New Drugs for Myeloma. Key Words. Bortezomib Lenalidomide Multiple myeloma Thalidomide

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1 The Oncologist Myelomas New Drugs for Myeloma PAUL G. RICHARDSON, CONSTANTINE MITSIADES, ROBERT SCHLOSSMAN, NIKHIL MUNSHI, KENNETH ANDERSON Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA LEARNING OBJECTIVES Key Words. Bortezomib Lenalidomide Multiple myeloma Thalidomide After completing this course, the reader will be able to: 1. Discuss the impact of novel agents on the treatment paradigm for multiple myeloma. 2. Explain the importance of combination regimens and in particular the ability to rechallenge patients with a combination of drugs that may each have been administered separately before. 3. Describe the toxicity profiles of the agents being used with a focus on key side effects and discuss the potential value of these agents in special populations, such as those with renal failure. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit at CME.TheOncologist.com ABSTRACT Although multiple myeloma remains incurable with conventional treatments, management of the disease has recently been transformed with the introduction of three novel agents, bortezomib, thalidomide, and lenalidomide. The proteasome inhibitor bortezomib is approved for the treatment of patients who have received one prior therapy; there is a growing body of clinical evidence showing its effectiveness alone and in combination in the frontline setting, with high response rates and consistently high rates of complete response. Thalidomide plus is approved as frontline treatment of multiple myeloma. Other combination regimens including thalidomide have demonstrated substantial activity in both relapsed and frontline settings. Recently, the thalidomide analogue lenalidomide has been approved, in combination with, for the treatment of patients who have received one prior therapy; this regimen has shown promising results in the frontline setting. These agents represent a new generation of treatments for multiple myeloma that affect both specific intracellular signaling pathways and the tumor microenvironment. Other novel, targeted therapies are also being evaluated in preclinical and clinical studies. Regimens incorporating bortezomib, thalidomide, lenalidomide, and other novel agents, together with commonly used conventional drugs, represent a promising future direction in myeloma treatment. At present, further investigation is required to assess the safety and activity of combinations integrating these other novel agents. However, bortezomib, thalidomide, and lenalidomide are now in widespread clinical use. This review therefore focuses on the extensive clinical data available from studies of these drugs in the treatment of newly diagnosed and advanced multiple myeloma. The Oncologist 2007;12: Disclosure of potential conflicts of interest is found at the end of this article. Correspondence: Paul G. Richardson, M.D., Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Dana 1B02, Boston, Massachusetts 02115, USA. Telephone: ; Fax: ; paul_richardson@dfci.harvard.edu Received November 13, 2006; accepted for publication March 8, AlphaMed Press /2007/$30.00/0 doi: /theoncologist The Oncologist 2007;12:

2 Richardson, Mitsiades, Schlossman et al. 665 INTRODUCTION Multiple myeloma remains incurable with conventional treatments, with a median survival duration of 3 5 years [1 8]. The disease follows a relapsing course in the majority of patients, regardless of treatment regimen or initial response to treatment. Novel, more effective treatment approaches are required in order to improve outcomes and extend survival. Recently, the management of patients with multiple myeloma has been transformed by the introduction and approval of three new agents. Bortezomib (Velcade ; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceuticals Research and Development, L.L.C., Raritan, NJ) received full approval in 2005 for the treatment of patients who have received at least one prior therapy [9]; thalidomide (Thalomid ; Celgene Corp., Summit, NJ) in combination with was approved in early 2006 for the treatment of newly diagnosed multiple myeloma; and the thalidomide analogue lenalidomide (Revlimid ; Celgene Corp., Summit, NJ), also in combination with, has recently been approved for the treatment of patients who have received at least one prior therapy. These three agents represent a new generation of therapies for multiple myeloma that both affect specific intracellular signaling pathways within the tumor cell and also target the tumor microenvironment. Bortezomib is a novel, first-in-class proteasome inhibitor that has antiproliferative, proapoptotic, antiangiogenic, and antitumor activity through inhibition of proteasomal degradation of numerous regulatory proteins [10 13]. In preclinical studies, bortezomib has demonstrated synergistic or additive antitumor activity with agents commonly used in the treatment of multiple myeloma, including doxorubicin, melphalan, and, as well as activity in myeloma cells resistant to these agents [14 16]. Thalidomide and lenalidomide also exhibit their antineoplastic activity in multiple myeloma through multiple mechanisms of action, including inhibition of angiogenesis, induction of apoptosis, immunomodulation, antiproliferative effects, inhibition of cytokine signaling, and stimulation of T-cell activity [17 22]. Preclinical studies have shown that both drugs induce apoptosis in myeloma cells resistant to melphalan, doxorubicin, and, and potentiate the activity of and bortezomib [23, 24]. Other novel targeted therapies are also being evaluated in preclinical and clinical studies, including arsenic trioxide [25 27], interleukin-1 receptor antagonists [28], cyclic depsipeptides [29], farnesyltransferase inhibitors [30], the p38 mitogen-activated protein kinase inhibitor SCIO-469 [31], histone deacetylase inhibitors [32], and heat-shock protein 90 inhibitors, including KOS-953 [33]. These agents have demonstrated antimyeloma activity in preclinical models and early-phase clinical studies; arsenic trioxide has been studied most extensively, both as monotherapy [25 27] and in combination with other agents [34 37]. Regimens incorporating bortezomib, thalidomide, lenalidomide, and these novel agents, together with commonly used conventional therapies, represent a promising future paradigm in the treatment of myeloma. At present, further investigation is required to assess the safety and activity of these novel agents and their combinations. However, bortezomib, thalidomide, and lenalidomide are now in widespread clinical use. Therefore, this review focuses on the extensive clinical data available on bortezomib, thalidomide, and lenalidomide in the treatment of patients with advanced and newly diagnosed multiple myeloma. Efficacy results from studies of each agent alone and in combination in the relapsed/refractory and frontline settings are reviewed; all response rates reported are based on the stringent European Group for Blood and Marrow Transplantation (EBMT) criteria [38], unless otherwise stated. The toxicity profiles of the agents are addressed, with a focus on the key toxicities, and the potential for use of these new agents in special populations is reviewed. BORTEZOMIB Activity in Relapsed and/or Refractory Multiple Myeloma Bortezomib with or without was shown to be active in two phase II studies in patients with relapsed/ refractory multiple myeloma SUMMIT (Study of Multiple Myeloma Managed with proteasome Inhibition Therapy, [39]) and CREST (Clinical response and efficacy study of bortezomib in the treatment of relapsing myeloma, [40]) (Table 1) [34, 39 67]. The international, randomized phase III Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial in patients with relapsed multiple myeloma following 1 3 prior therapies showed that single-agent bortezomib provides a significantly longer time to progression (TTP), higher response rate, and superior survival compared with high-dose [43]. Bortezomib is the only single agent to date that has been shown to provide a survival benefit in the setting of relapsed multiple myeloma; in an updated analysis of the APEX trial after extended follow-up (median, 22 months), the median overall survival (OS) time was 29.8 months with bortezomib versus 23.7 months with. This 6-month benefit was seen despite 62% of patients crossing over to receive bortezomib [42]. Overall response (43%) and complete response (complete

