In 2004, multiple myeloma was diagnosed in more than 15,000 people in the United States and will account for approximately 20% of deaths due to hematologic malignancies. Although traditional therapies such as melphalan (Alkeran)/prednisone, combination chemotherapy with VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), and high-dose chemotherapy with stem cell transplantation have shown some success, median survival remains between 3 to 5 years. Treatment options for patients with multiple myeloma have increased in recent years, with the promise of improvement in survival. New agents, such as the proteasome inhibitor bortezomib (Velcade), the antiangiogenic and immunomodulator thalidomide (Thalomid) and its analogs, such as lenalidomide (Revlimid), together with other small molecules, including arsenic trioxide (Trisenox), and other targeted therapies, have been studied alone and in combination with other antineoplastic therapies, either as induction therapy prior to stem cell transplantation or in patients with relapsed disease. Bortezomib recently was approved in the United States for the treatment of multiple myeloma in patients who have received at least one prior therapy. The use of bortezomibbased regimens as front-line therapy as well as the use of other agents in multiple myeloma remain under investigation, and approvals for both thalidomide and lenalidomide are hoped for soon, with the overall prospect of patient outcome continuing to be increasingly positive.
In 2004, multiple myeloma was diagnosed in more than 15,000 people and accounted for approximately 11,000 deaths, representing 20% of fatalities due to hematologic malignancies in the United States. Multiple myeloma is a hematologic B-cell malignancy associated with elevated serum and urine immunoglobulins, plasma cell infiltration of the bone marrow, soft-tissue plasmacytomas, and skeletal complications. Traditional therapies for multiple myeloma have included the combination of the alkylating agent melphalan (Alkeran) with the steroid prednisone; combination chemotherapy with VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone); high-dose chemotherapy with autologous stem cell transplantation (SCT); and nonmyeloablative or fully ablative allogeneic transplantation.[2,3] Although many patients respond to treatment, relapse is inevitable and median survival remains between 3 and 5 years[3,4]; hence, the need for new approaches is critical. Multiple new agents for the treatment of multiple myeloma are under clinical examination, including the proteasome inhibitor bortezomib (Velcade), thalidomide (Thalomid) and its analogs such as lenalidomide (Revlimid), and arsenic trioxide (Trisenox), as well as a variety of other therapeutic strategies. This review briefly covers these emerging therapeutics and discusses their potential in myeloma therapy. It is important to note that clinical trials have applied different criteria to measure response to treatment. Commonly used response criteria and modified versions include those of the Southwest Oncology Group (SWOG), the Eastern Cooperative Oncology Group (ECOG), and the European Group for Blood and Marrow Transplantation (EBMT), which all share certain outcome measures (eg, paraprotein reduction). However, the EBMT criteria define response more stringently and are now accepted as the most rigorous standard in drug development. Nevertheless, response rates from various agents should be compared with caution, because the criteria to measure response differ between trials. Bortezomib The proteasome, a multisubunit protease complex, plays an essential role in protein homeostasis in both normal and neoplastic cells. The proteasome is critical to regulated degradation of proteins involved in essential cellular functions, including protein turnover, cell adhesion, cell-cycle progression, antigen presentation, and inflammation.[8-10] Inhibition of proteasome function offers encouraging possibilities for the treatment of cancer, and various natural and synthetic molecules have been used to study proteasome inhibition in neoplastic cells. However, only bortezomib (formerly known as PS-341), a boronic acid peptide derivative and potent (Ki = 0.6 nM), selective, reversible proteasome inhibitor, has entered trials and been approved for clinical use. Mechanisms of Action
