Myelomas. A Practical Update on the Use of Bortezomib in the Management of Multiple Myeloma. The Oncologist 2006;11:51 61

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1 This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Myelomas A Practical Update on the Use of Bortezomib in the Management of Multiple Myeloma JesÚs San Miguel, a Joan Bladé, b Mario Boccadoro, c Jamie Cavenagh, d Axel Glasmacher, e Sundar Jagannath, f Sagar Lonial, g Robert Z. Orlowski, h Pieter Sonneveld, i Heinz Ludwig j a Hospital Clinico Universitario de Salamanca, Salamanca, Spain; b Institut d Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; c University of Turin, Turin, Italy; d St. Bartholomew s Hospital, London, United Kingdom; e University of Bonn, Bonn, Germany; f St Vincent s Comprehensive Cancer Center, New York, New York, USA; g Winship Cancer Institute, Atlanta, Georgia, USA; j Virchow-University Hospital, Berlin, Germany; h Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA; i Erasmus Medical Center, Rotterdam, The Netherlands Learning Objectives Key Words. Bortezomib Multiple myeloma Practical guidelines Treatment After completing this course, the reader will be able to: 1. Discuss clinical trial data for treatment with bortezomib monotherapy and bortezomib-based combination therapy in patients with multiple myeloma who have received at least one prior therapy. 2. Discuss the management of the most common adverse events associated with bortezomib, including peripheral neuropathy and thrombocytopenia. 3. Describe prognostic factors in patients with multiple myeloma who have received at least one prior therapy. CME Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com Abstract Despite intensive therapy, multiple myeloma (MM) remains an incurable disease, and novel treatment approaches are therefore needed to improve outcome. Bortezomib is the first proteasome inhibitor to be approved by the U.S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products for the treatment of refractory or relapsed MM following the failure of at least two prior lines of therapy. Recently, it also received approval from the FDA for use as a second-line agent. An expert panel of hematologists met at the Ninth Congress of the European Hematology Association to review clinical data and experience in the treatment of MM with bortezomib, including bortezomib-based combination therapy. The conclusions of this expert panel, together with updated clinical data from the American Society of Hematology 46th Annual Meeting, provide a practical update on the use of bortezomib in MM. Bortezomib has demonstrated significant antitumor activity as a single agent in refractory and/or relapsed MM, with a significantly longer survival than with dexamethasone (1-year overall survival rate of 80% vs. 66%) and a 78% longer median time to progression. In combination therapy, patient responses suggest the possibility of chemosensitization and synergy. Furthermore, bortezomib does not appear to have an adverse effect Correspondence: Jesús San Miguel, M.D., Hematology Department, Hospital Clinico Universitario de Salamanca, Servicio de Hematologia, Paseo de San Vicente 58, Salamanca E-37007, Spain. Telephone: ; Fax: ; Mobile: ; sanmigiz@usal.es Received May 31, 2005; accepted for publication October 17, AlphaMed Press /2006/$12.00/0 The Oncologist 2006;11:

2 52 Practical Update on Bortezomib in Multiple Myeloma on subsequent stem cell therapy. Bortezomib is well tolerated; most side effects are only mild to moderate and are manageable. Information is given on the practical management of the most common adverse events, including peripheral neuropathy and thrombocytopenia, and the use of bortezomib in renal and hepatic impairment. The Oncologist 2006;11:51 61 Introduction Multiple myeloma (MM) remains an incurable disease despite intensive therapy such as high-dose melphalan (Alkeran ; GlaxoSmithKline, Philadelphia, gsk.com) and autologous stem cell transplantation [1]. Novel treatment approaches have included the use of thalidomide (Thalomid ; Celgene Corporation, Warren, NJ, and its immunomodulatory derivatives (e.g., lenalidomide) and the proteasome inhibitor bortezomib (Velcade ; Millennium Pharmaceuticals, Inc., Cambridge, MA, formerly known as PS-341) [2]. Bortezomib is a synthetic, boronic acid dipeptide with multiple effects on MM cell lines and primary human MM cells, including blocking the activation of nuclear factorkappa B (NF-κB) [1, 3]. Bortezomib also has a role in overcoming tumor resistance to corticosteroids or conventional cytotoxic agents, which may be partly a result of the capacity of bortezomib to inhibit DNA repair mechanisms [4]. Bortezomib is the first proteasome inhibitor to enter clinical trials. Based on results from phase II trials, bortezomib was approved by the U.S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA) for patients with relapsed and refractory MM who have received at least two prior lines of therapy and progressed on their last therapy. Recently, the FDA also granted approval for the use of bortezomib after only one prior line of therapy, and the EMEA has approved the use of bortezomib as a monotherapy for use in patients with MM who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplantation. An expert panel of hematologists met at the Ninth Congress of the European Hematology Association to discuss the practical management of bortezomib in relapsed and refractory MM. Their conclusions are summarized here, together with updated clinical data presented at the American Society of Hematology's 46th Annual Meeting. Efficacy and Safety of Bortezomib Following encouraging preliminary phase I clinical trial results [5], 202 patients (193 evaluable for response) with relapsed or refractory MM were treated in the pivotal phase II SUMMIT trial [6] with bortezomib (1.3 mg/m 2 i.v.) on days 1, 4, 8, and 11 of a 21-day cycle for a maximum of eight cycles. Patients with progressive disease (after two cycles) or stable disease (after four cycles) could receive supplementary dexamethasone (Decadron ; Merck & Co., Inc., Whitehouse Station, NJ, Patients who in the investigators opinion would