3 666 New Drugs for Myeloma Table 1. Clinical trials of bortezomib in patients with multiple myeloma Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-toevent data Key toxicities For previously treated multiple myeloma (relapsed and/or refractory) Richardson et al. [39, 41] Jagannath et al. [40] Bortezomib Bortezomib Richardson et al. Single-agent bortezomib [42, 43] a versus high-dose Kropff et al. [44] Bortezomib Kropff et al. [45] a Bortezomib cyclophosphamide on days 1, 4, 8, and 11 for up to eight 3-wk cycles;, 20 mg may be added on day of/day after bortezomib for suboptimal response Bortezomib, 1.0 mg/m 2, on days 1, 4, 8, and 11 for up to eight 3-wk cycles;, 20 mg, may be added on day of/day after bortezomib for suboptimal response on days 1, 4, 8, and 11 for up to eight 3-wk cycles;, 20 mg, may be added on day of/day after bortezomib for suboptimal response on days 1, 4, 8, and 11 for up to eight 3-wk cycles followed by treatment on days 1, 8, 15, and 22 for up to three 5-wk cycles on days 1, 4, 8, and 11 for up to eight 3-wk cycles;, 20 mg on day of/day after bortezomib on days 1, 4, 8, and 11 for up to eight 3-wk cycles followed by bortezomib, 1.3 mg/m 2, on days 1, 8, 15, and 22 for up to three 5-wk cycles;, 20 mg, on day of/day after bortezomib; cyclophosphamide, 50 mg, daily 202/193 27%; CR/nCR, 10% (bortezomib alone) 28/27 30%; CR/nCR, 11%; dex, 37%; CR/nCR, 19% 26/26 38%; CR/nCR, 4%; dex, 50%; CR/nCR, 4% DOR, 13 mos (bortezomib alone); TTP, 7 mos; OS, 17 mos DOR, 9.5 mos; TTP, 7 mos; OS, 26.7 mos DOR, 13.7 mos; TTP, 11 mos; OS, not reached 333/315 43%; CR/nCR, 15% DOR, 7.8 mos; TTP, 6.2 mos; OS, 29.8 mos 15/15 73%; CR/nCR, 7% EFS, not reached; OS, not reached 50/50 82%; CR/nCR, 12% EFS, 12 mos; OS, not reached NA NA Grade 3/4: thrombocytopenia, 28%/3%; peripheral neuropathy, 12%/ 0%; fatigue, 12%/0%; neutropenia, 11%/3%; vomiting, 8%/ 1%; anemia, 8%/0%; diarrhea, 7%/1%; pain in limb, 7%/0%; dehydration, 7%/0%; nausea, 6%/0%; weakness, 5%/4% NA NA Grade 3/4: thrombocytopenia, 29%/0%; neutropenia, 11%/0%; lymphopenia, 11%/0%; hyponatremia, 11%/0%; pain in limb, 11%/0%; peripheral neuropathy, 4%/ 4% NA NA Grade 3/4: neutropenia, 23%/0%; thrombocytopenia, 19%/4%; peripheral neuropathy, 15%/0%; pneumonia, 15%/0%; lymphopenia, 12%/0%; weakness, 12%/0%; hyponatremia, 8%/0%; pain in limb, 8%/0% NA NA Grade 3/4: thrombocytopenia, 26%/4%; neutropenia, 12%/2%; anemia, 9%/1%; peripheral neuropathy, 7%/1%; diarrhea, 7%/0%; fatigue, 5%/ 1%; dyspnea, 5%/ 1% NA NA Grade 3/4: thrombocytopenia, 0%/47% (no bleeding); neutropenia, 27%/7%; fatigue, 20%/0%; anemia, 13%/7%; peripheral neuropathy, 7%/0%; infection, 7%/0%; herpes zoster, 7%/0% NA NA Dose-limiting grade 3/4: thrombocytopenia, 0%/19%; infection, 25%/0%; peripheral neuropathy, 19%/ 0%; herpes zoster, 17%/0%; fatigue, 15%/0%; cardiovascular, 9%/0%; diarrhea, 8%/0%; orthostatic hypotension, 6%/0% (continued)

4 Richardson, Mitsiades, Schlossman et al. 667 Table 1. (Continued) Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-toevent data Key toxicities Reece et al. [46] a Bortezomib cyclophosphamide prednisone Suvannasankha et al. [47] Orlowski et al. [48] Biehn et al. [49] Bortezomib methylprednisolone Bortezomib pegylated liposomal doxorubicin Orlowski et al. Bortezomib pegylated [50] a liposomal doxorubicin versus single-agent bortezomib Friedman et al. [51] b Jakubowiak et al. [52] a Bortezomib pegylated liposomal doxorubicin Berenson et al. [53] Bortezomib melphalan Bortezomib, mg/m 2, on days 1, 8, and 15, or days 1, 4, 8, and 11; cyclophosphamide, 150/ 300 mg/m 2, on days 1, 8, 15, and 22; prednisone, 100 mg, every other day; 28-day cycles and methylprednisolone, 500 2,000 mg, on days 1, 8, and 15 of a 28-day cycle Bortezomib, mg/m 2, on days 1, 4, 8, and 11; pegylated liposomal doxorubicin, 30 mg/m 2, on day 4; up to eleven 3-wk cycles on days 1, 4, 8, and 11; pegylated liposomal doxorubicin, 30 mg/m 2, on day 4; up to eight 3-wk cycles 21/20 45%; CR/nCR, 15% NR NA NA Grade 3/4 (cycles 2 8 only): hyperglycemia, 29%/0%; neutropenia, 24%/5%; hypophosphatemia, 19%/ 10%; thrombocytopenia, 14%/5% 29 62%; CR/nCR, 7% TTP, 6.6 mos; DOR, 6.7 mos; OS, 20.2 mos 24/22 73% CR/nCR: 36% TTP: 9.3 mos; OS: 38.3 mos 324/303 48%; CR/nCR, 14% TTP, 9.3 mos; DOR, 10.2 mos; OS, not reached Bortezomib, as above 322/310 43%; CR/nCR, 11% TTP, 6.5 mos; DOR, 7.0 mos; OS, not reached on days 1, 4, 8, and 11; pegylated liposomal doxorubicin, 30 mg/m 2, on day 4;, 40 mg, on days 1 4, then 20 mg on day of/day after bortezomib; six 3-wk cycles Bortezomib, mg/m 2, on days 1, 4, 8, and 11; melphalan, mg/kg, on days 1 4; up to eight 4-wk cycles NA NA Grade 3: peripheral neuropathy, 7% NA NA Grade 3: thrombocytopenia, 43%; lymphopenia, 40%; neutropenia, 17%; fatigue, 14%; pneumonia, 14%; peripheral neuropathy, 12%; febrile neutropenia, 10%; diarrhea, 10% (toxicities reported in 42 patients, including 18 with other advanced hematologic malignancies) NA NA Grade 3/4: neutropenia, 30%; thrombocytopenia, 22%; anemia, 9%; diarrhea, 7%; asthenia, 6%; fatigue, 5%; hand foot syndrome, 5% NA NA Grade 3/4: thrombocytopenia, 15%; neutropenia, 14%; anemia, 9%; neuralgia, 5% 23/23 65%; CR/nCR, 22% NR NA NA Grade 3/4: fatigue, thrombocytopenia, infections, neutropenia, diarrhea, neuropathy, DVT/ PE 35/34 47%; CR/nCR, 15% PFS, 8 mos NA NA Grade 3/4: neutropenia, 34%/6%; thrombocytopenia, 37%/3%; anemia, 23%/6%; hypocalcemia, 6%/0% (continued)