Several mechanisms by which bortezomib elicits antitumor effects in multiple myeloma have been identified. Inhibition of the proteasome with bortezomib has been shown to decrease myeloma cell proliferation through stabilization of the tumor suppressor p53 and the cyclin-dependent kinase inhibitors p21 and p27.[13,14] Bortezomib also promotes apoptosis via stabilization of the proapoptotic Bid and Bax proteins and inhibitor- κBα (IκBα), as well as activation of the c-Jun NH2-terminal kinase (JNK), as illustrated in Figure 1.[14-16] Stabilization of IκBα has been shown to result in inhibition of nuclear factor κB (NF-κB) activation and to prevent upregulation of the antiapoptotic Bcl-2, Bcl-xL, and XIAP proteins.[17,18] These effects produce an increase in caspase-9-mediated apoptosis. Activated JNK also increases AP-1-mediated upregulation of Fas protein (CD95), which promotes caspase-8-mediated apoptosis.[ 19] Therefore, treatment with bortezomib may ultimately restore an apoptotic phenotype to myeloma cells through increased activation of both the intrinsic and extrinsic pathways. The antitumor activity of bortezomib also occurs in part through indirect effects on the bone marrow microenvironment (Figure 2). Bortezomib has been shown to inhibit the adhesion of myeloma cells with bone marrow stromal cells (BMSCs), thereby preventing the release of cytokines such as interleukin (IL)-6, vascular endothelial growth factor (VEGF), and insulin growth factor-1 (IGF-1). Bortezomib- mediated inhibition of these cytokines, which promote proliferation, survival, and angiogenesis, has resulted in decreased viability of myeloma cells, as well as sensitization to antineoplastic agents. This chemosensitization may also result from inhibition of NF-κB- mediated release of VEGF and IL-6 production by the BMSCs. NF-κB activity also has been associated with chemoresistance, and loss of NF-κB- mediated protection may result in chemosensitization. Importantly, evidence has shown that normal cells are less sensitive to proteasome inhibition than neoplastic cells and that proteasome activity has recovered in normal tissues within 24 hours following treatment.[12,21] Relapsed, Refractory Multiple Myeloma
The results of a number of clinical studies of bortezomib in relapsed and/or refractory multiple myeloma are summarized in Table 1.[22-34] Phase I trials suggested that multiple myeloma is sensitive to proteasome inhibition and that a dosing schedule allowing for a 72-hour interval between individual doses and a drugfree rest period every third week has manageable toxicities.[35,36]
- SUMMIT-Based in part on the results of these studies, as well as highly supportive and provocative preclinical data in in vitro and in vivo models of multiple myeloma, SUMMIT, a phase II trial, focused on patients with multiple myeloma that had both relapsed after prior therapy and was refractory to the last therapy. Patients (N = 202) received bortezomib, 1.3 mg/m2 twice weekly for 2 weeks, with a 1-week rest between cycles. Responses were determined using modified EBMT criteria. Complete response (CR) was defined as absence of paraprotein (undetectable by both electrophoresis and immunofixation), normal serum calcium concentration, and stable skeletal disease. To better define the range of responses classified as partial response (PR) by EBMT criteria, SUMMIT and CREST (described below) investigators included a new response category-near CR (nCR)- defined as 100% disappearance of paraprotein by electrophoresis but retention of positive immunofixation profile, with stable bone disease and a normal serum calcium concentration. Overall, 27% of the 193 evaluable patients demonstrated a major response (PR or better), with 4% achieving CR, an additional 6% achieving nCR, and 18% PR. A landmark analysis demonstrated that patients who achieved a major response to bortezomib after two cycles survived significantly longer than those who did not (P = .007). Median survival with or without extended treatment was 17 months. Data from an extension study with 63 patients showed that extended treatment with bortezomib for up to 32 cycles was associated with a manageable safety profile. Bortezomib was effective in improving aspects of patient care such as improvement in global quality of life and reduction in disease symptoms. When patients who achieved major responses were analyzed apart from the remainder of the population, bortezomib treatment improved the overall quality of life and resulted in clinical benefits such as increased hemoglobin levels and platelet counts. Response rates were independent of number or type of prior therapies and other prognostic factors such as chromosome 13 deletion and β2-microglobulin levels. Responses were, however, significantly associated with the percentage of plasma cells in the bone marrow and patient age. The most frequently reported toxicities of bortezomib were gastrointestinal, with nausea and diarrhea being most prevalent, along with fatigue, cyclical thrombocytopenia that recovered by the first day of the subsequent cycle, and peripheral neuropathy that resolved or improved in the majority of patients following discontinuation of treatment.
- CREST-The CREST study examined bortezomib in multiple myeloma patients who had relapsed after first-line therapy. In this study of 54 patients with relapsed or refractory disease, two dosing schedules-bortezomib at 1.0 mg/m2, and 1.3 mg/m2, administered on days 1, 4, 8, and 11 with a 1-week rest each 3-week cycle-were assessed. The response rates (CR + PR) were 30% and 38% for patients who received bortezomib alone at 1.0 or 1.3 mg/m2, respectively. The toxicities observed were similar to those reported in SUMMIT.