continue to receive clinical benefit went on to an extension protocol after eight cycles. The median number of prior treatment lines was six (range, 2 15): 91% of patients had disease refractory to their last therapy, defined by progression during treatment or within 60 days of the completion of therapy. According to an independent review committee using the stringent European Group for Blood and Marrow Transplantation (EBMT) criteria [7], the overall response rate (ORR) was 35%, within which 4% of patients showed a complete response (CR) (immunofixation [IF] negative), 6% a near CR (ncr) (IF positive), 18% a partial response (PR), and 7% a minor response (MR). A further 24% of patients experienced stable disease (Fig. 1). Among patients who received supplementary dexamethasone (n = 74), 18% (13/74) subsequently achieved a PR or MR, including six patients with MM who had disease refractory to dexamethasone prior to bortezomib therapy, defined as progressive disease within 30 days of treatment with a steroid-containing regimen [8]. For 12 patients, this response was the first CR they had achieved (63% of patients with a CR). The median overall survival (OS) duration was 17 months [6, 9]. The median time to progression (TTP) for all patients was 7 months, which was more than twice as long as the median TTP during the patients last treatment prior to enrollment (p =.01). In the context of this heavily pretreated population, the response duration and OS achieved during the SUMMIT trial were nearly double that expected for a similarly, heavily treated population [6]. The most common drug-related adverse events were gastrointestinal (nausea, diarrhea), which were usually mild to moderate and may have been partly related to autonomic neuropathy. Grade 3 toxicities included thrombocytopenia (28%), peripheral neuropathy (PN, 12%), fatigue (12%), and neutropenia (11%) [6]. In another phase II study, the CREST trial [9], patients with relapsed MM after one line of therapy were randomized to receive bortezomib at a dose of either 1.3 mg/m 2 or 1.0 mg/m 2. According to independent review using EBMT criteria, ORRs (CR + PR + MR) for bortezomib alone at the higher and lower doses were 50% (90% confidence inter- The Oncologist

3 San Miguel, Bladé, Boccadoro et al. 53 val [CI], 32.7% 67.3%) and 33% (90% CI, 18.6% 50.9%), respectively (Table 1). The median durations of response (DoR) for patients treated with either bortezomib alone or in combination with dexamethasone were 13.7 months and 9.5 months for the 1.3 mg/m 2 and 1.0 mg/m 2 doses of bortezomib, respectively. At 26 months of follow-up, the median OS for patients treated with 1.0 mg/m 2 bortezomib was 26.7 months but had not been reached for those receiving 1.3 mg/m 2 bortezomib. The incidences of PN, diarrhea, nausea, and vomiting were substantially lower in patients receiving 1.0 mg/m 2 bortezomib (Fig. 2). These results suggest that the 1.0-mg/m 2 dose may help to reduce toxicity, enabling patients who would otherwise experience excessive toxicity at the standard 1.3-mg/m 2 dose to continue receiving bortezomib therapy. More recently, the largest randomized phase III trial performed to date in relapsed MM (Assessment of Proteasome Inhibition for Extending Remissions [APEX] trial; n = 669) demonstrated a significant survival benefit for patients treated with bortezomib when compared with those treated with high-dose dexamethasone. Patients had Figure 1. SUMMIT phase II trial of bortezomib in patients with multiple myeloma, response rates with bortezomib alone. Of 202 patients, 193 were evaluable for assessment of response and duration of response. Responses were assessed by an independent review committee according to European Group for Blood and Marrow Transplantation criteria: a complete response was defined by a negative immunofixation test for myeloma protein in serum and urine, absence of soft-tissue plasmacytomas, normal serum calcium concentration, stable skeletal disease, and <5% plasma cells in the bone marrow in two specimens obtained 6 weeks apart; a near-complete response (immunofixation positive) was defined by the absence of myeloma protein on electrophoresis, independent of immunofixation-fixation test status, stable bone disease, and normal serum calcium concentration. Abbreviations: CR, complete response: IRC, independent review committee; MR, minor response; PR, partial response; SD, stable disease. From [6]. Figure 2. CREST phase II trial of bortezomib in patients with multiple myeloma. Incidence of adverse events that occurred at a 20% greater rate in the 1.3 mg/m 2 dose group relative to the 1.0 mg/m 2 dose group by Common Toxicity Criteria grade, showing a trend toward less toxicity with dose reduction. Abbreviations: G, grade; NOS, not otherwise specified. From [8]. Table 1. CREST phase II study: summary of responses to bortezomib (IRC-evaluated population, n = 53) Confirmed response combined Bortezomib alone (%) (90% CI) Bortezomib alone (%) (90% CI) Overall response (CR + PR + MR) 33 ( ) 50 ( ) CR + PR 30 ( ) 38 ( ) Confirmed response by category CR + ncr 11 ( ) 4 ( ) PR 19 ( ) 35 ( ) MR 4 ( ) 12 ( ) NC b PD/NE (nonresponders) b a One patient with nonsecretory myeloma was not evaluable. b Confidence intervals not calculated. Abbreviations: CI, confidence interval; CR, complete response; IRC, independent review committee; MR, minimal response; NC, no change; ncr, near-cr; NE, not evaluable; PD, progressive disease: PR, partial response. From [8]. Bortezomib dose group 1.0 mg/m 2 (n = 27) a 1.3 mg/ m 2 (n = 26)

