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Review

Oncology 2006;70:474–482 DOI: 10.1159/000099284

Management of Multiple Myelomawith Bortezomib: Experts Review the Data and Debate the Issues

Mario Dicato

a Mario Boccadoro

b Jamie Cavenagh

c Jean-Luc Harousseau

d

Heinz Ludwig

e Jesús San Miguel

f Pieter Sonneveld

g

for the Multiple Myeloma Experts Debate Group

a Department of Hematology-Oncology, Luxembourg Medical Center, Luxembourg , Luxembourg; b

Division of Hematology, University of Torino, Torino , Italy; c

St Bartholomew’s Hospital and Royal London Hospital, London , UK; d

Department of Clinical Hematology, University Hospital Nantes, Nantes , France; e Department of Medicine

and Hematology/Medical Oncology, Wilhelminen Hospital, Vienna , Austria; f Department of Hematology, University Hospital, Salamanca , Spain; g

Department of Hematology, Erasmus Medical Center, University of Rotterdam, Rotterdam , The Netherlands

conducted a series of debates with over 450 clinicians to dis-cuss the efficacy of bortezomib vis-à-vis other available ther-apies. Of primary concern was the place of bortezomib in maximizing efficacy throughout the course of the disease and treatment by increasing response rates and improving duration of response, while maintaining an acceptable level of toxicity. The experts concluded that bortezomib, with its unique mechanism of action and demonstrated clinical ef-ficacy and safety, should be considered as standard, early treatment in patients with relapsed multiple myeloma, espe-cially after first relapse. Copyright © 2006 S. Karger AG, Basel

Introduction

Multiple myeloma is the second most common hema-tologic malignancy with an estimated incidence in Eu-rope of 19,000 new cases per year. The incidence of mul-tiple myeloma increases with age, with the median age at diagnosis between 65 and 70 years. During the course of

Key Words Multiple myeloma � Bortezomib � Thalidomide � Proteasome inhibition

Abstract Cure for multiple myeloma is rare; the success of treatment is measured by response, and length of remissions and sur-vival. Initial treatment for patients young and fit enough is high-dose chemotherapy with autologous stem cell trans-plantation. Various chemotherapy regimens are employed as initial therapy in patients who cannot withstand the au-tologous stem cell transplantation regimen, and for treat-ment of refractory or relapsed disease. Commonly used agents either alone or in combination have included dexa-methasone, vincristine, doxorubicin, melphalan, cyclophos-phamide, etoposide, cisplatin and, more recently, thalido-mide. Within the past few years, the first-in-class proteasome inhibitor bortezomib has been introduced for the treatment of relapsed multiple myeloma with data demonstrating ef-ficacy and safety. Throughout Europe, a faculty of experts

Received: April 18, 2006 Accepted after revision: November 18, 2006 Published online: February 2, 2007

Oncology

Mario Dicato, MD, FRCP(Edin) Centre Hospitalier Rue Nicolas-Ernest Barble 4 Luxembourg 1210 (Luxembourg) Tel. +352 44 11 3103, Fax +352 44 12 15, E-Mail dicato.mario@chl.lu

© 2006 S. Karger AG, Basel0030–2414/06/0706–0474$23.50/0

Accessible online at:www.karger.com/ocl

Management of Multiple Myeloma with Bortezomib

Oncology 2006;70:474–482 475

the disease and treatment, patients experience a series of remissions and relapses. Median duration of survival is 2–3 years in older patients, and 5 years in younger pa-tients who can undergo high-dose therapy with autolo-gous stem cell transplantation (ASCT), but it can vary as much as less than 6 months to more than 10 years, the variability arising from heterogeneity in myeloma cell bi-ology and multiple host factors [1] .