- APEX-APEX, an international, multicenter phase III study, compared bortezomib with high-dose dexamethasone in 669 patients with relapsed or refractory multiple myeloma. The dexamethasone arm of the trial was stopped after a preplanned interim analysis revealed significant clinical benefits in survival and time to disease progression for patients receiving bortezomib. Dexamethasone patients were allowed to cross over to receive bortezomib in a companion study.
- Bortezomib/Dexamethasone- Preclinical evidence supports the concept that the effectiveness of bortezomib could be enhanced through combination with antineoplastic therapy. The combination of bortezomib with dexamethasone has resulted in at least additive anticancer effects in multiple myeloma cells. Bortezomib has also markedly sensitized multiple myeloma cell lines to chemotherapeutic agents such as melphalan, mitoxantrone (Novantrone), and doxorubicin, and these combinations have yielded synergistic effects.[20,21] Based on these preclinical data in multiple myeloma models, the addition of dexamethasone was permitted in both the SUMMIT and CREST phase II studies if patients presented with suboptimal responses to bortezomib monotherapy (progressive disease after two cycles or stable disease after the first four cycles). In SUMMIT, responses were observed in 13 (18%) of 74 evaluable patients who received dexamethasone with bortezomib after having demonstrated stable or progressive disease with single-agent bortezomib. In CREST, the combination of bortezomib with dexamethasone also resulted in additional responses, with response rates (CR + PR) of 37% and 50% at the two dose levels. Furthermore, responses to bortezomib plus dexamethasone were seen in patients previously documented as having refractory disease. Results from a phase I study assessing combination therapy with pegylated liposomal doxorubicin (Doxil) in a variety of refractory hematologic malignancies, including multiple myeloma, have been reported. Patients (N = 42, including 24 with multiple myeloma) received doses of bortezomib ranging from 0.90 to 1.5 mg/m2 on days 1, 4, 8, and 11, with liposomal doxorubicin (30 mg/m2) on day 4 of the 3-week cycle. In patients with multiple myeloma (n = 22 evaluable), this combination resulted in 5 CRs, 3 nCRs, and 8 PRs (72% CR or PR), while five patients had either a minor response or stable disease. Cycle 1 grade 3/4 doselimiting toxicities included diarrhea, constipation, hyponatremia, hypotension, confusion, neutropenia, and syncope. Clinically relevant (grade 3/4) toxicity related to drug treatment observed after cycle 1 included constipation, cytopenias, diarrhea, fatigue, impotence, palmar-plantar erythrodysesthesia, and peripheral neuropathy. More than 60% of patients who were resistant to or who relapsed from prior anthracycline therapy responded.
- Bortezomib/Melphalan-Based on preclinical evidence of synergy between bortezomib and melphalan in multiple myeloma,[20,21] Berenson and colleagues examined combination bortezomib and melphalan in patients (N = 28) with relapsed or refractory multiple myeloma in a dose-escalation study. In a preliminary report, bortezomib was given at an initial low dose of 0.7 to 1.0 mg/m2 twice weekly for 2 weeks every 4 weeks, in conjunction with melphalan ranging from 0.025 to 0.25 mg/kg on days 1 to 4 every 4 weeks. Initial responses at this dose of bortezomib were encouraging, with over 40% of patients showing a clinical response (CR or PR). Grade 3 toxicities in this study were primarily hematologic. The majority of patients (> 75%) with baseline low-grade peripheral neuropathy (n = 8) exhibited stable neuropathy, but neuropathy in two patients worsened transiently.
- Bortezomib/Thalidomide-In an initial report of 56 multiple myeloma patients who had relapsed following autologous transplantation, treatment with a combination of bortezomib (1.0 or 1.3 mg/m2) and thalidomide (50 to 200 mg) with or without dexamethasone was examined. Neither chromosomal abnormalities nor drug doses appeared to affect responses, although survival tended to be higher in patients without compared to those with chromosomal abnormalities. Grade 3/4 cumulative neurotoxicity was not seen in cycles 1 to 4. The preliminary results of a phase II study of bortezomib (1.3 mg/m2) in combination with thalidomide (100 mg) and liposomal doxorubicin (20 mg) suggested that this combination could induce major responses with manageable toxicities in patients with relapsed or refractory disease.
