis R, et al.A phase II, multicenter, safety and efficacy study of combination treatment with melphalan, arsenic trioxide, and ascorbic acid (MAC) in patients with relapsed or refractory multiple myeloma: interim analysis. Blood2004; 104: 659a-659a.
103.
Barbey JT, Soignet S.Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med2001; 135: 842-843.
104.
Ohnishi K, Yoshida H, Shigeno K, et al.Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med2000; 133: 881-885.
105.
Camacho LH, Soignet SL, Chanel S, et al.Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J Clin Oncol2000; 18: 2620-2625.
106.
Santra A, Maiti A, Das S, et al.Hepatic damage caused by chronic arsenic toxicity in experimental animals. J Toxicol Clin Toxicol2000; 38: 395-405.
107.
Tallman MS, Andersen JW, Schiffer CA, et al.Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood2000; 95: 90-95.
108.
Trisenox (arsenic trioxide) injection. Prescribing information available at http://www.cticseattle.com/products_mprofhtm.