There are relatively few effective treatment options for patients with multiple myeloma. Traditional treatment includes combination chemotherapy with melphalan/prednisone and vincristine/doxorubicin/dexametha-sone. Myeloablation with high-dose chemotherapy and subsequent rescue with ASCT is a mainstay for patients fit enough to withstand the regimen, usually patients less than 65 years of age. The immunomodulators, thalido-mide and lenalidomide, alone or in combination with dexamethasone, have been shown to be effective in mul-tiple myeloma.

Bortezomib is a first-in-class proteasome inhibitor that has shown remarkable efficacy in multiple myeloma. Bortezomib specifically targets the ubiquitin-proteasome pathway; the proteasome plays a key role in the degrada-tion of ubiquinated proteins in general, and specifically proteins that control tumor cell growth and survival. By targeting the proteasome and acting on the multiple my-eloma cells as well as the microenvironment, bortezomib has been shown to increase response in patients with multiple myeloma, especially in patients with relapsed and refractory disease. Bortezomib is currently indicated for the treatment of relapsed and refractory multiple my-eloma, including use as second-line treatment after first relapse.

In a series of debates held throughout Europe in the first half of 2005, a group of experts met with over 450 clinicians and discussed clinical questions regarding bortezomib for the treatment of multiple myeloma. The goal of the debates was to raise issues important to the clinician who treats multiple myeloma, and arrive at a consensus on the most effective approaches to yield the most successful outcomes.

Bortezomib

Bortezomib is a first-in-class proteasome inhibitor de-signed to interfere with the ubiquitin-proteasome path-way that is critical in regulating protein degradation and controlling cell growth [2, 3] . Briefly, the proteasome is a large multiprotein that is present in the cytoplasm and

nucleus of eukaryotic cells, functioning to degrade pro-teins that are marked with a poly-ubiquitin chain into peptides and free ubiquitin [2, 4] . Through this mecha-nism, the proteasome allows the activation of NF- � B by degrading the inhibitory protein I � B; NF- � B is necessary to regulate the viability of cells through transcription of inhibitors of apoptosis in response to environmental stress or cytotoxic agents, and has been implicated in controlling cell surface expression of adhesion molecules involved in tumor metastasis and angiogenesis [2] . Pro-teasome inhibition, therefore, could inhibit tumor growth, metastases, and angiogenesis through multiple mechanisms [2] .

Bortezomib is a dipeptide boronic acid analog that in-hibits the 20S core proteolytic complex of the 26S protea-some. Preclinical studies showed bortezomib to be active in a wide variety of malignancies as a single agent and in combination with other cancer treatments [5] , and early clinical trials indicated considerable activity in resistant and refractory multiple myeloma. Phase I clinical trials in patients with a variety of malignancies evaluated the pharmacodynamics of bortezomib and established dose and regimen [6, 7] . Data from these studies show that proteasome activity was significantly inhibited within1 h of bortezomib administration and returned to base-line levels within 72 h. Proteasome inhibition was dose dependent and related to both the dose in milligrams per meter squared and the total dose administered [6] with no significant difference in the mean percentage of inhi-bition 1 h after dosing on individual dosing days [7] .

The recommended initial dosing regimen for bortezo-mib is 1.3 mg/m 2 on days 1, 4, 8, and 11 in a 21-day cycle (10-day rest period); dose can be reduced to 1.0 mg/m 2 , if necessary, to control adverse effects. Bortezomib is ad-ministered as a 3- to 5-second IV bolus through a periph-eral or central IV catheter followed by a standard saline flush. In clinical trials, bortezomib was administered for up to 8 cycles, with an additional 3 cycles as mainte-nance.

Bortezomib for the Treatment of Relapsed Multiple Myeloma

The treatment objective for the patient diagnosed with multiple myeloma is to elicit complete and durable re-sponse, thereby prolonging time to progression and ex-tending survival. Results from the phase II SUMMIT [8] and CREST [9] clinical trials and phase III APEX [10] clinical trial with bortezomib have demonstrated high re-

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Oncology 2006;70:474–482476

sponse rates, prolonged time to progression, and extend-ed survival in patients with relapsed or refractory mul-tiple myeloma. Table 1 summarizes design and results from these trials.