Newly Diagnosed Multiple Myeloma
Bortezomib has also demonstrated activity as monotherapy or in combination regimens in the treatment of patients with newly diagnosed multiple myeloma in a number of preliminary reports (Table 1).[29-34] Although we have shown that single-agent bortezomib on the standard dose and schedule produced an overall response rate of 45% with manageable toxicities in newly diagnosed patients and less peripheral neuropathy compared with other studies, clinical trials of bortezomib- based combinations in this setting appear more promising, with particularly high CR/nCR rates.[30-34] Jagannath et al found that bortezomib with dexamethasone (40 mg on the day of and after bortezomib administration) with less than PR after two cycles, or less than CR after four cycles, yielded CR, nCR, or PR in the majority of patients with newly diagnosed multiple myeloma. The combination of bortezomib with dexamethasone also appeared to serve as an appropriate induction therapy prior to stem cell transplantation, because the combination was well tolerated and SCT was feasible. Cavenagh et al conducted a trial of bortezomib, 1.3 mg/m2, on days 1, 4, 8, and 11 for up to four 3-week cycles, with dexamethasone, 40 mg, on days 1 to 4, 8 to 11, and 15 to 18 of cycle 1 and on days 1 to 4 of subsequent cycles and doxorubicin, 0, 4.5, or 9.0 mg/m2, on days 1 to 4 in the front-line setting. In this study, over 20% of patients achieved CR, the vast majority had PR, and stem cell collection was feasible in all but one of 21 patients. The regimen of bortezomib, 1.0 to 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of up to four 6-week cycles or on days 1, 8, 15, and 22 of up to five 5-week cycles, with melphalan, 9.0 mg/m2, and prednisone, 60 mg/m2, on days 1 to 4 also demonstrated impressive activity with manageable toxicity.[ 33] In this phase I/II study, no dose-limiting toxicities were observed with bortezomib treatment for up to 49 weeks. Preliminary data from another study also have demonstrated very encouraging results with the use of bortezomib, thalidomide, and dexamethasone[ 34] in the front-line setting. Thalidomide After its introduction in the 1950s as a sedative, thalidomide was linked to serious birth defects and was consequently removed from the marketplace in the 1960s. It regained its position as a viable therapeutic agent when it was discovered to be efficacious in the treatment of erythema nodosum leprosum and has since been investigated in a variety of conditions.[ 40] Most importantly, although still considered experimental, thalidomide is now commonly used to treat multiple myeloma either as monotherapy or in combination with dexamethasone. Specifically, the efficacy and toxicity of thalidomide have been extensively studied in patients with relapsed, refractory, and newly diagnosed multiple myeloma. Mechanisms of Action
Although the antitumor mechanisms of thalidomide have not been fully defined, evidence suggests that induction of apoptosis, inhibition of cytokine production and angiogenesis, and immune modulation of T cells and natural killer cells are involved.[ 41-43] Thalidomide has been shown to promote apoptosis through the extrinsic pathway via activation of caspase-8 and inhibition of caspase inhibitor of apoptosis protein-2 (cIAP-2) (Figure 1). The antimyeloma activity of thalidomide is also partially attributable to inhibition of the interaction of multiple myeloma cells with BMSCs (Figure 2). The reduced adhesion results in reduced secretion of cytokines, including IL-6, VEGF, and IGF-1, decreased cell viability and angiogenesis, and chemosensitization of multiple myeloma cells. Inhibition of angiogenesis may be important, because microvessel density-a marker for angiogenesis- increases as multiple myeloma progresses, and a high level of angiogenesis is associated with decreased survival. However, because paraprotein responses to thalidomide have not always correlated with differences in microvessel density, other mechanisms such as immunomodulation and effects of adhesion may be key. Importantly, immune modulation by thalidomide appears to involve activation of phosphatidylinositol 3-kinase and increased IL-2 secretion of T lymphocytes as well as natural killer cell-mediated tumor cell lysis.
Dr. Richardson is a member of the advisory boards and speakers bureaus for Celgene and Millennium. Dr. Anderson receives grant support from Novartis, Millennium, and Celgene.
1. Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer J Clin 54:8-29, 2004.
2. Bensinger WI, Maloney D, Storb R: Allogeneic hematopoietic cell transplantation for multiple myeloma. Semin Hematol 38:243-249, 2001.
3. Rajkumar SV, Gertz MA, Kyle RA, et al: Current therapy for multiple myeloma. Mayo Clin Proc 77:813-822, 2002.
4. Zaidi AA, Vesole DH: Multiple myeloma: An old disease with new hope for the future. CA Cancer J Clin 51:273-285, 2001.