4 54 Practical Update on Bortezomib in Multiple Myeloma received one to three prior lines of therapy [10]. The study was terminated early following achievement of the primary end point of superior TTP at a preplanned interim analysis, and dexamethasone-treated patients were crossed over to the bortezomib treatment arm. Based on a median followup of 8.3 months, bortezomib demonstrated a 78% greater median TTP (p <.0001) and a significant 1-year survival advantage (80% vs. 66%; p =.005) compared with dexamethasone. As second-line therapy, bortezomib compared favorably with dexamethasone, with a median TTP of 7 months versus 5.6 months (p =.021) and 1-year survival rates of 89% and 72% (p =.0098), respectively. Patients treated with bortezomib as second-line therapy also had a higher response rate (CR + PR) than those receiving second-line dexamethasone: 45% versus 26% (p =.004). In patients who had received more than one prior line of treatment, the median TTP was 4.9 months versus 2.9 months (p <.0001), and the ORRs (CR + PR) were 34% and 13% (p <.0001) for patients treated with bortezomib and dexamethasone, respectively [11]. These results indicate better efficacy with earlier treatment. Prognostic Factors Multivariate analyses conducted on the SUMMIT patient population [6, 12] have shown that a shorter DoR was correlated with hypoalbuminemia and a lower Karnofsky performance status (KPS) score, a shorter TTP was correlated with elevated C-reactive protein level or abnormal cytogenetics, and a shorter OS was correlated with >50% plasma cell bone marrow infiltration (PCBM), a lower platelet count, and a lower albumin level. In a multivariate analysis, lower response rates were associated only with >50% PCBM and older age ( 65 years) (p <.05). Response was not influenced by sex, isotype of myeloma, serum level of β 2 -microglobulin, or the type or number of previous therapies. Cytogenetic analyses were available for 172 patients; 147 (85%) analyses were performed by standard cytogenetic techniques, 18 (10%) were performed by fluorescence in situ hybridization, and seven were accomplished with other methods. Patients with chromosome 13 deletions, detected in 26 of the 172 (15%) cases analyzed, demonstrated a similar response rate as patients with other cytogenetic abnormalities (24% vs. 28%, respectively). This finding is unique to bortezomib and has not occurred with other therapies. Time to Response and Optimum Duration of Therapy There are no clear clinical guidelines regarding the optimum duration of therapy: the median time to response is rapid and occurs within two cycles of therapy. However, some patients take longer to respond, and so it is important for patients to continue bortezomib treatment beyond two cycles in the absence of overt evidence of progressive disease (PD by EBMT criteria [7]). In the SUMMIT trial, patients with confirmed CRs could receive two further cycles of bortezomib, while patients with stable disease after four cycles or PD after two cycles were allowed to receive oral dexamethasone (20 mg) on the day of and day after each bortezomib dose. Sixty-three of 256 (25%) patients in the SUMMIT and CREST trials were treated in an extension trial of SUMMIT (17 and 46, respectively) [13]. They received a median of seven additional cycles of therapy, yielding a total median duration of therapy of 45 weeks or 14 cycles (range, 7 32) in the parent and extension studies. At a median follow-up of 19.1 months, the median OS for all patients treated with bortezomib in either the SUMMIT trial alone or in both SUMMIT and the extension study was 17.2 months, compared with 16 months after eight cycles of therapy in the SUMMIT study alone [9]. The median DoR was 12 months for patients treated with bortezomib in the SUMMIT trial, compared with 14.1 months for patients treated in both SUMMIT and the extension study who achieved a CR or PR after bortezomib monotherapy [9]. These results indicate that patients who do not achieve a CR (PR, MR) may benefit from receiving eight or more cycles of bortezomib. Forty-six patients (73%) either continued dexamethasone into the extension study or had dexamethasone added for a median of three cycles during the extension study. The safety profiles were similar in the extension and parent trials, with no evidence of cumulative toxicities, including neurotoxicity. The most commonly reported grade 3 4 toxicities were thrombocytopenia (29%) which showed a consistent pattern of recovery during the rest period of each cycle diarrhea (11%), anemia (11%), and neutropenia (10%). These results indicate that retreatment with, or continuation of, bortezomib with or without dexamethasone beyond 6 months is safe and that toxicities are manageable in patients with relapsed and/or refractory MM [13]. Bortezomib-Based Combination Therapies In addition to being a rational treatment target in MM, proteasome inhibition may also be a rational approach for sensitization to chemotherapeutic agents [4, 14, 15]. Drug resistance in highly chemoresistant MM cell lines has been overcome by combining a subtherapeutic dose of bortezomib with the cytotoxic agents melphalan, doxorubicin (Adriamycin ; Bedford Laboratories, Bedford, OH, or mitoxantrone (Novantrone ; Serono, Inc., Rockland, MA, The Oncologist

5 San Miguel, Bladé, Boccadoro et al. 55 [16, 17]. Moreover, a synergistic effect in combination with dexamethasone has been observed. These and other findings have led to phase I/II clinical trials of bortezomibbased combination regimens in MM. Preliminary results with bortezomib plus melphalan have been reported in 26 heavily pretreated patients with MM [15], with a response in 67% (16/24 evaluable) of patients (1 CR, 1 ncr, 6 PRs, 8 MRs). Toxicities were manageable, with grade 3 adverse events predominantly associated with myelosuppression in patients with baseline cytopenias. Dose escalation is continuing with melphalan plus a fixed dose of bortezomib (1.0 mg/m 2 ). The responses observed in patients previously treated with either drug suggest that chemosensitization, and possibly synergy, might be occurring with combined low-dose bortezomib and melphalan [15]. Bortezomib combined with pegylated liposomal doxorubicin (PegLD; Doxil ; Alza Pharmaceuticals, Mountain View, CA; alza.com; Rubex ; Bristol-Myers Squibb, Princeton, NJ, was safely administered to patients with advanced hematologic malignancies, achieving a CR or ncr in 8/22 evaluable patients with MM, including several patients with anthracycline-refractory disease, and a PR in a further eight patients [18]. Bortezomib (1.30 mg/m 2 ) with PegLD (30 mg/m 2 ) was recommended for further study. Research trials by the M. D. Anderson Cancer Center group [19] and the Arkansas group [20] have explored whether the addition