In the phase II studies, previous treatments (range 1–7) included corticosteroids, alkylating agents, anthracy-clines, thalidomide, stem cell transplant, and in the CREST study [9] , local radiotherapy. Primary endpoints were response rates defined as complete response (CR), partial response (PR), or minimal response as defined by the European Blood and Marrow Transplant criteria. Most patients received bortezomib as 1.3 mg/m 2 IV bolus over 3–5 s in a 21-day cycle administered on days 1, 4, 8, and 11; in the CREST study [9] , half the patients were randomized to receive 1.0 mg/m 2 .

In the SUMMIT study, overall response for 193 pa-tients with measurable disease was 35% [8] . Median time to first response was 1.3 months; median time to disease

progression was 7 months, as compared with 3 months during the last treatment before enrollment (p = 0.01). Median duration of response to bortezomib was 12 months and median survival for all patients was 16 months. Patients who achieved CR or PR to bortezomib alone after 2 cycles had significantly longer survival than other patients (p = 0.007).

In the randomized CREST study, response to bortezo-mib monotherapy was 33% for patients with measurable disease who received the 1.0 mg/m 2 dose, and 50% for patients who received the 1.3 mg/m 2 dose [9] . Median time to first response was 1.3 months for patients who received bortezomib 1.0 mg/m 2 , and 1.5 months for pa-tients who received bortezomib 1.3 mg/m 2 . Median time to disease progression for patients who received bortezo-mib 1.0 or 1.3 mg/m 2 alone or with dexamethasone was 7 and 11 months, respectively; median duration of re-sponse was 9.5 and 13.7 months, respectively.

Table 1. Summary of bortezomib efficacy in phase II and III clinical trials

Phase II studySUMMIT [8]

Phase II studyCREST [9]

Phase III studyAPEX [10]

Study design open label, multicenter

open label, multicenter, random-ized; 2 dose levels of bortezomib

open label, multicenter, randomized to bortezomib or dexamethasone

Concomitantdexamethasone allowed

yes yes no

Patients relapsed or refractory; n = 202

relapsed during/following 1st line treatment; n = 54

relapsed; n = 669

Bortezomib dosage 1.3 mg/m2 IV on days 1, 4, 8, 11; 21-day cycle; max. 8 cycles

1.0 mg/m2 (n = 28) or 1.3 mg/m2 (n = 26) on days 1, 4, 8, 11;21-day cycle; max. 8 cycles

induction (8 cycles): 1.3 mg/m2 IV on days 1, 4, 8, 11; 21-day cyclemaintenance (3 cycles): 1.3 mg/m2 on days 1, 8, 15, 22; 35-day cycle(273 treatment days; n = 333)

Dexamethasone dosage for suboptimal response1: 20 mg PO on day of and day after bortezomib

for suboptimal response1: 20 mg PO on day of and day after bortezomib

induction (4 cycles): 40 mg PO on days 1–4, 9–12, 17–20, 35-day cyclemaintenance (5 cycles): 40 mg PO on days 1–4, 28-day cycle (280 treatment days; n = 336)

Overall response:Phase II studies: CR + PR + MRPhase III study: CR + PR

35% 1.0 mg/m2: 33%+ dexamethasone: 44%1.3 mg/m2: 50%+ dexamethasone: 62%

1st relapse:bortezomib: 45%; dexamethasone: 26% (p = 0.0035)≥2nd relapse:bortezomib: 34%; dexamethasone: 13% (p < 0.0001)

MR = Minimal response.1 Progressive disease after 2 cycles or stable disease after 4 cycles.