5. 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 Oncol 1:453-461, 1983.
6. Gassmann W, Pralle H, Haferlach T, et al: Staging systems for multiple myeloma: A comparison. Br J Haematol 59:703-711, 1985.
7. 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 Haematol 102:1115-1123, 1998.
8. An B, Goldfarb RH, Siman R, et al: Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ 5:1062-1075, 1998.
9. Cobb RR, Felts KA, Parry GC, et al: Proteasome inhibitors block VCAM-1 and ICAM-1 gene expression in endothelial cells without affecting nuclear translocation of nuclear factor-kappa B. Eur J Immunol 26:839-845, 1996.
10. Craiu A, Gaczynska M, Akopian T, et al: Lactacystin and clasto-lactacystin beta-lactone modify multiple proteasome beta-subunits and inhibit intracellular protein degradation and major histocompatibility complex class I antigen presentation. J Biol Chem 272:13437-13445, 1997.
11. Almond JB, Cohen GM: The proteasome: A novel target for cancer chemotherapy. Leukemia 16:433-443, 2002.
12. Adams J, Palombella VJ, Sausville EA, et al: Proteasome inhibitors: A novel class of potent and effective antitumor agents. Cancer Res 59:2615-2622, 1999.
13. 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 Res 61:3071-3076, 2001.
14. Hideshima T, Mitsiades C, Akiyama M, et al: Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS- 341. Blood 101:1530-1534, 2003.
15. Pei XY, Dai Y, Grant S: The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells. Leukemia 17:2036-2045, 2003.
16. Li B, Dou QP: Bax degradation by the ubiquitin/proteasome-dependent pathway: Involvement in tumor survival and progression. Proc Natl Acad Sci U S A 97:3850-3855, 2000.
17. 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.
18. Dong QG, Sclabas GM, Fujioka S, et al: The function of multiple IkappaB: NF-kappaB complexes in the resistance of cancer cells to Taxolinduced apoptosis. Oncogene 21:6510-6519, 2002.
19. Mitsiades N, Mitsiades CS, Poulaki V, et al: Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99:14374-14379, 2002.
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. 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.
23. 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.
24. Richardson P, Sonneveld P, Schuster MW, et al: Bortezomib or high dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352:2487-2498, 2004.
25. Orlowski RZ, Voorhees PM, Garcia RA, et al: Phase I trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood epub ahead of print, 2005.
26. Berenson J, Yang H, Swift R, et al: Bortezomib in combination with melphalan in the treatment of relapsed or refractory multiple myeloma: A phase I/II study (abstract 209). Blood 104:64a, 2004.
27. Chanan-Khan A, Miller KC, McCarthy P, et al: A phase II study of Velcade (V), Doxil (D) in combination with low-dose thalidomide (T) as salvage therapy for patients (pts) with relapsed (rel) or refractory (ref) multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM): Encouraging preliminary results (abstract 2421). Blood 104:665a-666a, 2004.
28. Zangari M, Barlogie B, Prather J, et al: Marked activity also in Del 13 multiple myeloma (MM) of PS 341 (PS) and subsequent thalidomide (THAL) in a setting of resistance to postautotransplant salvage therapies (abstract 387). Blood 100:105a, 2002.
29. Richardson PG, Chanan-Khan A, 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.
30. Jagannath S, Durie B, Wolf JL, et al: Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 129:776-783, 2005.
31. 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.
32. Cavenagh J, Popat R, Curry N, et al: PAD combination therapy (PS-341/bortezomib, Adriamycin and dexamethasone) for previously untreated patients with multiple myeloma (abstract 1478). Blood 104:413a, 2004.
33. Mateos MV, Blade J, Diaz Mediavilla J, et al: A phase I/II national, multicenter, open-label study of bortezomib plus melphalan and prednisone (V-MP) in elderly untreated multiple myeloma patients (abstract 3462). Blood 104:943a, 2004.
34. Alexanian R, Wang LW, Weber DM, et al: VTD (Velcade, thalidomide, dexamethasone) as primary therapy for newly-diagnosed multiple myeloma (abstract 210). Blood 104:64a, 2004.
35. 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 Res 8:2505-2511, 2002.
36. 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 Oncol 20:4420-4427, 2002.