5 668 New Drugs for Myeloma Table 1. (Continued) Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-toevent data Key toxicities Popat et al. [54] a Bortezomib melphalan Chari et al. [55] a Bortezomib pegylated liposomal doxorubicin melphalan Hrusovsky et al. Bortezomib [56] a bendamustine Berenson et al. Bortezomib arsenic [34] b trioxide ascorbic acid Yeh et al. [57] c Bortezomib 153 Smlexidronam on days 1, 4, 8, and 11; melphalan, mg/ m 2, on day 2; up to eight 4-wk cycles;, 20 mg, may be added on day of/day after bortezomib for suboptimal response Bortezomib, mg/m 2, on days 1, 4, 8, and 11; pegylated liposomal doxorubicin, mg/m 2, on day 1; melphalan, 5 10 mg/ m 2, on day 1; up to six 4-wk cycles Bortezomib, mg/m 2, on days 1, 4, 8, and 11; bendamustine, 60 mg/m 2, on days 1 and 8;, 24 mg, on days 1 3 and 8 10; ondansetron, 8 mg, on days 1, 4, 8, and 11; 3-wk cycles Bortezomib, mg/m 2, on days 1, 4, 8, and 11; arsenic trioxide, mg/kg, on days 1, 4, 8, and 11; ascorbic acid, 1,000 mg, on days 1, 4, 8, and 11; up to eight 3-wk cycles Bortezomib, mg/m 2, on days 1, 4, 8, and 11; 153 Smlexidronam, mci/kg, on day 3; 8-wk cycle Chanan-Khan et al. Bortezomib KOS-953 Bortezomib, [58] c mg/m 2, and KOS-953, mg/m 2,on days 1, 4, 8, and 11; 3-wk cycles For newly diagnosed multiple myeloma (frontline) Anderson et al. Bortezomib [59] c on days 1, 4, 8, and 11; up to eight 3-wk cycles 22/21 52%; CR/nCR, 5% TTP, 6.8 mos; OS, not reached NA NA Grade 3: thrombocytopenia, 45%; neutropenia, 27%; peripheral neuropathy, 18% 5/4 25%; CR/nCR, 25% NR NA NA Grade 3 neutropenia in one patient 17/17 71% e ; CR/nCR, 12% DOR, 6 mos NA NA No significant toxicities reported 22/22 9%; CR/nCR, 0% PFS, 5 mos; OS, not reached; 1-yr PFS, 34%; 1-yr OS, 74% NA NA Grade 4 thrombocytopenia, 5% 12/12 17%; CR/nCR, 8% NR NA NA Grade 3/4: headache, 17%/ 0%; leg cramps, 8%/0%; neutropenia, 8%/0%; thrombocytopenia, 0%/8% 28/21 19%; CR/nCR, 10% NR NA NA Dose-limiting: grade 4 hepatotoxicity, pancreatitis, metabolic acidosis; other grade 3/4: anemia, 14%; thrombocytopenia, 11%; elevated AST, 11%; elevated ALT, 7%; vomiting, 7% 66/63 40%; CR/nCR, 10% DOR, 8.5 mos; TTP, 6 mos NR NR All grades: peripheral neuropathy, 58% (2% grade 3/4); constipation, 57%; nausea, 48%; fatigue, 43%; rash, 33%; upper respiratory infection, 17% (continued)

6 Richardson, Mitsiades, Schlossman et al. 669 Table 1. (Continued) Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-toevent data Key toxicities Dispenzieri et al. Bortezomib [60] a on days 1, 4, 8, and 11 for eight 3-wk cycles; then bortezomib, 1.3 mg/m 2, every other week Mateos et al. [61] Bortezomib melphalan prednisone Jagannath et al. Bortezomib [62] a Harousseau et al. [63] Bortezomib Harousseau et al. Bortezomib [64] a versus VAD induction therapy Oakervee et al. [65] Bortezomib doxorubicin Popat et al. [66] a Bortezomib doxorubicin Bortezomib, mg/m 2, on days 1, 4, 8, 11, 22, 25, 29, and 32 for four 6-wk cycles followed by bortezomib, mg/m 2, on days 1, 8, 15, and 22 for five 5-wk cycles; melphalan, 9 mg/m 2, and prednisone, 60 mg/m 2, on days 1 4 of each cycle on days 1, 4, 8, and 11;, 40 mg, on day of/day after bortezomib for suboptimal response; up to six 3-wk cycles on days 1, 4, 8, and 11;, 40 mg, on days 1 4 and 9 12 for cycles 1 and 2, and on days 1 4 for cycles 3 and 4; up to four 3-wk cycles As above 420/165 (including comparator arm) on days 1, 4, 8, and 11; doxorubicin, 0, 4.5, or 9 mg/m 2, on days 1 4 of each cycle;, 40 mg, on days 1 4, 8 11, and for cycle 1 and days 1 4 for cycles 2 4; up to four 3-wk cycles Bortezomib, 1.0 mg/m 2, on days 1, 4, 8, and 11; doxorubicin, 9 mg/m 2, on days 1 4 of each cycle;, 40 mg, on days 1 4, 8 11, and for cycle 1 and days 1 4 for cycles 2 4; up to four 3-wk cycles 43/19 68% NR NR NR Grade 3: hyponatremia, 21%; diarrhea, 14%; fatigue, 12%; hypercalcemia, 7%; vomiting, 7% 60/53 89%; CR/nCR, 43% PFS, 91% f ; EFS, 83% f ; projected 2-yr survival rate, 86% 50/48 90%; CR/nCR, 19% PFS, 15 mos; 1-yr survival rate, 93% 52/48 67%; CR/nCR, 21% NR 90%; CR/nCR, 33% NA NA Grade 3: thrombocytopenia, 51%; neutropenia, 43%; peripheral neuropathy, 17%; diarrhea, 16%; infection, 16%; anemia, 10%; constipation, 8%; asthenia, 5% NR 1-yr survival rate, 100% Grade 3: peripheral neuropathy/neuropathic pain, 12%; neutropenia, 10%; diarrhea, 6% NR Grade 3: infection, 10%; peripheral neuropathy, 6% (in 50 patients who received study drugs) 82%; CR/nCR, 20% NR NR NR Neurologic toxicities, 27% (4% grade 3 or 4); fever/ infection, 14% 21/21 95%; CR/nCR, 29% NR 95%; CR/nCR, 57% 20/19 89%; CR/nCR, 16% NR 100%; CR/nCR, 54% NR Grade 3: infection, 19%; shingles, 14%; line infection, 14%; peripheral neuropathy, 5%; neutropenia, 5%; nausea/ vomiting, 5%; postural hypotension, 5%; atrial fibrillation, 5%; hyperglycemia, 5% NR Grade 3: liver function test, 15%; psychiatric, 10%; fatigue, 5%; thrombocytopenia, 5%; neutropenia, 5%; infection, 5% (continued)