of bortezomib to the combination of thalidomide and dexamethasone can improve the response rate in newly diagnosed, and also in relapsed, patients with MM. Alexanian et al. [19] reported on 30 newly diagnosed patients treated with bortezomib at escalating doses ( mg/m 2 ). Eighty percent of the 30 patients included so far have responded, with a >75% reduction in serum monoclonal component and a >95% reduction in Bence Jones protein. Responses were very rapid, with a median time to remission of 0.6 months. Although both bortezomib and thalidomide are neurotoxic drugs, grade 3 4 neuropathy was not observed during this short duration of therapy. Moreover, stem cells were easily collected in all 12 patients who were intensified, indicating that this regimen does not damage hematopoietic cell precursors. Zangari et al. [20] reported on a phase I/II study of 79 patients with advanced and refractory MM treated with bortezomib in combination with thalidomide. Dexamethasone was permitted for suboptimal response after three cycles. Fifty-two percent of the 34 evaluable patients had a CR plus PR. No dose-limiting toxicities were reported in cohort 7 (bortezomib, 1.3 mg/m 2, plus thalidomide, 150 mg), and the study has not reached a maximum-tolerated dose. The higher dose of bortezomib (1.3 mg/m 2 ) was associated with longer event-free survival (EFS), although no such association was noted with higher doses of thalidomide (>100 mg/day) [20]. In contrast to the results of Alexanian et al. [19], grade 3 neurotoxicity was observed in 9% of patients. Interestingly, prior therapy for longer than 5 years and no prior thalidomide exposure were associated with longer EFS [20]. Use of Bortezomib in Renal Insufficiency Therapeutic options are limited for patients with MM and renal impairment. Jagannath et al. [21] reported that patients with renal impairment can be safely and effectively treated with bortezomib. Ten patients with creatinine clearance levels of ml/min were enrolled in the phase II trials (SUMMIT and CREST). Compared with the overall study population, these patients had higher levels of β 2 - microglobulin, lower KPS scores, and more light-chain disease. Dosing was initiated at 1.3 mg/m 2 in six patients and at 1.0 mg/m 2 in four patients. Seven of the 10 patients completed the full eight cycles of therapy, and two patients continued to receive bortezomib in an extension trial of SUMMIT. Responses in the 10 patients with severe renal impairment included two PRs, one MR, and one stable disease (four patients progressed, two patients were not evaluable). The response rate in this small subset of patients with severe renal impairment was, thus, similar to that obtained for the overall SUMMIT population (35%) [21]. For 256 patients enrolled in the phase II studies (SUM- MIT and CREST), the incidence of serious adverse events appeared to increase with decreasing renal function, with incidences of 41%, 51%, and 60% occurring at creatinine clearance levels of >80, 51 80, and 50 ml/min, respectively [21]. Adverse events grade 3 that occurred in 10% of patients with creatinine clearance levels of >80, 51 80, and 50 ml/min included thrombocytopenia, fatigue, diarrhea, anemia, neutropenia, PN, dyspnea, and weakness (Table 2). The incidences of grade 3 weakness, diarrhea, dyspnea, pyrexia, and constipation in patients with creatinine clearance levels of >80 ml/min were less than those observed in patients with creatinine clearance levels 50 ml/min (Table 2). However, the only adverse event with a statistically significant higher incidence was dyspnea (p =.01) [21]. Formal studies are under way to define the pharmacokinetics and safety of bortezomib with varying renal impairment. Clinical judgment should be used to assess potential risks and benefits of bortezomib in the presence of renal impairment. Until further data are available, patients with creatinine clearance levels 30 ml/min can be treated with the standard bortezomib regimen

6 56 Practical Update on Bortezomib in Multiple Myeloma Table 2. Adverse events grade 3 in patients stratified according to renal function Creatinine clearance (ml/min) Adverse event > Thrombocytopenia 30% 27% 33% Fatigue 12% 10% 10% Diarrhea 7% 6% 10% Anemia 10% 6% 10% Neutropenia 12% 15% 17% Peripheral neuropathy 11% 9% 13% Dyspnea 1% a 4% 12% a Weakness 6% 5% 10% Pyrexia 2% 5% 6% Constipation 2% 1% 4% a p =.01 From [21]. (1.3 mg/m 2 on days 1, 4, 8, and 11 of a 21-day cycle). However, these patients should be monitored carefully, and in cases of neutropenia or other significant toxicities, the dose should be reduced from 1.3 mg/m 2 to 1.0 or 0.7 mg/m 2. Patients Receiving Hemodialysis Currently, no data have been published and no formal recommendations are available regarding bortezomib in patients on hemodialysis. As a precautionary measure, these patients should be monitored particularly closely for toxicities when treated with bortezomib. In one recently completed phase II trial, the starting dose of bortezomib was reduced to 1.0 mg/m 2 for patients with significant renal impairment, including those on hemodialysis. Bortezomib is a small molecule and could be dialyzable. For this reason, it may be advisable to administer bortezomib on nondialysis days as long as there are at least 72 hours between doses. Alternatively, because bortezomib has a short half-life, some researchers administer bortezomib after dialysis, or at least 2 hours or more before dialysis. Additional results from formal studies of the safety and efficacy of bortezomib in patients with renal impairment are awaited. Use of Bortezomib in Hepatic Insufficiency Limited data are available regarding bortezomib therapy in patients who have hepatic impairment. In the SUMMIT trial, which excluded patients with significantly elevated levels of bilirubin or transaminases, bortezomib administration had no obvious effect on levels of hepatic transaminases, alkaline phosphatase, and bilirubin during eight cycles of treatment [6]. However, a recent case of bortezomib-induced hepatic toxicity has been reported [22]. Evaluation of bortezomib in patients with hepatic impairment is ongoing. Because bortezomib