37. Richardson PG, Barlogie B, Berenson J, et al: Survival, duration of response, and time to progression with bortezomib in patients with relapsed and refractory multiple myeloma: An update with additional follow-up. Hematol J 5:S129, 2004.
38. Berenson JR, Jagannath S, Barlogie B, et al: The safety of prolonged therapy with the proteasome inhibitor bortezomib (VELCADE) in relapsed and/or refractory multiple myeloma (MM). Hematol J 5:S129, 2004.
39. Jagannath S, Richardson P, Barlogie B, et al: Phase II trials of bortezomib in combination with dexamethasone in multiple myeloma (MM): Assessment of additional benefits to combination in patients with sub-optimal responses to bortezomib alone (abstract 2341). Proc Am Soc Clin Oncol 22:582, 2003.
40. Matthews SJ, McCoy C: Thalidomide: a review of approved and investigational uses. Clin Ther 25:342-395, 2003.
41. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96:2943-2950, 2000.
42. Davies FE, Raje N, Hideshima T, et al: Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98:210-216, 2001.
43. Mitsiades N, Mitsiades CS, Poulaki V, et al: Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 99:4525-4530, 2002.
44. Rajkumar SV, Mesa RA, Fonseca R, et al: Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res 8:2210-2216, 2002.
45. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999.
46. Hayashi T, Hideshima T, Akiyama M, et al: Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: Clinical application. Br J Haematol 128:192-203, 2005.
47. 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. Blood 98:492-494, 2001.
48. Rajkumar SV, Fonseca R, Dispenzieri A, et al: Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clin Proc 75:897-901, 2000.
49. 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.
50. 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.
51. Rajkumar SV, Blood E, Vesole DH, et al: Thalidomide plus dexamethasone versus dexamethasone alone in newly diagnosed multiple myeloma (E1A00): Results of a phase III trial coordinated by the Eastern Cooperative Oncology Group (abstract 205). Blood 104:63a, 2004.
52. Palumbo A, Bertola A, 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.
53. Zangari M, Barlogie B, Jacobson J, et al: Revimid 25 mg (REV 25) * 20 versus 50 mg (REV 50) * 10 q 28 days with bridging of 5 mg * 10 versus 10 mg * 5 as post-transplant salvage therapy for multiple myeloma (MM) (abstract 1642). Blood 102:450a, 2003.
54. Richardson P, Jagannath S, Schlossman R, et al: A multi-center, randomized, phase 2 study to evaluate the efficacy and safety of 2 CC- 5013 dose regimens when used alone or in combination with dexamethasone (Dex) for the treatment of relapsed or refractory multiple myeloma (MM) (abstract 825). Blood 102:235a, 2003.
55. Rajkumar SV, Hayman SR, Lacy MQ, et al: Combination therapy with CC-5013 (Lenalidomide; Revlimid™) plus dexamethasone (Rev/Dex) for newly diagnosed myeloma (MM) (abstract 331). Blood 104:98a, 2004.
56. Ghobrial I, Kumar S, Porrata L, et al: Thalidomide does not affect immune reconstitution post-autologous bone marrow transplantation in multiple myeloma (abstract 1679). Blood 100:434a, 2002.
57. Ahmad I, Alam A, Hahn T, et al: Thalidomide plus VAD (vincristine, doxorubicin and dexamethasone) salvage therapy for VAD-refractory multiple myeloma, prior to autologous peripheral blood stem cell transplant (PBSCT) (abstract 4980). Blood 98:307b, 2001.
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 openlabel multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin Proc 79:875-882, 2004.
59. Santos ES, Goodman M, Byrnes JJ, et al: Thalidomide effects in the post-transplantation setting in patients with multiple myeloma. Hematology 9:35-39, 2004.
60. Stewart K, Chen C, Howson-Jan K, et al: A randomized phase II dose-finding trial of thalidomide and prednisone as maintenance therapy for myeloma following autologous stem cell transplant (abstract 1073). Proc Am Soc Clin Oncol 21:269a, 2002.
61. Attal M, Harousseau JL, Leyvraz S, et al: Maintenance treatment with thalidomide after autologous transplantation for myeloma: First analysis of a prospective randomized study of the Intergroupe Francophone du Myelome (IFM 99 02) (abstract 535). Blood 104:155a, 2004.
62. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082-4085, 1994.