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Oncology 2006;70:474–482 477

In the phase III APEX study [10] , bortezomib as a sin-gle agent was compared to high-dose dexamethasone in patients with relapsed multiple myeloma ( table 1 ). Pri-mary endpoint was time to progression; secondary end-points included survival and response rate (CR + PR) us-ing the European Blood and Marrow Transplant crite-ria.

Updated results are available with median follow-up at 15.8 months [11] . Median time to progression was 6.2 and 3.5 months for patients who received bortezomib and dexamethasone, respectively (p ! 0.001). Significant dif-ferences (p ! 0.001) were demonstrated between bortezo-mib and dexamethasone for overall survival at 1 year, 80 versus 67%, respectively, and response rate, 43 versus 18%, respectively. As shown in table 1 , patients who re-ceived bortezomib after first relapse had higher response rates compared to patients who received bortezomib later in the disease course. While results with bortezomib are impressive, the magnitude of difference between bort-ezomib and dexamethasone must be interpreted with caution since most patients had received corticosteroids previously. In these patients, it would be expected that response to bortezomib, a new agent in their treatment regimen, would be higher than to dexamethasone.

In an additional analysis, the effect of deletion of chro-mosome 13, del(13), on response and survival was evalu-ated for patients who received bortezomib or dexametha-sone [12] . A matched-pair analysis balanced for adverse prognostic variables (treatment type, patient age, number of prior therapies, � 2 -microglobulin and albumin levels) compared 21 of the 24 assessable del(13) patients with 41 patients with wild-type chromosome 13. For 62 evaluable patients in the matched-pair analysis, a significant (p = 0.0090) decrease in survival was noted among patients

with del(13) compared with those without the deletion, regardless of treatment. A significant (p = 0.0020) de-crease in survival was noted for patients with del(13) de-tected by metaphase cytogenetic analysis who received dexamethasone. No difference in survival or response rate, however, was noted in patients with del(13) who re-ceived bortezomib (25% response in patients with del(13) versus 35% in patients without the deletion).

Greater Efficacy of Bortezomib after First Relapse A subanalysis of the phase III APEX trial [10] was con-

ducted to evaluate response to single-agent bortezomib in patients experiencing first relapse [13] . Significantly greater efficacy was demonstrated for bortezomib as sec-ond-line therapy versus dexamethasone for median time to progression (7.0 vs. 5.6 months, respectively; p = 0.0021), and CR + PR (45 vs. 26%, respectively; p = 0.0035). Analyses of median time to progression for patients who received bortezomib or dexamethasone as later salvage therapy demonstrated significantly (p ! 0.0001) lower median times to progression for each agent (4.9 and 2.9 months, respectively) and lower response rates (34 vs. 13%, respectively) compared to patients who received these agents after first relapse.

Bortezomib Administered in Combination Clinical evidence suggests that combining bortezo-

mib with conventional chemotherapy results in higher response rates, perhaps due to synergy of different mech-anisms of action. Numerous clinical trials have evaluated bortezomib in combination with dexamethasone, mel-phalan, doxorubicin, and thalidomide for relapsed or re-fractory multiple myeloma. Tolerance to these combina-tions was acceptable, with predictable and manageable toxicities.

Bortezomib and Dexamethasone The protocol for the phase II clinical trials of bortezo-

mib [8, 9] allowed the addition of dexamethasone for sub-optimal response. Table 2 summarizes responses for one trial that analyzed differences in response when dexa-methasone was added to bortezomib [9] . The addition of dexamethasone increased overall response to 44% for pa-tients who received bortezomib 1.0 mg/m 2 and to 62% for patients who received bortezomib 1.3 mg/m 2 . In another trial, overall response rate was 80% for 15 patients with advanced multiple myeloma [14] ; 8 of 10 patients with a chromosome 13 deletion achieved at least a PR. Median time to response was 3 weeks and responses were inde-pendent of prognostic parameters.