is metabolized primarily by cytochrome enzymes, significant hepatic impairment may affect the metabolism of bortezomib and increase the likelihood of drug-to-drug interactions. Until further data are available, patients with slight hepatic impairment should be monitored particularly closely during treatment with bortezomib; while those with significant liver disease, as defined by times the upper limits of normal for liver enzymes, should not receive bortezomib. Use of Anti-Infective Prophylaxis Further data are required before formal recommendations can be made for anti-infective prophylaxis. Meanwhile, the use of anti-infective prophylaxis varies among treatment centers. Some centers have observed a higher incidence of herpes zoster infection and give acyclovir (Zovirax ; GlaxoSmithKline, Philadelphia, prophylaxis with bortezomib combination therapy, including bortezomib plus dexamethasone. Other centers give prophylaxis only to patients who have a history of infections. Research to clarify these issues is ongoing. Management of Side Effects During Bortezomib Therapy According to combined safety data from the phase II trials (n = 228) (Fig. 3) [23], the most common adverse events for all patients with MM at the standard 1.3-mg/m 2 dose of bortezomib were asthenia (fatigue, weakness, malaise) (65%), gastrointestinal effects (nausea, 64%; diarrhea, 51%; constipation, 43%; vomiting, 36%), thrombocytopenia (43%), and PN (37%), with the latter usually being reversible [24]. Peripheral Neuropathy PN has been associated with several agents used in the treatment of MM, including thalidomide and vincristine (Oncovin ; Eli Lilly and Company, Indianapolis, as well as with the disease itself. PN that develops with bortezomib therapy is primarily sensory, characterized by pain, paresthesias, burning dyesthesias, and numbness, with feet affected more often than hands. In the 256 patients treated with bortezomib in the SUM- MIT and CREST phase II trials, 35% developed treatment-emergent PN, with 13% and <1% (one patient) of patients developing grade 3 and 4 PN, respectively [24]. Overall, in the pooled data from the phase II trials, dose reductions were required in 12% of patients, with 5% The Oncologist

7 San Miguel, Bladé, Boccadoro et al. 57 discontinuing bortezomib because of PN. In this same population, 35 patients with significant PN were followed up after dose reduction or discontinuation; 71% showed improvement or resolution of PN on treatment or after discontinuation. The median time to improvement or resolution of PN was 47 days (range, days) from the last dose of bortezomib. However, approximately 80% of patients entered the SUMMIT and CREST trials with evidence of baseline PN. Of patients without PN, only 2/60 (3%) developed grade 3 PN during treatment [24]. Of patients without PN in the SUMMIT and CREST studies, 41 entered the extension trial; only 5 (12%) of those patients experienced PN with additional bortezomib treatment. A further 16 of 22 (73%) patients in the extension study, who had experienced PN during SUMMIT or CREST, did not report a worsening of PN. Early detection of PN is essential. The development of even mildly painful PN should prompt dose modification of bortezomib from the standard 1.3 mg/m 2. A lower frequency of PN was found in the CREST trial with the 1.0- mg/m 2 bortezomib dose than with the standard 1.3-mg/m 2 Figure 3. Combined safety data showing all reported (drugrelated or not) adverse events ( 30% overall) for patients with multiple myeloma at the standard bortezomib dose of 1.3 mg/ m 2 (n = 228) in phase II trials. From [23]. dose, suggesting that dose reduction with maintained efficacy is feasible. Patients should be encouraged to report any difficulty or limitation of functional ability (e.g., writing or getting dressed, particularly with tasks such as fastening buttons). The Common Toxicity Criteria (CTC) for grading the severity of PN may not be the optimal assessment tool for PN resulting from bortezomib, particularly because of the inclusion of subjective assessments and exclusion of pain as a criterion. Regular clinical assessment by symptom history taking and subjective assessment of functionality, both at baseline and during therapy with bortezomib, are central to evaluating changes in patient symptoms. A patientreported questionnaire specific for neurotoxicity, such as the Functional Assessment of Cancer Therapy/Gynecology Oncology Group-Neurotoxicity questionnaire, may be very useful in alerting physicians to this problem [25]. With early detection and the use of an algorithm established for dose reduction based on experience in phase II trials (Table 3) [6, 23], more patients can be promptly diagnosed and dose reductions implemented. Gabapentin (Neurontin ; Pfizer Pharmaceuticals, New York, com) or amitriptyline may aid in the management of PN. In addition, vitamin supplements and topical application of capsaicin cream may also be of benefit. Thrombocytopenia The most common hematologic toxicity associated with bortezomib therapy is transient thrombocytopenia [23, 26], which returns toward baseline in the rest period between treatment cycles (Fig. 4). On average, the pattern of decrease and recovery in platelet counts, which occurs during each cycle of therapy, is consistent throughout eight cycles of treatment, with no evidence of cumulative thrombocytopenia. In responding patients, mean platelet counts at predose baseline (day 1) appear to increase progressively with successive cycles of treatment from the second cycle onwards. Table 3. Prescribing information. Recommended a dose modifications for bortezomib-related neuropathic pain and/or peripheral neuropathy (PN) Severity of PN Modification of dose and regimen Grade 1 with no pain No action Grade 1 with pain or grade 2 Reduce bortezomib to 1.0 mg/m 2 Grade 2 with pain or grade 3 Withhold bortezomib therapy until symptoms of toxicity have resolved; when toxicity resolves, reinitiate bortezomib treatment and reduce dose to 0.7 mg/m 2 and change treatment schedule to once per week Grade 4 Discontinue bortezomib a Based on dose modifications in phase II multiple myeloma studies. From[23].