7 670 New Drugs for Myeloma Table 1. (Continued) Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-toevent data Key toxicities Orlowski et al. [67] d Bortezomib pegylated liposomal doxorubicin Friedman et al. [51] b Bortezomib pegylated liposomal doxorubicin on days 1, 4, 8, and 11; pegylated liposomal doxorubicin, 30 mg/m 2, on day 4; up to eight 3-wk cycles on days 1, 4, 8, and 11; pegylated liposomal doxorubicin, 30 mg/m 2, on day 4;, 40/20 mg, on day of/day after bortezomib in cycles 1/2 6; 3-wk cycles 29/15 80%; CR/nCR, 13% NR NR NR SAEs: tumor lysis syndrome, dyspnea, edema, abdominal pain with nausea and vomiting, dehydration, confusion, herpes zoster infection 21/21 81%; CR/nCR, 29% NR NR NR Grade 3/4: fatigue, thrombocytopenia, infections, neutropenia, diarrhea, neuropathy, DVT/PE a Preliminary data presented at the American Society of Hematology Annual Meeting. b Preliminary data presented at the European Hematology Association Annual Meeting. c Preliminary data presented at the American Society of Clinical Oncology Annual Meeting. d Preliminary data presented at the International Myeloma Workshop. e Southwest Oncology Group criteria. f At 16 months. Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; CR, complete response; DOR, duration of response; DVT/PE, deep venous thrombosis/pulmonary embolism; EFS, event-free survival; NA, not applicable; ncr, near complete response; NR, not reported; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SAE, serious adverse event; SCT, stem cell transplantation; TTP, time to progression; VAD, vincristine, doxorubicin,.

8 Richardson, Mitsiades, Schlossman et al. 671 Table 2. Clinical trials of combination regimens including both bortezomib and thalidomide or lenalidomide in patients with multiple myeloma Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-to-event data Key toxicities For previously treated multiple myeloma (relapsed and/or refractory) Padmanabhan et al. Bortezomib pegylated [70] a liposomal doxorubicin thalidomide Zangari et al. [73] b Bortezomib thalidomide Teoh et al. [75] c Bortezomib thalidomide zoledronic acid Leoni et al. [69] a Bortezomib liposomal doxorubicin thalidomide Bortezomib thalidomide Hollmig et al. [68] b Bortezomib doxorubicin thalidomide Palumbo et al. [71] Bortezomib melphalan prednisone thalidomide Terpos et al. [72] a Bortezomib melphalan thalidomide on days 1, 4, 15, and 18; pegylated liposomal doxorubicin, 20 mg/m 2, on days 1 and 15; thalidomide, 200 mg/day; up to six 4-wk cycles Bortezomib, mg/m 2,on days 1, 4, 8, and 11; thalidomide, mg/day, from cycle 2;, 20 mg, on day of/day after bortezomib for suboptimal response after 3 cycles; up to eight 3-wk cycles on days 1, 4, 8, and 11; thalidomide, 50 mg/ day;, 20 mg, on days 1 4, 8 11, and 15 18; zoledronic acid, 4 mg, on day 1; up to eleven 3-wk cycles Bortezomib, 1.0 mg/m 2, on days 1, 4, 8, and 11; liposomal doxorubicin, 50 mg/m 2, on day 4; thalidomide, 100 mg/day;, 24 mg, on day of/day after bortezomib; up to four 4-wk cycles As above, minus liposomal doxorubicin Bortezomib, mg/m 2,on days 1, 4, 8, and 11; doxorubicin, mg/m 2, on days 1 4 and 9 12; thalidomide, mg/day, on days 1 12;, mg, on days 1 4 and 9 12 Bortezomib, mg/m 2, on days 1, 4, 15, and 22; melphalan, 6 mg/ m 2, and prednisone, 60 mg/m 2,on days 1 5; thalidomide, 50 mg, daily; six 5-wk cycles Bortezomib, 1.0 mg/m 2, on days 1, 4, 8, and 11; melphalan, 0.15 mg/ kg, on days 1 4;, 12 mg/m 2, on days 1 4 and 17 20; thalidomide, 100 mg/day; for four 4-wk cycles 23/17 65% d ; CR/nCR, 23% 85/85 55% e ; CR/nCR, 16% 14/14 93%; CR/nCR, 64% 27/27 74%; CR/nCR, 33% 18/18 50%; CR/nCR, 17% 20/16 63% e,f ; CR/nCR, 25% 30/30 67%; CR, 17% 44/41 66%; CR/nCR, 37% PFS, 11 mos; OS, 16 mos EFS, 9 mos; OS, 22 mos NA NA No grade 3/4 nonhematologic toxicities NA NA Most common grade 3/4 toxicities were thrombocytopenia and neutropenia NR NA NA Grade 3: painful peripheral neuropathy, 14%; thrombocytopenia (transient), 36% PFS, not reached; OS, not reached PFS, 8 mos; OS, 13 mos 89% survival at 6 mos 1-yr PFS, 61%; 1-yr OS, 84% NA NA Grade 4 hematologic toxicity in 18% NA NA NR NA NA Grade 3: thrombocytopenia, 40% f NA NA Grade 3/4: neutropenia, 23%/ 20%; thrombocytopenia, 20%/ 13%; anemia, 13%/3%; neuropathy, 7%/0%; herpes zoster reactivation, 7%/0% PFS, 9.6 mos NA NA Grade 3: thrombocytopenia, 20%; neutropenia, 8%; anemia, 7%; peripheral neuropathy, 6% (continued)