Table 2. Response to bortezomib alone and with dexamethasone (Dex) in patients with relapsed/refractory disease [9]

Responses Bortezomib1.0 mg/m2

(n = 27), %

Bortezomib1.3 mg/m2

(n = 26), %

alone plus Dex alone plus Dex

Overall response(CR + PR + MR) 33 44 50 62CR + near CR 11 19 4 4PR 19 19 35 46MR 4 7 12 12

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Bortezomib and Melphalan A phase I/II study evaluated the efficacy of bortezo-

mib (0.7 or 1.0 mg/m 2 IV) plus oral melphalan 0.025–0.25 mg/kg [15] . Twenty-six patients were heavily pretreated with 2–7 prior therapies. Response rate of 67% occurred at all dose levels, with CR and PR independent of prior treatment, including bortezomib and melphalan. Median time to progression was 8 months (range: 1–18 months).

Bortezomib and Thalidomide In a phase I/II clinical trial, 85 patients with advanced

or refractory multiple myeloma received bortezomib (1.0 or 1.3 mg/m 2 ) and thalidomide in increasing doses (from 50 to 200 mg) dependent on the appearance of neurotox-icity, with dexamethasone added at cycle 4 if PR was not achieved [16] . After cycle 1, 13% of patients had PR or bet-ter with bortezomib alone, including 5% who achieved near CR or better. Maximum response was seen after completing 3 additional cycles of treatment: 52% PR or better and 12% near CR; 68% of patients had 6 25% re-duction in M protein. Event-free survival at 12 months was 37% for all patients. Multivariate analysis evaluated 17 potentially relevant prognostic markers [17] . Prior therapy (36% of patients) was associated with significant-ly improved survival (hazard ratio 0.4, p = 0.03). Interest-ingly, prior treatment with thalidomide (78% of patients) was associated with significantly worse survival after bortezomib + thalidomide treatment (hazard ratio 4.1,p = 0.05).

Bortezomib, Doxorubicin, Thalidomide A phase II trial evaluated bortezomib 1.3 mg/m 2 IV,

doxorubicin 20 mg/m 2 IV, and oral thalidomide, with low-dose coumadin to prevent venous thromboembo-lism [18] . Patients had stage III relapsed/refractory dis-ease and had received 1–7 prior therapies. Objective clin-ical response was seen in 78% (11/14) of evaluable pa-tients. The regimen was effective and well tolerated without limiting venous thromboembolism or neuropa-thy.

Bortezomib, Doxorubicin, Thalidomide, and Dexamethasone Twenty previously treated patients with refractory or

relapsed multiple myeloma were enrolled in a study to evaluate the efficacy of combination regimens with bort-ezomib, doxorubicin, thalidomide, and dexamethasone [19] . A PR was recorded for 50% of 14 patients evaluable for response. Median decrease in serum M protein was 57% and 93% in urine M protein; while none of 13 pa-

tients had normal bone marrow, a median reduction in monoclonal plasmacytosis of 50% was noted. Results show that doxorubicin is a beneficial addition to bortezo-mib-based therapy and overcomes resistance in patients who were resistant to bortezomib/thalidomide/dexa-methasone.

Sequence of Bortezomib and Thalidomide Thalidomide is an immunomodulatory agent for the

treatment of relapsed or refractory disease [20–23] and has also shown response in untreated multiple myeloma [24–26] . The precise mechanism of action of thalidomide is not fully understood, but it is believed to have numer-ous actions against multiple myeloma cells, including an-tiangiogenic effects.

The primary consideration when deciding on the se-quence of bortezomib and thalidomide is administration of the most effective agent that will allow subsequent treatment following eventual relapse. There may be a preference to use bortezomib before thalidomide because of peripheral neuropathy which occurs in approximately 33% of patients with multiple myeloma even before ther-apy [27] . Peripheral neuropathy, reported in 50–80% of patients that have received thalidomide for multiple my-eloma, is a major treatment-limiting toxicity for this agent [28, 29] . The severity and reversibility of peripheral neu-ropathy with thalidomide depend on dose and duration of treatment [30] ; higher thalidomide doses are associ-ated with grade 3 peripheral neuropathy, which is usu-ally not reversible, in about one third of patients [28] . Pe-ripheral neuropathy was reported in about one third of the patients who received bortezomib in the phase II and phase III clinical trials, with the majority of incidents less than grade 3 [10, 31] . Unlike thalidomide, peripheral neu-ropathy with bortezomib resolved in about 74% of pa-tients with significant distress [31] . The consensus was that bortezomib should generally be considered before thalidomide to avoid prejudice for the next choice of treatment due to peripheral neuropathy.

Bortezomib as First-Line Treatment

Bortezomib has shown activity as first-line treatment in newly diagnosed, untreated multiple myeloma in two phase II studies [32, 33] . In one study, overall response after more than 2 cycles of therapy (n = 22) was 64% [32] . Peripheral neuropathy occurred in 21% of patients and was mainly grade 2 and managed with dose modifica-tion.

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Oncology 2006;70:474–482 479

In the second study, patients (completed, n = 23) re-ceived single-agent bortezomib with added dexametha-sone for less than PR after 2 cycles or less than CR after 4 cycles of treatment [33] . Overall major response was 83%. Best response was recorded for 43% of patients after cycle 2, 39% after cycle 4, and 13% after cycle 6. The addition of dexamethasone (61% of patients) increased response in 9 patients. Peripheral neuropathy (grades 1–3) occurred in 56% of patients; 12% had neuropathic pain, which re-solved when treatment was discontinued.

Bortezomib for Induction Treatment A number of phase I/II clinical trials have investigated

the use of bortezomib in combination with chemothera-py, including dexamethasone, for induction treatment prior to ASCT ( table 3 ) [34–37] . The conclusion from these studies is that bortezomib is an effective adjunct to standard induction regimens, with excellent response, successful mobilization of peripheral blood stem cells, and good tolerance.

Bortezomib as First-Line Treatment in Older Patients Patients over the age of 65 years who are newly diag-

nosed with multiple myeloma are usually not candidates for ASCT because of increased risk with high-dose che-

motherapy. A phase I/II clinical trial evaluated the addi-tion of 1.0 or 1.3 mg/m 2 of bortezomib to the usual regi-men of melphalan and prednisone in 60 patients 6 65 years of age with newly diagnosed, untreated multiple myeloma [38] . In this elderly population (half the patients were 1 75 years of age), response rate was 89%, including 32% immunofixation-negative CR; half of the evaluated patients had immunophenotypic remission, i.e. no de-tectable plasma cells at 10 –4 to 10 –5 sensitivity. Event-free survival and overall survival at 16 months were 83 and 90%, respectively. The combination was well tolerated; side effects were primarily gastrointestinal events, throm-bocytopenia, neutropenia, fatigue, and peripheral neu-ropathy.

Bortezomib in Patients with Renal Impairment Approximately half of patients diagnosed with multi-

ple myeloma have renal pathology manifested as a de-crease in creatinine clearance (CrCl), and about 25% will develop progressive renal failure during the course of the disease [39] . A retrospective analysis of the bortezomib phase II studies [8, 9] assessed toxicity and response in patients with renal impairment who were not on dialysis [40] . Of the total 256 patients evaluable, over half (59%) had renal impairment defined as mild (CrCl 51–80 ml/

Table 3. Summary of clinical studies using bortezomib for induction treatment in patients with multiple myeloma (MM)

Study Induction agents Patients Response Toxicity

Oakervee et al. [34] bortezomib 1.3 mg/m2 + adriamycin 0, 4.5, or 9.0 mg/m2

+ dexamethasone 40 mg (PAD)

untreated MM; n = 21 95% CR/PR95% successfully mobilized PBSC

48% peripheral neurop-athy (43% was grade 1)

Harousseau et al. [35] bortezomib 1.3 mg/m2 + dexamethasone 40 mg

newly diagnosed MM; n = 47

83% CR/PR100% successful PBSC

1 grade 3 peripheral neuropathy

Hollmig et al. [36] bortezomib 1.0 or 1.3 mg/m2 + melphalan 100–250 mg/m2

high-risk, advanced MM; n = 37

39% PR 14% grade 3 mucositis; 30% diarrhea; 14% febrile neutropenia; 38% pneumonia/sepsis; 59% fatigue

Barlogie et al. [37] bortezomib 1.3 mg/m2 + thalidomide 50 or 100 mg + dexamethasone 20 or 40 mg (VDT) + cisplatin 10 mg/m2 + adriamycin 10 mg/m2 + cyclophosphamide 400 mg/m2 + etoposide 40 mg/m2 (PACE)

newly diagnosed MM; n = 57

>near CR 16% by cycle 2; 26% after cycle 2; 40% after 1st ASCT; 100% PBSC mobilization

myelosuppression and nonhematologic toxicities similar to DT-PACE

PBSC = Peripheral blood stem cells.

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min; n = 99), moderate (CrCl 30–50 ml/min; n = 42), and severe (CrCl ! 30 ml/min; n = 10).

Renal function had no appreciable effect on the ability to complete 8 full cycles of bortezomib treatment or re-sponse rates. Response rate for patients with normal renal function (CrCl 1 80 ml/min; n = 101) was 45% compared to 33, 25, and 30% for patients with mild, moderate, and severe renal impairment, respectively. Rates of grade 3 or 4 adverse events were similar across all categories of renal function.

Other Measures of Bortezomib Efficacy: Hemoglobin Response and Quality of Life In the phase II SUMMIT study [8] , secondary end-

points for bortezomib efficacy included additional mea-sures of clinical benefit, i.e. effect on hemoglobin levels and changes in quality of life. For the 53 patients with CR or PR, hemoglobin increased by at least 1 g/dl in 89%, and by at least 2 g/dl in 72%; none of these patients needed a blood transfusion after cycle 4 of bortezomib treatment. Responses were associated with increases in platelet count, levels of normal immunoglobulins, and Karnof-sky performance scores [8] . Global quality of life and physical measures of quality of life such as disease symp-toms, pain, and fatigue all improved in patients with clin-ical response.

Tolerance Table 4 summarizes adverse events in the phase II and

III clinical trials of bortezomib. In all clinical trials of bortezomib, the toxicity profile has been predictable and consistent, with peripheral neuropathy and thrombocy-topenia considered the most important adverse effects. These toxicities are manageable with dose reduction and

usually reversible when bortezomib treatment is conclud-ed. During clinical trials, peripheral neuropathy, of which the majority of incidents were less than grade 3, resolved or improved in 43% of patients while treatment contin-ued.

In a retrospective analysis of thrombocytopenia in pa-tients enrolled in the bortezomib phase II clinical trials, the frequency of grade 4 thrombocytopenia was low ( ̂ 10%) and associated with initial baseline platelet count of ! 70 ! 10 3 / � l [41] . Thrombocytopenia was shown to be transient during bortezomib treatment, with platelet count returning to baseline during the rest period of each cycle.

Discussion

Treatment regimens for multiple myeloma have ad-vanced slowly over the past 40 years. In the 1980s, a sig-nificant breakthrough was myeloablation with ASCT, which has proven to be the most effective initial treat-ment for patients with newly diagnosed multiple myelo-ma. Since then, the most encouraging new developments include the immunomodulatory agent thalidomide, first used in multiple myeloma about a decade ago, and most recently bortezomib. Because bortezomib has a unique, targeted mechanism of action, it holds immense promise for patients with multiple myeloma, as clinical trials have demonstrated. However, as with any new therapy, ques-tions arise frequently regarding the optimum use and po-tential for bortezomib. It was the objective of these de-bates to determine the critical questions of clinicians and answer those questions, which resulted in consensus on a number of important issues.

When to administer bortezomib for the most effective response vis-à-vis other available therapies was an often-raised question. Bortezomib should be considered as standard treatment for patients with relapsed multiple myeloma, especially after first relapse. Whether to ad-minister bortezomib alone or in combination depends on the patient, the stage of disease, and previous treatment. In clinical trials, bortezomib as monotherapy resulted in good response rates, which were greater than response rates for dexamethasone alone [10] and increased with the addition of dexamethasone to bortezomib treatment [9, 14] . In addition to dexamethasone, chemotherapy agents that have been combined successfully with bort-ezomib include melphalan, doxorubicin, and thalido-mide [15, 17–19] . Continued investigation is evaluating optimal combinations, dose levels, and schedules.

Table 4. Most common adverse events (in %) from phase II and III clinical trials of bortezomib

Adverse event (all grades) Phase

II [8] II [9] III [10]

Thrombocytopenia 40 30 35Fatigue 41 70 42Nausea 55 54 57Diarrhea 44 44 57Constipation 16 37 42Vomiting 27 not recorded 35Peripheral neuropathy 31 41 36

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Given the excellent efficacy and safety profile of bort-ezomib in relapsed and refractory multiple myeloma, questions were raised regarding use as first-line treat-ment in newly diagnosed disease. Clinical data demon-strate that bortezomib is effective and well-tolerated when used as first-line treatment, alone and in combina-tion with dexamethasone, in newly diagnosed, untreated multiple myeloma [32, 33] . It may be especially useful as first-line treatment in older patients who are not candi-dates for ASCT. A phase I/II clinical trial is ongoing, with preliminary results showing a 91% response rate, good tolerance, and no dose-limiting toxicity in elderly pa-tients [38] . In younger patients, numerous induction reg-imens that include bortezomib have been investigated with the objective of increasing CR [33–37] . Bortezomib was shown to be an effective therapy for induction with good response and successful mobilization of peripheral blood stem cells. While investigation continues, it ap-pears that bortezomib can be used successfully alone and in combination as first-line treatment in newly diagnosed patients regardless of age and transplant status.

Conclusions

The debates raised and answered important questions about the clinical use of bortezomib, the newest agent for the treatment of relapsed or refractory multiple myeloma. Through review of clinical data and discussion, it was

concluded that bortezomib, alone or in combination with dexamethasone, should be used as soon as possible in pa-tients with multiple myeloma to increase response and prolong time to progression. Bortezomib after first re-lapse has been shown to be significantly more effective for extending median time to progression, 1-year surviv-al, and response rate compared to use as later salvage therapy. Bortezomib has also shown significant efficacy as first-line treatment, and is effective and well tolerated in special patient populations such as the elderly and pa-tients with renal impairment. Bortezomib, with its tar-geted mechanism of action, excellent efficacy profile, and predictable, manageable toxicities may become the back-bone of treatment for multiple myeloma.

Acknowledgements

Members of the Multiple Myeloma Experts Debate Group in addition to the authors: Bo Björkstrand, Karolinska University Hospital Huddinge, Stockholm, Sweden; Joan Bladé, Hospital Clinic, Barcelona, Spain; Michele Cavo, University of Bologna, Italy; Michel Delforge, Catholic University Leuven, Belgium; Jo-hannes Drach, Medical University, Vienna, Austria; Roman Hajek, Masaryk University Brno, Czech Republic; Gunnar Julius-son, Lund University Hospital, Sweden; Martin Kropff, Univer-sity Clinic of Münster, Germany; Gareth Morgan, The Royal Marsden Hospital, Sutton, UK; Amin Rahemtulla, Hammer-smith Campus of Imperial College of Science, Technology and Medicine, London, UK; Kari Remes, Turku University Hospital, Finland.

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