8 58 Practical Update on Bortezomib in Multiple Myeloma In an analysis of 228 patients who received bortezomib (1.3 mg/m 2 ) in the SUMMIT and CREST trials, 43% developed thrombocytopenia during treatment [23]; 13% developed grade 1 2 thrombocytopenia as a treatment-emergent adverse event, and 30% of patients developed grade 3 4 thrombocytopenia. This pattern of thrombocytopenia is independent of the degree of bone marrow involvement at baseline [26], with 64% and 58% reductions in platelet count in patients with >50% and <50% bone marrow involvement, respectively. The development of grade 3 4 thrombocytopenia associated with bortezomib is dependent upon the platelet count at baseline [26]. The baseline platelet count is itself dependent on possible chemotherapy-induced bone marrow impairment and particularly upon the severity of disease, which is reflected in the degree of bone marrow involvement or by the serum paraprotein level. As patients experience reductions in platelet count of approximately 60% during the dosing period, it is uncommon for patients to develop grade 4 thrombocytopenia unless the platelet count is <70,000/μl at baseline [26]. Serum thrombopoietin levels are not reduced in response to bortezomib therapy [26]. Bortezomib does not appear to be directly cytotoxic to most normal bone marrow cells or to destroy progenitor cells [27]. Platelet budding from megakaryocyte progenitors is thought to be dependent on NF-κB, and bortezomib may suppress this process temporarily, resulting in thrombocytopenia [26]. In phase II trials, thrombocytopenia was not associated with serious bleeding events, although there was one episode of gastrointestinal bleeding associated with grade 3 thrombocytopenia (platelet count <50,000/μl) [6, 23]. It is appropriate to perform complete blood counts prior to each dose of bortezomib for the first two cycles, and thereafter according to physician discretion, based Figure 4. Recovery of platelet counts prior to each successive cycle of therapy. Platelet counts drop during the dosing periods (days 1 11), normally returning toward baseline levels during the rest period (days 12 21). From [26]. on the degree of thrombocytopenia observed in the first two cycles and the response of the patient s bone marrow. However, in patients with baseline thrombocytopenia, platelet counts should be monitored continuously. For patients who develop significant thrombocytopenia by day 11 of each cycle (platelet count <30,000/μl), the platelet count should be rechecked on day 14 or 15 to determine if additional platelet suppression has occurred, and whether subsequent transfusion is needed to prevent bleeding episodes. In general, bortezomib should be withheld at the onset of grade 3 nonhematologic or grade 4 hematologic toxicity, excluding PN [23]. Once the toxicity has resolved, treatment may be restarted at a 25% reduced dose (1.3 mg/m 2 reduced to 1.0 mg/m 2 ; 1.0 mg/m 2 reduced to 0.7 mg/m 2 ). In clinical practice, some researchers give platelet transfusions and continue bortezomib administration without dose reduction under close observation, enabling treatment to continue uninterrupted, particularly during the first two treatment cycles. In patients with advanced MM with moderate to severe thrombocytopenia (platelet count <50,000/μl) and risk factors for bleeding, the potential benefit of bortezomib should be balanced against risks. Platelets, red blood cells, and growth factors may be used in the management of hematologic toxicities. In patients with anemia, the cause of anemia should be carefully investigated, and erythropoietin, iron, vitamin B 12, or folic acid should be administered if required. A similar situation applies to patients with neutropenia, in whom the use of G-CSF may be of benefit. Prophylactic platelet transfusions should be considered in patients with thrombocytopenia, particularly in those at high risk for bleeding. In the SUMMIT and CREST trials, the incidence of platelet support was low, with 14% of patients receiving platelet transfusions at cycle 1. The median baseline platelet count for patients who received platelet transfusions was 65,500/μl [26]. Thrombocytopenia that does not recover between treatment cycles may indicate progressive disease. Other Hematologic Toxicities Hematologic toxicities associated with bortezomib therapy include neutropenia and anemia, but these are not usually problematic. In the SUMMIT trial [6], 11% and 3% of patients developed grade 3 and grade 4 neutropenia, respectively; <1% of patients developed febrile neutropenia, and <1% discontinued treatment as a result of neutropenia. Development of severe anemia was uncommon, with 8% of patients developing grade 3 anemia and no cases of grade 4 anemia. The frequency of transfusion among responders decreased over the course of therapy. The Oncologist

9 San Miguel, Bladé, Boccadoro et al. 59 Some patients who were transfusion-dependent prior to therapy in the SUMMIT trial were observed to become transfusion-independent if they had a response. Fatigue and Other Asthenic Conditions In an analysis of pooled data from the SUMMIT and CREST trials [23], of 228 patients who received the 1.3- mg/m 2 bortezomib dose, the most common adverse events were asthenic conditions, which were reported by 65% of patients, leading to treatment discontinuation in 2% of patients (Table 4). In the SUMMIT trial, 41% of patients experienced fatigue and 12% developed grade 3 fatigue. The Functional Assessment of Chronic Illness Therapy Fatigue scores decreased in responders, indicating improvements in fatigue with disease reduction [28]. In the CREST trial, 73% and 68% of patients developed fatigue and 8% and 7% developed grade 3 fatigue at the 1.3-mg/m 2 and 1.0-mg/m 2 doses, respectively. The