63. Dredge K, Marriott JB, Macdonald CD, et al: Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 87:1166-1172, 2002.
64. Treston A, Swartz G, Conner B, et al: Preclinical evaluation of a thalidomide analog with activity against multiple myeloma and solid tumors: ENMD-0995 (S-(-)-3-(3-amino-phthalimido)- glutarimide) (abstract 3225). Blood 100:816a, 2002.
65. Corral LG, Haslett PA, Muller GW, et al: Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 163:380-386, 1999.
66. 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. Blood 100:3063-3067, 2002.
67. Dimopoulous M, Weber D, Chen C, et al: Evaluating oral lenalidomide (Revlimid) and dexamethasone versus placebo and dexamethasone in patients with relapsed or refractory multiple myeloma (abstract 0402). Haematologica 90(suppl 2):160, 2005.
68. Hunt B, Parmar K, Jones R, et al: Markers of endothelial and haemostatic activation in the use of CC-4047, a structual analogue of thalidomide, in relapsed myeloma (abstract 3216). Blood 100:814a, 2002.
69. 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 Oncol 22:3269-3276, 2004.
70. Lacy MQ, Dispenzieri A, Gertz M, et al: ENMD-0995 (S 3-APG), a novel thalidomide analogue, has promising clinical activity for patients with relapsed refractory multiple myeloma: preliminary results of a phase I clinical trial (abstract 1654). Blood 102:453a, 2003.
71. Streetly M, Jones R, Knight R, et al: An update of the use and outcomes of the new immunomodulatory agent CC-4047 (Actimid) in patients with relapsed/refractory myeloma (abstract 829). Blood 102:236a, 2003.
72. 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 Res 60:3065-3071, 2000.
73. Jing Y, Dai J, Chalmers-Redman RM, et al: Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood 94:2102-2111, 1999.
74. 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. Blood 96:1525-1530, 2000.
75. 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 Res 25:227-235, 2001.
76. Rousselot P, Larghero J, Labaume S, et al: Arsenic trioxide is effective in the treatment of multiple myeloma in SCID mice. Eur J Haematol 72:166-171, 2004.
77. Rousselot P, Larghero J, Arnulf B, et al: A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients. Leukemia 18:1518-1521, 2004.
78. Munshi NC, Tricot G, Desikan R, et al: Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia 16:1835-1837, 2002.
79. Hussein MA, Saleh M, Ravandi F, et al: Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol 125:470-476, 2004.
80. May JM, Qu Z, Li X: Requirement for GSH in recycling of ascorbic acid in endothelial cells. Biochem Pharmacol 62:873-881, 2001.
81. Bahlis NJ, McCafferty-Grad J, Jordan- McMurry I, et al: Feasibility and correlates of arsenic trioxide combined with ascorbic acidmediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res 8:3658-3668, 2002.
82. 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 (abstract 5271). Blood 102:386b, 2003.
83. Chanan-Khan A, Miller K, Sirinivasan S, et al: Combination of melphalan (M), ascorbic acid (A) and Trisenox (T) (MAT) as salvage therapy for patients (pts) with relapsed/refractory multiple myeloma (MM) (abstract 5284). Blood 102:389b, 2003.
84. Borad MJ, Swift R, Berenson JR: Efficacy of melphalan, arsenic trioxide, and ascorbic acid combination therapy (MAC) in relapsed and refractory multiple myeloma. Leukemia 19:154-156, 2005.
85. Hussein M, Mason J, Saleh M, et al: Arsenic trioxide (Trisenox®) in patients with relapsed or refractory multiple myeloma (MM): Final report of a phase II clinical study (abstract 5138). Blod 100:393b, 2002.
86. Singer J, Kirkhart B, Frank K, et al: Safety experience with Trisenox (arsenic trioxide) (abstract 5767). Blood 102:509b, 2003.
87. Friedman J, DiPersio J, Devine S, et al: 13 cis-retinoic acid (13cRA) + dexamethasone (Dex) + alpha interferon (IFN): An active combination when used as maintenance therapy following high dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) in patients with multiple myeloma (MM) (abstract 5264). Blood 102:384b, 2003.
88. Rajkumar S, Richardson P, Gertz M, et al: Novel therapy with 2-methoxyestradiol (2ME2) for the treatment of relapsed and plateau phase multiple myeloma (abstract 2564). Blood 102:692a, 2003.
89. Mittelman M, Zeidman A, Fradin Z, et al: Erythropoietin has an anti-myeloma effect: A clinical observation supported by animal studies (abstract 5127). Blood 100:391b, 2002.
90. van de Donk N, de Weerdt O, Veth G, et al: G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD-refractory myeloma (abstract 2556). Blood 102:690a, 2003.
91. Bahlis N, Liu L, Cooper B, et al: Phase II study of O6-benzylguanine (O6-BG) and BCNU in multiple myeloma (abstract 2420). Proc Am Soc Clin Oncol 22:602, 2003.
92. Catley L, Tai YT, Shringarpure R, et al: Proteasomal degradation of topoisomerase I is preceded by c-Jun NH2-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage in SN38-mediated cytotoxicity against multiple myeloma. Cancer Res 64:8746-8753, 2004.
93. Szmania S, Rosen N, Freeman J, et al: Cryopreserved tumor protein loaded dendritic cell vaccines induce potent immune responses in patient with poor prognosis multiple myeloma (abstract 1652). Blood 102:453a, 2003.
94. Borrello I, Biedryzcki B, Sheets N, et al: Autologous tumor combined with a GM-CSF-secreting cell line vaccine (GVAX) following autologous stem cell transplant (ASCT) in multiple myeloma (abstract 1794). Blood 102:493a, 2003.
95. Lust J, Lacy M, Dispenzieri A, et al: In smoldering/ indolent multiple myeloma (SMM/IMM) patients, interleukin-1 receptor antagonist (IL-1Ra) can decrease the C-reactive protein (CRP), plasma cell labeling index (PCLI), and percent bone marrow plasma cells: relevance of the IL-1/IL-6 axis to the progression of SMM/IMM to active MM (abstract 2538). Blood 102:685a, 2003.
96. Lacy M, Blood E, Kay N, et al: Interleukin- 12 treatment for plateau phase multiple myeloma: An Eastern Cooperative Oncology Group (ECOG) phase II trial (E1A96) (abstract 1549). Blood 100:399a, 2002.
97. Sung C, Stabin M, Brill A, et al: LymphoRad-131 pharmacokinetics and dosimetry in ongoing phase I multiple myeloma and non-Hodgkins lymphoma trials (abstract 2537). Blood 102:685a, 2003.
98. Bensinger W, Giralt S, Salzman D, et al: A phase II study to evaluate radiation dosimetry, pharmacokinetics and safety of 166Ho-DOTMP in patients with multiple myeloma undergoing autologous transplantation (abstract 3664). Blood 102:984a, 2003.
99. Giralt S, Bensinger W, Goodman M, et al: Long-term safety and efficacy data supporting new dosing of 166Ho-DOTMP skeletal targeted radiotherapy for multiple myeloma (abstract 3665). Blood 102:985a, 2003.
100. Iuliano F, Abruzzese E, Molica S, et al: Samarium(Sm)153 ethylene diamine tetramethylene phosphonate (153Sm-EDTMP) targeted radiotherapy and zoledronic acid is an effective option for elderly with symptomatic refractory multiple myeloma (abstract 1630). Blood 102:446a, 2003.
101. Lim S, Esler W, Periman P, et al: A phase I/II study of Rituxan (CD20 antibody) maintenance therapy following high dose melphalan and autologous HSCT for multiple myeloma (abstract 5467). Blood 100:472b, 2002.
102. Musto P, Carella A, Greco M, et al: Maintenance therapy with anti-CD20 monoclonal antibody after autologous stem cell transplantation in multiple myeloma may be associated with early relapse (abstract 1685). Blood 100:435a, 2002.
103. Mitsiades N, Mitsiades CS, Poulaki V, et al: Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: Therapeutic implications. Blood 99:4525-4530, 2002.
104. Liu Q, Hilsenbeck S, Gazitt Y: Arsenic trioxide- induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/ TRAIL. Blood 101:4078-4087, 2003.
105. Mitsiades CS, Treon SP, Mitsiades N, et al: TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: Therapeutic applications. Blood 98:795-804, 2001.
106. Bolick SC, Landowski TH, Boulware D, et al: The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drugresistant myeloma tumor cells. Leukemia 17:451- 457, 2003.
107. Alsina M, Fonseca R, Wilson EF, et al: Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 103:3271-3277, 2004.
108. Richardson PG, Schlossman R, Munshi N, et al: Phase I study of bortezomib in combination with lenalidomide in relapsed and refractory multiple myeloma. Haematologica 90:26- 27a, 2005.