9 672 New Drugs for Myeloma Table 2. (Continued) Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-to-event data Key toxicities Richardson et al. [74] b Bortezomib lenalidomide Musto et al. [76] a Bortezomib intermediate-dose melphalan thalidomide stem cell support For newly diagnosed multiple myeloma (frontline) Wang et al. [77] b Bortezomib thalidomide Badros et al. [78] Bortezomib thalidomide cisplatin doxorubicin cyclophosphamide etoposide (VDT-PACE) Barlogie et al. [79] c Bortezomib thalidomide cisplatin doxorubicin cyclophosphamide etoposide (VDT-PACE) Bortezomib, mg/m 2,on days 1, 4, 8, and 11; lenalidomide, 5 20 mg, on days 1 14;, 20 mg, on day of/day after bortezomib for PD; up to eight 3-wk cycles and melphalan, 50 mg/m 2, on days 6 and 3; thalidomide, 200 mg, and, 20 mg, on days 6to 3; hematopoietic stem cell support on day 0 Bortezomib, mg/m 2,on days 1, 4, 8, and 11; thalidomide, mg/day;, 20 mg, on days 1 4, 9 12, and 17 20; up to three 4-wk cycles Bortezomib, mg/m 2,on days 1, 4, and 8; thalidomide, mg/day, on days 1 8;, 40 mg, on days 1 4; cisplatin, 10 mg/m 2, doxorubicin, 10 mg/m 2, cyclophosphamide, 400 mg/m 2, and etoposide, 40 mg/m 2, on days 1 4; two 5-wk cycles Bortezomib, 1.0 mg/m 2, on days 1, 4, and 8; thalidomide, 200 mg/day;, 40 mg, on days 1 4; cisplatin, 10 mg/m 2, doxorubicin, 10 mg/m 2, cyclophosphamide, 400 mg/m 2, etoposide, 40 mg/m 2, on days 1 4; two 5-wk cycles 24/21 52%; CR/nCR, 10% 26/26 65%; CR/nCR, 15% 38/38 92%; CR/nCR: 18% 12/12 83%; CR/nCR, 17% NR NA NA Grade 3/4: thrombocytopenia, neutropenia, hyponatremia PFS, 6 mos NA NA Grade 3/4: thrombocytopenia, 46%/54%; anemia, 42%/38%; neutropenia, 0%/100%; pneumonia, 35%/0%; febrile neutropenia, 12%/0% NR 100%; CR/nCR: 34% NR 100%; CR/nCR, 75% 249 NR NR 92% at 18 mos; CR/nCR, 80% NR Grade 3: peripheral neuropathy, 8%; nonneutropenic infection, 8%; myelosuppression, 8%; DVT, 5% NR Grade 3: neutropenia, 100%; thrombocytopenia, 58%; anemia, 42%; neutropenic fever, 25%; infection, 25%; thrombosis, 17%; hyperglycemia, 17%; syncope, 8% OS g, 88%; EFS g, 83% Grade 2: thromboembolism, 27%; neuropathy, 10%; constipation, 7% a Preliminary data presented at the European Hematology Association Annual Meeting. b Preliminary data presented at the American Society of Hematology Annual Meeting. c Preliminary data presented at the American Society of Clinical Oncology Annual Meeting. d Southwest Oncology Group criteria. e M-protein reduction. f Response rate and toxicity reported after one cycle of treatment. g 18-month probability. Abbreviations: CR, complete response; DVT, deep venous thrombosis; EFS, event-free survival; NA, not applicable; ncr, near complete response; NR, not reported; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SCT, stem cell transplantation; TTP, time to progression.

10 Richardson, Mitsiades, Schlossman et al. 673 response/near complete response [CR/nCR], 15%) rates with bortezomib were also higher in the updated analysis than at initial analysis [42]. Results from the APEX trial also indicate that bortezomib is more active when used earlier in the relapsed setting, with TTP, duration of response (DOR), and OS appearing to be longer and response rate higher among patients with only one prior therapy compared with those with two or three prior therapies [43]. Substantial activity has also been demonstrated in studies of bortezomib in combination with other commonly used agents for multiple myeloma. Notably, combination regimens including bortezomib and doxorubicin or liposomal doxorubicin have been shown to provide high overall response and CR/nCR rates, with promising OS and timeto-events data [48 52, 68 70]. For example, in a phase I trial of bortezomib plus liposomal doxorubicin in patients with advanced hematologic malignancies, the response rate among 22 evaluable patients was 73%, including a 36% CR/nCR rate [48]. An updated analysis after extended follow-up showed that the regimen provided substantially better results compared with patients last prior regimen in terms of the median TTP (9.3 versus 3.8 months) and median time from start of therapy to start of subsequent therapy (24.2 versus 5.9 months). The median OS time was 38.3 months for these heavily pretreated patients [49]. Preliminary data from a randomized phase III study of bortezomib plus liposomal doxorubicin versus single-agent bortezomib in patients with relapsed/refractory multiple myeloma showed that the combination produced a longer median TTP (9.3 versus 6.5 months) and median DOR (10.2 versus 7.0 months) than with bortezomib alone, although the response rate (48% versus 43%) and CR/nCR rate (14% versus 11%) were comparable. The median OS time had not yet been reached [50]. An important aspect of the phase I study of bortezomib plus liposomal doxorubicin was that responses were seen in 8 of 13 patients who had progressive disease (PD), stable disease (SD), or an initial response followed by PD or SD with a previous anthracycline-based regimen [48], suggesting that the combination of bortezomib plus doxorubicin may overcome resistance. This is supported by the results from a study of bortezomib, liposomal doxorubicin, and thalidomide, in which responses were seen despite prior failure of regimens containing bortezomib, doxorubicin, or thalidomide [70]. The overall response rate was 65%, including a 23% CR/nCR rate (Southwest Oncology Group [SWOG] criteria) [70]. Similarly, a response rate of 63%, including a 25% CR/nCR rate, was seen with a regimen comprising bortezomib, doxorubicin, thalidomide, and, despite use of these agents in previous therapies [68]. The addition of liposomal doxorubicin to bortezomib, thalidomide, and has also been shown to produce a higher response rate (74% versus 50%; CR/nCR rate, 33% versus 17%) and longer median progression-free survival (PFS) and OS times than with the triplet regimen [69]. Responses were seen despite patients having previously received bortezomib, doxorubicin, thalidomide, and [69]. This superior activity may reflect the synergistic activity seen with bortezomib and doxorubicin in preclinical studies [15, 16]. Bortezomib and melphalan combination regimens have also been shown to be active [53, 54, 71, 72]. In a doseescalation study of bortezomib plus oral melphalan, the response rate was 47% (including a 15% CR/nCR rate), with responses seen in five of six (83%) patients at the maximum-tolerated dose [53]. Similarly, results from a doseescalation study of bortezomib plus low-dose i.v. melphalan showed a response rate of 43%, rising to 52% with the addition of for patients with suboptimal response [54]. Activity appeared greatest in patients receiving the highest melphalan dose [54]. The addition of thalidomide, along with or prednisone, appears to increase the activity of the combination regimen, with response rates of 66% (37% CR/nCR rate) [72] and 67% (17% CR/nCR rate) [71] for the - and prednisone-containing regimens, respectively. Bortezomib has also been studied in combination with thalidomide and [73], and lenalidomide plus, in patients with suboptimal response to the doublet combination [74]. The response rates with these regimens were 55% (16% CR/nCR rate) [73] and 52% (10% CR/nCR rate) [74], respectively, indicating that these agents can be administered in combination with promising activity, and supporting the notion of dual apoptotic signaling. The median event-free survival (EFS) and OS times with bortezomib, thalidomide, and were 9 months and 22 months, respectively. However, these were shorter in patients who had received prior thalidomide [73], suggesting that the combination may be more active if used in advance of other thalidomide-containing regimens. The response rate in the study of bortezomib plus lenalidomide is especially encouraging as nearly all patients had received prior thalidomide, half had received bortezomib, and approximately 10% had received prior lenalidomide [74]. Activity in Previously Untreated Multiple Myeloma Bortezomib-based therapies have demonstrated encouraging activity in 13 studies in the frontline setting, both as induction therapy prior to stem cell transplantation (SCT) and as therapy for patients not proceeding to, or not eligible for,

11 674 New Drugs for Myeloma SCT (Table 1 [34, 39 67] and Table 2 [68 79]). These studies, in more than 700 patients, have shown high response rates, and consistently high CR/nCR rates that are greater than those seen with standard induction regimens and conventional therapies. Bortezomib has been studied as a single agent in the frontline setting [59, 60]. In one phase II study in patients eligible for SCT, the response rate was 40%, with a 10% CR/nCR rate. This CR/nCR rate is substantial for a single-agent therapy in the frontline setting [59]. Notable activity has also been demonstrated in patients with high-risk multiple myeloma (elevated 2 -microglobulin, high plasma cell labeling index, or chromosome 13 deletion) [60]. One of the highest CR rates ever seen with conventional or induction therapy was reported in a phase I/II study of bortezomib in combination with melphalan and prednisone (MP) in 60 patients aged 65 years who were ineligible for SCT [61]. In 53 evaluable patients, the response rate was 89%, with a 43% CR/nCR rate (32% CR, 11% ncr). Importantly, among patients with a CR who were assessed for malignant plasma cells using multiparametric flow assay at a sensitivity level of one residual plasma cell in 10, ,000 normal cells, half had no detectable myeloma cells, representing immunophenotypic remission [61]. At 16 months, the PFS, EFS, and OS rates in these elderly patients (half were aged 75 years) were 91%, 83%, and 90%, respectively. These results are highly promising; the median OS time seen with MP is 2 3 years [80, 81], while the projected 2-year OS rate in this study is 86%. The triplet regimen is now being compared with MP in an international phase III trial. Regimens containing bortezomib plus doxorubicin are also demonstrating substantial activity. The combination of bortezomib, doxorubicin, and (PAD) has been investigated as induction therapy prior to SCT [65, 66]. In 21 patients, the response rate to PAD was 95%, including a 29% CR/nCR rate, prior to SCT [65]. Eighteen patients underwent transplant. The response rate in all 21 patients remained at 95%, but the CR/nCR rate was higher at 57% [65]. This high CR/nCR rate is important because CR status following SCT is associated with a longer OS time [82 85], as is CR status following non-sct therapy [86]. Similar results were obtained with a reduced-dose PAD regimen. In 19 evaluable patients, the response rate was 89%, including a 16% CR/nCR rate; 13 patients subsequently underwent SCT, and the response rate post-sct was 100%, with a 54% CR/nCR rate [66]. The PAD regimen is currently being compared with vincristine, doxorubicin, and (VAD) as induction therapy prior to SCT in an international phase III trial. The use of liposomal doxorubicin instead of doxorubicin in the PAD regimen is also being investigated. In 21 evaluable patients, the response rate was 81% with a 29% CR/nCR rate, the same as with PAD [51]. A similar response rate of 80% with a 13% CR/nCR rate has been reported in a Cancer and Leukemia Group B study of bortezomib plus liposomal doxorubicin [67]. The doublet regimen of bortezomib plus has been investigated as induction therapy in three trials [62 64]. In a phase II study by the Intergroupe Francophone du Myélome (IFM), the combination produced a response rate of 67%, including a 21% CR/nCR rate, prior to SCT in 48 evaluable patients [63]. Among 42 patients who proceeded to SCT, the post-sct response rate was 90%, with a 33% CR/nCR rate [63]. Similarly, substantial activity was reported in another study in which potential candidates for SCT received bortezomib alone initially, with added for suboptimal response [62]. In 48 evaluable patients, the response rate was 90%, with a 19% CR/nCR rate; 23 patients proceeded to SCT. The 1-year OS rate in those going on to SCT was 100% [62]. Preliminary results from an IFM phase III study of bortezomib plus compared with VAD as induction therapy prior to SCT showed a higher postinduction response rate (82% versus 67%) and CR/nCR rate (20% versus 9%) with bortezomib plus. In addition, among evaluable patients who had undergone a single SCT, a greater proportion of the patients who had received induction with bortezomib plus, compared with VAD, achieved a very good partial response (VGPR) or better (78% versus 55%), obviating the need for a second SCT [64]. Bortezomib in combination with thalidomide and is also active in the frontline setting. The response rate in a single-center study of 38 patients was 92%, including an 18% CR rate; importantly, responses were achieved rapidly, eliminating the need for further therapy prior to SCT [77]. In total, 26 patients proceeded to SCT, following which the response rate in all 38 patients was 100%, including a 34% CR rate [77]. This triplet regimen has also been investigated as induction therapy prior to SCT in combination with cisplatin, doxorubicin, cyclophosphamide, and etoposide the VDT-PACE regimen [78, 79]. VDT-PACE is being employed as induction therapy prior to tandem transplants in the Total Therapy 3 approach; the addition of bortezomib to the previous Total Therapy 2 plus thalidomide approach appears to result in a higher CR rate, higher yield of stem cells, and faster completion of transplants [79]. These results suggest that bortezomib-based combination regimens could provide a valuable treatment option in the frontline setting. Importantly, use of bortezomib-based

12 Richardson, Mitsiades, Schlossman et al. 675 induction regimens does not impair stem cell mobilization and harvesting prior to SCT, and neutrophil and platelet engraftment is prompt following SCT [62 66, 78, 79, 87]. The higher CR/nCR rates associated with bortezomibbased induction may potentially result in superior clinical outcomes with SCT. Key Side Effects of Bortezomib The safety profile of bortezomib in the relapsed setting has been well characterized and is generally manageable, with prolonged exposure in some patients shown to be well tolerated. In an extension study of the SUMMIT and CREST trials, no new or cumulative toxicities were reported [88]. Importantly, no additive toxicities were reported in the studies of bortezomib-based combination regimens. Similarly, in frontline studies, the toxicities associated with bortezomib alone and in combination were generally predictable and manageable, with no unexpected adverse events reported. The most common toxicities associated with bortezomib treatment include fatigue, gastrointestinal events, and peripheral neuropathy, with the most commonly reported grade 3 toxicities being peripheral neuropathy, thrombocytopenia, neutropenia, and anemia. Bortezomibrelated peripheral neuropathy is an important and doselimiting toxicity. Based on findings from the SUMMIT and CREST studies, specific management guidelines were developed [89] and subsequently tested in the APEX study. In the APEX study, bortezomib-related peripheral neuropathy was shown to be reversible in the majority of patients [90]. Similarly, in the SUMMIT and CREST trials it was shown to resolve or improve in 71% of patients with grade 3 peripheral neuropathy and/or neuropathy requiring discontinuation [89]. Comparable results have been observed in the frontline setting [59, 65]. The hematologic toxicities associated with bortezomib have also been well characterized and shown to be generally predictable and manageable. Bortezomib-related thrombocytopenia and neutropenia are transient and cyclical; in patients experiencing thrombocytopenia, platelet counts decrease and recover predictably during each bortezomib treatment cycle with no evidence of cumulative toxicity [91, 92]. Notably, despite a higher incidence of grade 3 thrombocytopenia with bortezomib compared with in the APEX trial, the incidence of significant bleeding events, including grade 3 bleeding events, serious bleeding, and cerebral hemorrhage, was similar between the two arms [91]. Not surprisingly, patients with low platelet counts at baseline ( /l) have been shown to be at a higher risk for grade 3 thrombocytopenia, and so bortezomib use in such patients warrants caution but is feasible and can be effective [92]. THALIDOMIDE Activity in Relapsed or Refractory Multiple Myeloma Thalidomide has been widely used in patients with relapsed or refractory multiple myeloma for a number of years, following the initial report of single-agent activity in 1999 [93], and more recent developments in the frontline setting have confirmed its efficacy. Table 3 [94 116] summarizes a number of key studies and recent reports; specifically, response rates of 25% 48% by paraprotein reduction have been reported with single-agent thalidomide in patients with relapsed or refractory multiple myeloma [93, 94, ]. A recent systematic review of phase II studies calculated an overall response rate of 29% [120]. The response rate has been shown to be substantially higher when thalidomide is combined with and cyclophosphamide [121]. For example, thalidomide plus has been proven to be effective in relapsed/refractory multiple myeloma [95, ], with response rates of 42% 72% (CR/nCR rates not available; various response criteria), while the addition of cyclophosphamide (the CTD regimen) has resulted in response rates of 57% 83%, with CR/nCR rates of 2% 17% (various response criteria) [96, ]. The combination of thalidomide plus liposomal doxorubicin and has recently been shown to be very active, with a response rate of 76%, including a 32% CR/nCR rate [98]. The addition of vincristine to this regimen has also been studied, producing a response rate of 76%, with a 20% CR rate [99], although concerns regarding cumulative neurotoxicity remain. Other combinations are listed in Table 2 and Table 3. Activity in Previously Untreated Multiple Myeloma Thalidomide plus has been extensively studied and was recently approved in the frontline setting. Response rates of 48% 80%, including 4% 16% CR/nCR rates (various response criteria), have been reported in phase II studies of thalidomide plus as induction therapy (Table 3) [ , 129]. In addition, the regimen has been compared with alone in two randomized phase III studies [106, 107]. In a study coordinated by the Eastern Cooperative Oncology Group, the response rate with thalidomide plus was significantly higher than with alone (n 100; 63% versus 41%), with 4% versus 0% of patients achieving a CR [106]. The second, larger phase III trial,

13 676 New Drugs for Myeloma Table 3. Key clinical trials of thalidomide in patients with multiple myeloma Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-to-event data Key toxicities For previously treated multiple myeloma (relapsed and/or refractory) Barlogie et al. [94] Thalidomide Thalidomide, mg/day Palumbo et al. [95] Thalidomide (at first relapse) Thalidomide (at second relapse and beyond) Dimopoulos et al. [96] Thalidomide pulsed cyclophosphamide Palumbo et al. [97] Thalidomide melphalan prednisone Offidani et al. [98] Thalidomide liposomal doxorubicin Hussein et al. [99] Thalidomide liposomal doxorubicin vincristine Thalidomide, 100 mg/ day, continuously;, 40 mg, on days 1 4 of each month Thalidomide, 400 mg/ day, on days 1 5 and 14 18;, 20 mg/day, on days 1 5 and 14 18; cyclophosphamide, 150 mg/m 2, every 12 hours on days 1 5; three 4-wk cycles Thalidomide, mg/day, continuously; prednisone, 50 mg/day, every other day; i.v. melphalan, 20 mg/m 2, every 4th mo Thalidomide, 100 mg/day; liposomal doxorubicin, 40 mg/m 2, on day 1;, 40 mg, on days 1 4 and 9 12; up to six 4-wk cycles Thalidomide, mg/day; liposomal doxorubicin, 40 mg/m 2, on day 1; vincristine, 2 mg, on day 1;, 40 mg, on days 1 4; six 4-wk cycles 169/169 30% d ; CR, 2% 2-yr EFS, 20%; 2-yr OS, 48% 62/62 56% d PFS, 17 mos; 3-yr OS rate, 60% 58/58 46% d PFS, 11 mos; OS, 19 mos 53/53 60% d ; CR/nCR, 5% 24/24 42%; CR/nCR, 13% 50/50 76%; CR/nCR, 32% TTP, 8.2 mos; OS, 17.5 mos NA NA Grade 2: CNS, 25%, gastrointestinal, 16%, peripheral neuropathy, 9% NA NA Tingling and numbness, 19%; constipation, 18%; sedation, 13% NA NA NA NA Grade 3/4: Neutropenia, 18%/8% PFS, 9 mos NA NA Constipation, tingling, sedation EFS, 17 mos; PFS, 22 mos; OS, not reached 49/49 76%; CR, 20% PFS, 15.5 mos; OS, 39.9 mos NA NA Grade 3: neutropenia, 16%; nonhematologic toxicities, 12%; venous thromboembolic disease, 12%; severe infection, 16% NA NA Grade 3/4: neuropathy, 22%; neutropenia, 14%; pneumonia, 12%; palmar plantar erythrodysesthesia, 8%; fatigue, 6%; thrombocytopenia, 5% (includes 53 patients with newly diagnosed disease) (continued)

14 Richardson, Mitsiades, Schlossman et al. 677 Table 3. (Continued) Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-to-event data Key toxicities For newly diagnosed multiple myeloma (frontline) Abdelkefi et al. [100] Thalidomide Cavo et al. [101] Thalidomide Hussein et al. [102] a Thalidomide Rajkumar et al. [103] Thalidomide Weber et al. [104] Thalidomide Dingli et al. [105] Thalidomide Rajkumar et al. [106] Thalidomide Thalidomide, 200 mg/day, for 75 days;, 20 mg/m 2, on days 1 4, 9 12, and in 1st and 3rd mos, and on days 1 4 in 2nd mo; 3 mos of therapy Thalidomide, mg/ day;, 40 mg/ day, on days 1 4, 9 12, and of odd cycles and days 1 4 of even cycles; four 4-wk cycles Thalidomide, mg/ day;, 40 mg/ day, on days 1 4, 9 12, and 17 20; three 5-wk cycles Thalidomide, mg/ day;, 40 mg/ day, on days 1 4, 9 12, and of odd cycles and days 1 4 of even cycles; 4-wk cycles Thalidomide, mg/ day;, 20 mg/ m 2, on days 1 4, 9 12, and 17 20; at least 3 monthly cycles Thalidomide, 200 mg/day;, 40 mg, on days 1 4, 9 12, and (odd cycles only); 4-wk cycles Thalidomide, 200 mg/day;, 40 mg/day, on days 1 4, 9 12, and 17 20; four 4-wk cycles 60/60 74%; CR/nCR, 24% (pre/posttransplantation status not indicated) 71/71 66%; CR/nCR, 8% 130/25 (for response to induction therapy) 80%; CR/nCR, 4% NR NR NR Grade 3: infections, 12%; constipation, 5%; neuropathy, 5% NR NR NR Grade 3: DVT, 16%; constipation, 14%; fatigue, 10%; infections, 7%; neuropathy, 6% NR NR NR 21% DVT in first 23 patients, leading to protocol amendment; grade 4: hypercoagulability, bone pain; grade 3: gastrointestinal events, fatigue, hypercoagulability, bone pain 50/50 64% e NR NR NR Grade 3/4: thrombosis, 12%; constipation, 8%; rash, 6% d ; CR/nCR, 16% 21/21 48%; CR/nCR, 5% 103/99 63% e ; CR/nCR, 4% NR NR NR All grades: constipation, 55%; fatigue, 55%; rash/dry skin, 55%; numbness and tingling, 50%; edema, 35%; tremors, 30%; thrombolic/embolic events, 15%; infection, 13%; unsteadiness, 13% PFS, 11 mos; TTP, 18 mos; OS, 21 mos NA NA Grade 3: thrombosis, 10%; constipation, sedation, neuropathy, edema, fatigue, fever, syncope, anxiety, cardiovascular, inner ear, all 5% NR NR NR Grade 3: thrombosis/embolism, 20%; hyperglycemia, 15%; fatigue, 15%; dyspnea, 11%; neutropenia, 9%; hypocalcemia, confusion, and constipation, all 8%; neuropathy, 7%; muscle weakness, 6%; edema, 6%; pneumonia, 5% (continued)

15 678 New Drugs for Myeloma Table 3. (Continued) Study Agents Regimen n of patients (enrolled/ evaluable) Response rate Time-to-event data response rate time-to-event data Key toxicities Rajkumar et al. [107] b Thalidomide Ludwig et al. [108] a Thalidomide Macro et al. [109] Thalidomide versus VAD induction therapy Goldschmidt et al. [110] a Thalidomide doxorubicin Hussein et al. [99] Thalidomide liposomal doxorubicin vincristine Zervas et al. [111] Thalidomide vincristine liposomal doxorubicin Zervas et al. [112] c Thalidomide vincristine liposomal doxorubicin Offidani et al. [113] Thalidomide liposomal doxorubicin Thalidomide, mg/ day;, 40 mg/ day, on days 1 4, 9 12, and 17 20; four 4-wk cycles Thalidomide, mg/ day;, 40 mg, on days 1 4 and every other cycle; 4-wk cycles Thalidomide, 200 mg/day, for 3 mos;, 40 mg, on days 1 4, wks 1, 3, 5, 7, 9, and 13 Thalidomide, 200/400 mg/ day; doxorubicin, 9 mg/m 2, on days 1 4;, 40 mg, on days 1 4, 9 12, and 17 21; three 4-wk cycles Thalidomide, mg/ day; liposomal doxorubicin, 40 mg/m 2, on day 1; vincristine, 2 mg, on day 1;, 40 mg, on days 1 4; six 4-wk cycles Thalidomide, 200 mg/day; vincristine, 2 mg, on day 1; liposomal doxorubicin, 40 mg/m 2, on day 1;, 40 mg, on days 1 4 (and in cycle 1); up to four 4-wk cycles 235/235 49%; CR/nCR, 5% 190 (including comparator arm)/61 51%; CR/nCR, 21% TTP, not reached; OS, not reached NA NA Grade 3: DVT/PE, 18%; pneumonia, 8%; hyperglycemia, 6%; grade 4 toxicities seen in 31% NR NA NA Grade 2/3: neuropathy, 25%; psychological toxicity, 20%; skin toxicity, 12%; thromboembolic complications, 8% 100/100 VGPR, 25% NR VGPR, 44% NR Venous thrombosis/pe, 23%; peripheral neuropathy, 17% 406/406 (including comparator arm) 80%; CR/nCR, 7% 53/53 83%; CR, 36% PFS, 28.2 mos; OS, not reached at 50-mo follow-up 39/39 74%; CR/nCR, 10% (after four cycles) NR 91%; CR/nCR, 19% NR DVT, 8% (with low molecular weight heparin prophylaxis) NA NA Grade 3/4: neuropathy, 22%; neutropenia, 14%; pneumonia, 12%; palmar plantar erythrodysesthesia, 8%; fatigue, 6%; thrombocytopenia, 5% (includes 49 patients with relapsed disease) NR NR 22-mo EFS rate, 55%; 22- mo OS rate, 74% Grade 3/4: neutropenia, 15%; thrombocytopenia, 15%; neutropenic infection, 13%; DVT, 10%; constipation, 10%; non-neutropenic infection, 8%; mucositis, 5%; rash, 5% As above 115/80 81% NR NR NR Constipation, 57%; dizziness/ somnolence, 54%; peripheral neuropathy, 46%; neutropenia, 15%; skin rash, 13%; thrombocytopenia, 10%; DVT, 10%; edema, 10% Thalidomide, 100 mg/day;, 40 mg, on days 1 4 and 9 12; liposomal doxorubicin, 40 mg/m 2,on day 1; 4-wk cycles 50/50 88%; CR/nCR, 48% Projected 3-yr: TTP rate, 60%; EFS rate, 57%; OS rate, 74% NA NA Grade 3: infection, 22%; venous thromboembolic disease, 14%; neutropenia, 12%; constipation, 10%; fatigue, 6% (continued)