onset of fatigue usually occurred during treatment cycles 1 and 2, persisting for several cycles prior to resolution. Low-dose prednisone (Deltasone ; Pfizer Pharmaceuticals) and careful attention to hydration may be of benefit in managing fatigue. Treatment should be withheld at the onset of any treatment-emergent grade 3 fatigue. Once symptoms resolve, therapy may be reinitiated after a 25% dose reduction. Gastrointestinal Effects In pooled data from 228 patients treated with bortezomib (1.3 mg/m 2 ) in phase II clinical studies [23], the most common gastrointestinal adverse effects were nausea (64%), diarrhea (51%), constipation (43%), and vomiting (35%). These may occur at any time during treatment, but in clinical trials, most occurred during the first or second cycle and were generally of mild to moderate severity. Nausea and vomiting may require the use of antiemetics. Generally, diarrhea may be controlled with antidiarrheal agents, such as loperamide hydrochloride (Imodium ; Table 4. Incidence of fatigue and other asthenic conditions in patients receiving the standard 1.3 mg/m 2 bortezomib dose (SUMMIT and CREST) (n = 228) Overall (%) Grade 3 4 (%) Bortezomib discontinued (%) Fatigue Weakness 20 6 <1 Malaise 11 <1 <1 Lethargy 4 <1 0 From [23]. McNeil Consumer and Specialty Pharmaceuticals, Fort Washington, PA, com) or diphenoxylate hydrochloride (Lomotil ; Pfizer Pharmaceuticals). Mild diarrhea may be controlled by dietary changes. For acute diarrhea, seen primarily in patients with previous bowel motility problems, options to alleviate symptoms include fiber supplements. Patients should be advised regarding appropriate measures to avoid dehydration. Fluid and electrolyte replacement may be required. Constipation may be managed with stool softeners and laxatives. Patients should be encouraged to drink as much fluid as possible, avoiding caffeine. It should be noted that constipation may also be a result of autonomic neuropathy in the form of paralytic ileus, although further study is needed to confirm this hypothesis. Finally, acute pancreatitis has also been reported [23]. Hypotension The pooled data from 228 patients treated in phase II trials with 1.3 mg/m 2 bortezomib revealed orthostatic/postural hypotension in 27 (12%) patients (4% grade 3, no grade 4) [23]. Bortezomib should be used cautiously in patients with a history of syncope, patients receiving medications known to be associated with hypotension, and dehydrated patients. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, increased salt intake, or the administration of corticosteroids with mineralocorticoid effects. Patients should rise slowly, keep physically active, and drive vehicles or operate machinery with caution. They should report any episodes of hypotension or symptoms of light-headedness, dizziness, or fainting. This symptom may be reduced by concomitant hydration (500 ml normal saline) with each dose of bortezomib. Tumor Lysis Syndrome Tumor lysis syndrome (TLS) is rare in MM, with an incidence of 1.4% (7/496) in patients with MM treated with bortezomib in three phase II multicenter trials [29] and one case report of bortezomib-related TLS [29]. In each of these cases, TLS developed during the first cycle of therapy, or within 21 days of retreatment with bortezomib. No patient died of TLS, and signs typically resolved within 1 week with supportive care. Patients with MM, particularly those with high tumor burden, should be monitored for signs of TLS during the first treatment cycle. Adequate hydration and allopurinol (Zyloprim ; Prometheus Laboratories, Inc., San Diego, com) administration should be considered if there is a risk for TLS [30].

10 60 Practical Update on Bortezomib in Multiple Myeloma Effect on Stem Cells Bortezomib does not adversely affect the production or engraftment of murine stem cells. In a murine bone marrow transplant model [27], after four cycles of treatment with bortezomib or saline control, the numbers of bone marrow progenitor cells were similar in both treatment groups; whereas, in mice transplanted with harvested stem cells, engraftment was similar between bortezomibtreated and saline-treated cells. Stem cell harvesting for transplantation and engraftment appeared unaffected by either front-line bortezomib [31] or combination therapies such as bortezomib combined with thalidomide plus dexamethasone [19]. Summary Bortezomib is the first proteasome inhibitor to be approved for the treatment of MM. It has established single-agent efficacy in the treatment of relapsed and refractory MM, with an ORR of 35% [6] and has demonstrated a 1-year survival rate that is greater than that seen with dexamethasone (80% vs. 66%), as well as a 78% longer TTP in patients with MM following one to three prior therapies [8]. Different treatment centers have developed various approaches to manage adverse events according to clinical experience. In general, bortezomib is well tolerated, with most side effects being mild to moderate. Thrombocytopenia is usually transient and reversible [26]. PN, for which patients have differing thresholds, can be managed with dose adjustments [12], although some researchers prefer to correct hypovitaminosis with vitamin B 12 therapy [32] before initiating bortezomib. Fatigue is reported by some researchers to be improved by i.v. fluid administration prior to each bortezomib dose, while others have observed improvement with corticosteroids or central stimulants (e.g., methylphenidate [Ritalin ; Novartis Pharmaceuticals Corporation, East Hanover, NJ, us.novartis.com], methamphetamine [Desoxyn ; Ovation Pharmaceuticals, Lincolnshire, IL, ovationpharma.com], or modafinil [Provigil ; Cephalon, Inc., West Chester, PA, In renal or hepatic dysfunction, formal studies are ongoing to define the optimal dose of bortezomib therapy. One report is encouraging, in which patients with renal dysfunction, even when severe, were able to achieve major responses to bortezomib without any apparent greater toxicity than patients without renal dysfunction [21]. Preclinical data indicate that bortezomib can enhance the antitumor efficacy of standard agents with activity in MM, including dexamethasone, melphalan, and doxorubicin. Preliminary clinical trial results with combination regimens are encouraging in the relapsed/refractory and front-line settings. Larger, multicenter trials are required to establish the effectiveness and manageability of bortezomib-based combination regimens. Retreatment with bortezomib in patients who have previously responded is feasible and is currently under investigation. Another area of great interest is the potential efficacy of bortezomib as maintenance therapy to prolong response duration. In conclusion, bortezomib has demonstrated significant antitumor activity as a single agent and, as part of combination therapy, may be able to re-establish sensitivity in chemoresistant disease in patients who have previously received single-agent therapy, including prior bortezomib. It is likely that bortezomib will play a role at several time points in the MM treatment paradigm, including front-line treatment. Disclosure of Potential Conflicts of Interest Dr. San Miguel is a speaker on the scientific advisory board for Millennium, Pharmion, and Johnson & Johnson. Dr. Sonneveld has acted as a consultant for OrthoBiotech. References 1 San Miguel JF, Gutierrez N, Garcia-Sanz R et al. Thalidomide and new drugs for the treatment of multiple myeloma. Hematol J 2003;4(suppl 3): Bruno B, Rotta M, Giaccone L et al. New drugs for treatment of multiple myeloma. Lancet Oncol 2004;5: Hideshima T, Mitsiades C, Akiyama M et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003;101: 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 2003;101: Orlowski RZ, Stinchcombe TE, Mitchell BS et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. 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11 San Miguel, Bladé, Boccadoro et al Richardson P, 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 2004;5(suppl 2):S Richardson P, Sonneveld P, Schuster M et al. Bortezomib demonstrates superior efficacy to high-dose dexamethasone in relapsed multiple myeloma: final report of the APEX study. Blood 2004;104:abstract Available at Accessed January 9, Sonneveld P, Richardson PG, Schuster MW et al. Bortezomib is more effective than high-dose dexamethasone at first relapse and provides better outcomes when used early rather than as later salvage therapy in relapsed multiple myeloma. Haematologica 2005;90(suppl 2): Richardson PG, Barlogie B, Berenson J et al. Prognostic factors for response parameters and overall survival in patients with multiple myeloma (MM) following treatment with bortezomib. Blood 2003;102:446a. 13 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 2004;5 (suppl 2):S Voorhees PM, Dees EC, O Neil B et al. The proteasome as a target for cancer therapy. Clin Cancer Res 2003;9: 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. Blood 2004;104:64a. 16 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 2003;9: Hideshima T, Richardson P, Chaunhan D et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001;61: 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 2005;105: Alexanian R, Wang LM, Weber DM et al. VTD (Velcade, thalidomide, dexamethasone) as primary therapy for newly diagnosed multiple myeloma. Blood 2004;104:64a. 20 Zangari M, Barlogie B, Hollmig K et al. Marked activity of Velcade plus thalidomide (V+T) in advanced and refractory multiple myeloma (MM). Blood 2004;104:413a. 21 Jagannath S, Barlogie B, Berenson JR et al. Bortezomib in recurrent and/ or refractory multiple myeloma. Initial clinical experience in patients with impaired renal function. Cancer 2005;103: Rosinol L, Montoto M, Cibeira MT et al. Bortezomib-induced severe hepatitis in multiple myeloma: a case report. Arch Intern Med 2005;165: Millennium Pharmaceuticals, Inc. Velcade (bortezomib) for injection. Prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc., Richardson PG, Briemberg H, Jagannath S et al. Characterization and reversibility of peripheral neuropathy in patients with advanced multiple myeloma treated with bortezomib (VELCADE). The SUMMIT and CREST Study Group. Hematol J 2004;5(suppl 2):S Calhoun EA, Welshman EE, Chang CH et al. Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 2003;13: Lonial S, Waller EK, Richardson PG et al. Evaluation of the degree of thrombocytopenia and associated risk factors following bortezomib therapy for relapsed multiple myeloma. Blood 2003;102:447a. 27 Fitzgerald M, Fraser C, Webb I et al. Normal hematopoietic stem cell function in mice following treatment with bortezomib. Biol Blood Marrow Transplant 2003;9: Lee S, Richardson PG, Barlogie B et al. Quality of life (QOL) and clinical benefit assessment in patients with relapsed and refractory multiple myeloma (MM) treated with bortezomib. Proc Am Soc Clin Oncol 2003;22: Mehta J, Jakob C, Singhal S et al. Bortezomib causes tumor lysis syndrome in approximately 1% of patients with myeloma. Blood 2003;102:386b. 30 Terpos E, Politou M, Rahemtulla A. Tumour lysis syndrome in multiple myeloma after bortezomib (VELCADE) administration. J Cancer Res Clin Oncol 2004;130: Jagannath S, Durie B, Wolf J et al. Bortezomib (Velcade, formerly PS- 341) as first-line therapy in patients with multiple myeloma (MM). Blood 2003; Baz R, Alemany C, Green R et al. Prevalence of vitamin B 12 deficiency in patients with plasma cell dyscrasias: a retrospective review. Cancer 2004;101: