030626 a phase 2 study of bortezomib in relapsed, refractory myeloma

The new england journal of medicine Paul G. Richardson, M.D., Bart Barlogie, M.D., Ph.D., James Berenson, M.D., Seema Singhal, M.D., Sundar Jagannath, M.D., David Irwin, M.D., S. Vincent Rajkumar, M.D., Gordan Srkalovic, M.D., Melissa Alsina, M.D., Raymond Alexanian, M.D., David Siegel, M.D., Robert Z. Orlowski, M.D., David Kuter, M.D., Ph.D., Steven A. Limentani, M.D., Stephanie Lee, M.D., Teru Hideshima, M.D., Ph.D., Dixie-Lee Esseltine, M.D., Michael Kauffman, M.D., Ph.D., Julian Adams, Ph.D., David P. Schenkein, M.D., and Kenneth C. Anderson, M.D.
b a c k g r o u n d
Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been From the Dana–Farber Cancer Institute, Boston (P.G.R., S.L., T.H., K.C.A.); Univer- shown in preclinical and phase 1 studies to have antimyeloma activity.
sity of Arkansas, Little Rock (B.B.); Cedars–Sinai Medical Center, Los Angeles (J.B.); Northwestern University Medical Center,Chicago (S.S.); St. Vincent’s Catholic Med- In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients ical Center, New York (S.J.); Alta Bates with relapsed myeloma that was refractory to the therapy they had received most re- Cancer Center, Berkeley, Calif. (D.I.); Mayocently. Patients received 1.3 mg of bortezomib per square meter of body-surface area Clinic, Rochester, Minn. (S.V.R.); Cleveland Clinic Foundation, Cleveland (G.S.); H. Lee twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles Moffitt Cancer Center, Tampa, Fla. (M.A.); (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, M.D. Anderson Cancer Center, Houstonon the day of and the day after bortezomib administration) was added to the regimen. (R.A.); Carol G. Simon Cancer Center, Mor- ristown, N.J. (D.S.); University of North The response was evaluated according to the criteria of the European Group for Blood Carolina, Chapel Hill (R.Z.O.); Massachu- and Marrow Transplantation and confirmed by an independent review committee.
setts General Hospital, Boston (D.K.); Char-lotte Medical Clinic, Charlotte, N.C. (S.A.L.);and Millennium Pharmaceuticals, Cam- bridge, Mass. (D.-L.E., M.K., J.A., D.P.S.).
Of 193 patients who could be evaluated, 92 percent had been treated with three or more Address reprint requests to Dr. Richardsonof the major classes of agents for myeloma, and in 91 percent, the myeloma was refrac- at the Department of Adult Oncology, Dana–Farber Cancer Institute, 44 Binney tory to the therapy received most recently. The rate of response to bortezomib was 35 St., Dana 1B12, Boston, MA 02115, or at percent, and those with a response included 7 patients in whom myeloma protein be- paul_richardson@dfci.harvard.edu.
came undetectable and 12 in whom myeloma protein was detectable only by immuno- fixation. The median overall survival was 16 months, with a median duration of response Copyright 2003 Massachusetts Medical Society. of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of pa-tients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia(in 11 percent). Grade 4 events occurred in 14 percent of patients.
c o n c l u s i o n s
Bortezomib, a member of a new class of anticancer drugs, is active in patients with re-lapsed multiple myeloma that is refractory to conventional chemotherapy.
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The new england journal of medicine bortezomib inhibited tumor-cell growth and pro- approximately 14,600 new cases of can- longed survival of mice carrying grafts of human mcer and 10,800 deaths annually in the myeloma cells.21 United States.1 Although conventional chemother- In a phase 1 study in patients with advanced he- apy and high-dose therapy2 with hematopoietic matologic cancer, bortezomib showed activity instem-cell rescue can prolong survival, few, if any, pa- nine patients with myeloma.37 This observation,tients are cured. Salvage therapies for relapsed dis- along with preclinical evidence of antimyelomaease are equally disappointing,3,4 and although tha- activity, provided the rationale for our open-labellidomide has shown promise,5,6 new treatments are phase 2 study of bortezomib for the treatment ofurgently needed.
We report here the effects of bortezomib (Vel- cade [Millenium Pharmaceuticals], formerly known as PS-341), a selective inhibitor of the proteasome,
in patients with multiple myeloma. The proteasome patients
is a multi-enzyme complex that is present in all cells. Study patients were at least 18 years of age, with re-
It degrades proteins that regulate cell-cycle progres- lapsed, refractory myeloma and a life expectancy of
sion7-12 and causes proteolysis of the endogenous more than three months. Measurable disease was
inhibitor of nuclear factor-kB (NF-kB), IkB. Deg- defined as a monoclonal immunoglobulin concen-
radation of IkB by proteasomes activates NF-kB, tration on serum electrophoresis of at least 1 g of
which, in turn, up-regulates the transcription of pro- IgG per deciliter or 0.5 g of IgA per deciliter or uri-
teins that promote cell survival, stimulate growth, nary excretion of at least 200 mg of monoclonal light
and reduce susceptibility to apoptosis. NF-kB acti- chain per 24 hours; patients with nonsecretory or
vation also induces drug resistance in myeloma cells oligosecretory myeloma had other evidence of meas-
and up-regulates the expression of adhesion mole- urable disease. All patients had had a relapse after
cules involved in the resistance of myeloma cells to undergoing conventional chemotherapy, and their
drugs. In addition, it modulates the secretion by myeloma was refractory to salvage chemotherapy,
bone marrow stromal cells of cytokines that medi- as defined by progression during treatment or with-
ate the growth, survival, and migration of myeloma in 60 days after the completion of treatment.
cells.13-19
Eligibility criteria included a Karnofsky perform- Bortezomib, a boronic acid dipeptide and a po- ance-status score of at least 60, a serum concentra- tent, selective, and reversible inhibitor of the protea- tion of aspartate aminotransferase or alanine ami-some, is, to our knowledge, the first agent in this notransferase no higher than three times the upperclass of small molecules to enter clinical trials. It is limit of the normal range, a serum total bilirubinadministered intravenously in 3 to 5 seconds, rapid- concentration no higher than twice the upper limitly disappears from the vascular compartment, and of the normal range, a measured or calculated creat-inhibits the proteasome, with a biologic half-life of inine clearance of more than 10 ml per minute, aapproximately 24 hours.20 Bortezomib has antitu- platelet count of at least 30,000 per cubic millimeter,mor activity in a variety of in vitro and in vivo models a hemoglobin concentration of at least 8 g per deci-of tumors, either alone21-25 or in combination with liter, and an absolute neutrophil count of at least 500common chemotherapeutic agents26-30 or radia- per cubic millimeter. Patients agreed to use contra-tion.31,32 It induces apoptosis in myeloma-cell lines ception, and women had a pregnancy test that wasand in myeloma cells from patients whose disease confirmed to be negative before enrollment. is resistant to conventional therapies. Bortezomib All patients gave written informed consent be- also down-regulates the expression of adhesion fore entering the study, which was performed in ac-
molecules by myeloma cells and bone marrow stro- cordance with the Declaration of Helsinki; approv-
mal cells, inhibits cell-adhesion–mediated drug re- al was obtained from the institutional review board
sistance, and decreases transcription and secretion at each of the participating centers.
of cytokines in the bone marrow milieu.14,22,33,34
Its molecular mechanisms entail more than NF-kB study design and treatment
inhibition,33,34 and in vitro, it enhances the antimy- Patients received bortezomib (1.3 mg per square
eloma activity of both conventional and novel che- meter of body-surface area) as an intravenous bolus
motherapeutic agents.19,33,35,36 In an in vivo study, (taking three to five seconds to administer) twice
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b o r t e z o m i b f o r r e l a p s e d , r e f r a c t o r y m y e l o m a weekly for 2 weeks, on days 1, 4, 8, and 11 in a 21-day of the immunofixation-test status, stable bone dis-cycle. Patients with progressive disease after two ease, and a normal serum calcium concentration.
cycles or stable disease after four cycles were eligi- Time-to-event analysis was performed according ble to receive 20 mg of oral dexamethasone on the to the Kaplan–Meier method. The time to the firstday of and the day after each dose of bortezomib. response was defined as the time from the initial ad-Participants received up to eight cycles of borte- ministration of bortezomib to the first evidence of azomib; those in whom there was continuing clini- confirmed response. The duration of a response wascal benefit could receive additional treatment with defined as the time from the achievement of a re-bortezomib in a separate extension study. Treatment sponse to progression. The time to disease progres-was withheld from patients with grade 3 or worse sion was defined as the time from the initial admin-nonhematologic toxic effects or grade 4 hemato- istration of bortezomib to disease progression,logic toxic effects until the effects had diminished without censoring of data for the addition of dexa-to grade 1 or better; after resolution, treatment was methasone or additional treatment with bortezomibresumed at a dose of 1.0 mg per square meter. Fur- received during the extension study. For the analysisther reduction to 0.7 mg per square meter was al- of treatment with bortezomib alone, data for pa-lowed, but lower doses were not permitted.
tients who received dexamethasone in combination The investigators and representatives from Mil- with bortezomib, additional bortezomib in the ex- lennium Pharmaceuticals designed the study. The tension study, or alternative therapy, as well as for
data were collected and analyzed by medical and sta- those patients who died without a reported date of
tistical representatives from Millennium in conjunc- progression, were censored at the last evaluation be-
tion with the investigators. All investigators had ac- fore they began receiving additional therapy or died.
cess to the primary data and participated in writing
this article. All participating institutions received assessment of safety and other secondary
grant support for the conduct of the study.
e n d p o i n t s
Adverse events were assessed at each visit and grad- a s s e s s m e n t o f e f f i c a c y
ed according to the National Cancer Institute Com- The primary end point was the overall rate of re- mon Toxicity Criteria (version 2.0) from the firstsponse to bortezomib (including complete respons- dose until 20 days after the last dose of bortezomib.
es, partial responses, and minimal responses). Sec- A neurologist performed a complete neurologicondary end points were the time to progression evaluation during initial screening, during treatmentduring treatment with bortezomib alone or during as needed, and at the end of treatment. Quality of lifetreatment with bortezomib in combination with was assessed with the use of the core quality-of-lifedexamethasone, survival, safety, the rate of response questionnaire (QLQ-C30), and the module on mul-to bortezomib in combination with dexamethasone, tiple myeloma (QLQ-MY24) of the European Organ-and the quality of life. Evaluation of responses was ization for Research and Treatment of Cancer, theperformed between days 15 and 18 of cycles 2, 4, 6, neurotoxicity subscale of the Gynecologic Oncologyand 8. Responses were assessed by an independent Group’s Functional Assessment of Cancer Therapyreview committee according to the criteria of the (FACT/GOG-NTX), and the fatigue subscale of theEuropean Group for Blood and Marrow Transplan- Functional Assessment of Chronic Illness Therapy.
tation (EBMT).38 These assessments were performed on day 1 of cy- A complete response was defined by a negative cles 1, 3, 5, and 7, as well as at the end of the study.
immunofixation test for myeloma protein in serum The time to progression during the last course of
and urine, the absence of soft-tissue plasmacyto- treatment before study entry was calculated on the
mas, a normal serum calcium concentration, stable basis of the date of relapse recorded by the investi-
skeletal disease, and less than 5 percent plasma cells gator. Paraprotein levels and skeletal radiographs
in the marrow in two specimens obtained six weeks were reviewed to verify the progression of myeloma
apart. Patients with insufficient data for an assess- during receipt of the last course of treatment.
ment of efficacy were considered to have had a treat-
ment failure. A near-complete (immunofixation- statistical analysis
positive) response was defined by the absence of The statistical analysis specified that a lower limit of
myeloma protein on electrophoresis, independent the two-sided 90 percent confidence interval for the
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The new england journal of medicine overall response rate that exceeded 10 percent would method.39,40 An analysis of survival among pa-be considered to be evidence of significant activity. tients who had a response as compared with pa-No formal comparisons of bortezomib alone with tients who did not have a response was performedbortezomib plus dexamethasone were planned or with the use of the landmark method at the end ofconducted. We performed univariate analyses using cycle 2.41Fisher’s exact test for categorical factors and logisticregression for continuous factors. In addition, we conducted a multivariate logistic-regression analy-
sis using all prognostic factors in the model and patients and treatment
then using a stepwise selection method in which From February to December 2001, 14 centers en-
terms were retained if they reached the 0.20 level of rolled 202 patients, 193 of whom could be evaluat-
significance. All descriptive statistical analyses were ed. Table 1 shows selected characteristics of all 202
performed with the use of SAS statistical software patients. Most (84 percent) had IgG or IgA myeloma
(version 8.2, SAS Institute). Analysis of the time to and advanced disease at diagnosis, 20 percent had
progression of disease during study treatment and a Karnofsky performance-status score of 70 or less,
during the last course of treatment was performed and 80 percent had symptoms of peripheral neurop-
with the use of the fixed-effect partial-likelihood athy at enrollment. The mean age was 60 years; 81
percent of the patients were white, 10 percent wereblack, and 60 percent were men. Of the 193 patientswho could be evaluated, 178 had previously been Table 1. Base-Line Characteristics of All 202 Patients.
treated with three or more of the major classes of Characteristic
agents for myeloma (Table 1), and the median num-ber of previous therapies was 6 (range, 2 to 15). The remaining 15 had received either two of the major classes of agents or a stem-cell transplant.
Durie–Salmon stage III multiple myeloma — % The median duration of treatment with borte- zomib was 3.8 months; 60 percent of patients com- pleted at least four cycles of therapy, and 39 percent received eight cycles. Of the 202 enrolled patients,54 (27 percent) discontinued treatment early be- Karnofsky performance score ≤70 — no./total no. (%) cause of progressive disease, and 45 (22 percent) discontinued treatment early because of adverse events; more than 90 percent of these 99 patients had not had a response to bortezomib.
e f f i c a c y
Of the 193 patients with measurable disease, 67 (35 percent) had a complete, partial, or minimal re- sponse to bortezomib alone (Table 2). Nineteen pa- tients had a complete or near-complete response.
The myeloma protein became undetectable by both Cytogenetic abnormalities — no./total no. (%)* electrophoresis and immunofixation in 7 of these 19 patients; in the remaining 12 patients, the myelo- ma protein became undetectable by electrophoresis, but the immunofixation test remained positive. For 12 of the 19 patients with a complete response, the response to bortezomib was the best response they had had to any therapy. The patients in whom a com-plete response was achieved were similar to the en- * Data are from standard cytogenetic analysis in 147 patients (85 percent), from tire group with respect to the extent of previous fluorescence in situ hybridization alone in 18 patients (10 percent), and from treatment (95 percent had received at least three analyses by other techniques in 7 patients.
major classes of drugs). Moreover, in 89 percent of Downloaded from www.nejm.org at ABT DOKUMENTATION on July 25, 2003.
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b o r t e z o m i b f o r r e l a p s e d , r e f r a c t o r y m y e l o m a patients with a complete response, disease had beenrefractory to the last therapy received. In an addi- Table 2. Responses to Bortezomib Monotherapy
among 193 Patients.
tional 24 percent of patients, the disease becamestable. An analysis of maximal myeloma-protein re- sponses without the use of the EBMT criteria re- Category of Response
Patients (%)
vealed a reduction of at least 50 percent in 37 percent of the patients, a reduction of at least 25 percent in48 percent of the patients, and a response ranging from a 25 percent reduction to a 25 percent increase The median time to a first response was 1.3 months. The median time to progression of disease among all 202 patients while they were receiving bortezomib alone was 7 months (6.6 months with- out censoring of the data for the addition of dexa-methasone or additional treatment with bortezomibin the extension study), as compared with 3 monthsduring the last treatment before enrollment (P=0.01 formance-status scores (see Supplementary Appen-by the fixed-effect partial-likelihood method) (Fig. dixes 1 and 2, available with the full text of this arti-1A). The median time to progression among pa- cle at http://www.nejm.org). Analysis of the qualitytients with a complete or partial response to borte- of life among 143 patients revealed maximal im-zomib alone was 13 months (12.5 months without provements in the mean global quality-of-life scorecensoring of data for the addition of dexamethasone and disease symptoms, including pain and fatigue.
or additional treatment with bortezomib in the ex- Patients with a complete or partial response alsotension study).
had a general improvement in global and physical- The median duration of the response among the domain scores on the QLQ-C30, as well as a de- 67 patients with a complete, partial, or minimal re- crease in the severity of symptoms of disease, pain,sponse to bortezomib alone was 12 months (11.4 and fatigue (see Supplementary Appendix 3, avail-months without censoring of data for the addi- able with the full text of this article at http://www.
tion of dexamethasone or additional bortezomib in nejm.org).
the extension study) (range, 1.3 to more than 16.7 Seventy-eight patients who had either stable or months) (Fig. 1B); the median duration of the re- progressive disease while receiving bortezomib
sponse among the 19 patients with a complete or alone subsequently received dexamethasone in com-
near-complete response was 15 months (with pa- bination with bortezomib, as specified in the pro-
tients who received bortezomib in the extension tocol. A total of 74 patients could be evaluated for a
study included in the analysis). Median survival response to this combination, and 13 of these pa-
among all 202 patients was 16 months (Fig. 1C). tients (18 percent) had a minimal or partial re-
According to a landmark analysis, achievement of sponse. In 6 of these 13 patients, the disease had
a complete or partial response to bortezomib alone previously been refractory to corticosteroid therapy.
after two cycles was associated with significantly
longer survival than that in all other patients (P= prognostic factors
0.007) (Fig. 1D).
The response to bortezomib was not influenced by Other secondary end points included additional sex, type of myeloma, serum level of beta -micro- measures of clinical benefit. Among patients with globulin, or type or number of previous therapies.
a complete or partial response, 89 percent had a Older age (≥65 years) was loosely associated withmaximal hemoglobin increase of at least 1 g per a lower response rate (32 percent, vs. 19 percentdeciliter, and 72 percent had a maximal hemoglobin among younger patients; P=0.06). In addition, pa-increase of at least 2 g per deciliter. None of the pa- tients with more than 50 percent plasma cells in thetients with a complete or partial response needed bone marrow at enrollment had a lower responsetransfusions after cycle 4. Responses were also as- rate (20 percent, vs. 35 percent among those with asociated with increases in the platelet count, levels lower percentage of plasma cells in bone marrow;of normal immunoglobulins, and Karnofsky per- P=0.03). Responses occurred in patients with ab- Downloaded from www.nejm.org at ABT DOKUMENTATION on July 25, 2003.
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The new england journal of medicine Figure 1. Responses to Bortezomib.
Panel A shows a Kaplan–Meier plot of time to progres- sion of disease in the 196 patients treated with bortezomib alone or all therapy (bortezomib plus dexamethasone) and the time to progression in the same 196 patients from the beginning of their last therapy to progression before entry into the study. Panel B shows the duration of the response in the 67 patients with a complete, partial, Proportion of Patients
without Progression
or minimal response to bortezomib alone or to borte- zomib plus dexamethasone. Panel C shows overall surviv-al among all 202 patients. Panel D shows overall survival Months since Study Entry
among the patients with a complete or partial response and among patients without such a response; this analy- sis was performed according to the landmark method at normalities in chromosome 13 and those without such abnormalities (24 percent and 28 percent, re- spectively). Only age and the percentage of plasma a Continued Response
Proportion of Patients with
cells in the bone marrow were significant predictors of a response in the multivariate analysis (P<0.05) Months since Study Entry
(see Supplementary Appendix 4, available with thefull text of this article at http://www.nejm.org).
The most common adverse events were gastroin- testinal symptoms, fatigue, thrombocytopenia, and sensory neuropathy (Table 3). Gastrointestinal Surviving
events were typically mild to moderate and were manageable with routine support. The most com- Proportion of Patients
mon grade 3 adverse events were thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), neuropathy (in 12 percent), and neutropenia (in 11 Months since Study Entry
percent). Grade 4 events (which occurred in a total of 14 percent of the patients) included thrombocyto- penia (in 3 percent) and neutropenia (in 3 percent), with a single case of febrile neutropenia (<1 per- cent). All other grade 4 adverse events occurred in 1 percent or less of the patients, and no patient had grade 4 neuropathy. Among the 33 patients who did Surviving
not have neuropathy before beginning bortezomib therapy, grade 3 neuropathy developed in 1 and Proportion of Patients
grade 1 or 2 neuropathy developed in 16. Overall, 12 percent of the patients required a reduction of the dose at least once, and 4 percent of patients discon- Months since Landmark (end of cycle 2)
tinued treatment because of peripheral neuropathy.
Drug-related adverse events led to discontinua- tion of bortezomib therapy in 36 patients (18 per- of bortezomib, the majority of them from causescent); no single event accounted for discontinuation related to progressive myeloma. In two patientsin more than 4 percent of patients. Ten patients (<1 percent), the cause of death was assessed as(5 percent) died within 20 days after the last dose possibly related to bortezomib treatment.
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b o r t e z o m i b f o r r e l a p s e d , r e f r a c t o r y m y e l o m a Table 3. Drug-Related Adverse Events Reported by at Least 10 Percent
of Patients and All Grade 3 or 4 Events Regardless of Relation to Bortezomib.*
In this phase 2 trial, we evaluated the efficacy ofbortezomib in patients with relapsed, refractory my- Bortezomib-
eloma. The overall response rate, including com- plete responses, was 35 percent. The median dura- Adverse Event
tion of responses was 12 months, and there was an increase by a factor of two to four in the time to pro- gression with bortezomib therapy as compared withthe last therapy patients received before entering the study. Responses were associated with increased hemoglobin levels and decreased transfusion re- quirements, improved quality of life, and improvedlevels of normal immunoglobulins.
The rates of major responses to bortezomib in patients with advanced, refractory myeloma are noteworthy. Complete responses are rare in popu- lations of patients with drug-refractory myeloma.
Although this trial was uncontrolled, we used sever- al methods to reduce bias in assessing the response to therapy. Each patient was used as his or her own control in the assessment of the time to progres-sion of disease relative to that with the last therapy received before enrollment, and a landmark analysis was performed to demonstrate an association be- tween a response to bortezomib alone and survival.
In addition, the median duration of survival amongpatients without a response (eight months) was within the range (six to nine months) that was ex- pected on the basis of the literature.3,42 It is alsonoteworthy that responsiveness to bortezomib did * Adverse events reported as drug-related are those that were considered by the not correlate with most of the standard prognostic investigator to be probably or possibly related to the study drug. All 202 pa-tients were included in this analysis.
factors, including the deletion of chromosome 13,which predicts a poor outcome with conventionaltherapy.
In our trial, 74 of the patients who could be eval- recovery occurring within the 10-day period during uated (37 percent) received dexamethasone with which treatment was suspended, and was not asso-bortezomib after having a suboptimal response to ciated with serious bleeding complications. The pat-bortezomib alone, and an improved response was tern of the thrombocytopenia is not consistent withachieved in 13 of them. Although it is impossible to the pattern typically observed with conventionaldetermine the contribution of each individual agent, chemotherapy.
the findings regarding the activity of this combina- The most clinically significant adverse event was tion of agents mirror the preclinical data22 and war- cumulative, dose-related peripheral sensory neurop-rant further investigation.
athy. New or worsening symptoms or signs of pe- Most adverse events could be managed with the ripheral sensory neuropathy were reported in 34 use of standard approaches; the incidence of grade percent of patients; overall, the incidence of grade4 adverse events was relatively low. Severe myelosup- 3 peripheral neuropathy was 12 percent, and therepression was uncommon, and grade 4 neutropenia, were no cases of grade 4 peripheral neuropathy;related febrile neutropenia, and sepsis were rare. moreover, complete resolution or improvement ofThrombocytopenia, the most common severe ad- peripheral neuropathy was observed in the majorityverse event, developed primarily in patients with a of patients during the follow-up period. Grade 3low base-line platelet count; it was transient, with neuropathy developed during treatment in only one Downloaded from www.nejm.org at ABT DOKUMENTATION on July 25, 2003.
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The new england journal of medicine patient who did not have neuropathy at base line, Supported by Millennium Pharmaceuticals.
suggesting that the incidence of neuropathy will be Drs. Richardson, Bargolie, and Anderson report having received payment from Millennium for lecturing and serving on its advisory lower in ongoing clinical trials of bortezomib in- board; Dr. Berenson having served as a paid consultant for and hav-volving patients with earlier-stage myeloma who do ing received lectures fees and grant support from Millennium; Dr.
not have preexisting neuropathy.
Singhal having received consulting and lecture fees from Millenni-um and owning stock in the company; Dr. Jagannath having served In conclusion, the novel proteasome inhibitor as a paid consultant to Millennium, Cellular Therapeutics, and bortezomib induces clinically significant respons- Orthobiotech; Dr. Rajkumar having received grants from Millenni-es, with manageable toxic effects, in patients with um and Entremed; Dr. Alexanian having served as a paid consultant to and having received grant support from Millennium; Dr. Siegel relapsed, refractory myeloma. An international, ran- having received lecture fees from Millennium and Celgene; Dr. Or-domized, multicenter phase 3 trial comparing bor- lowski having received consultant fees from Millennium; Dr. Li-tezomib with high-dose dexamethasone in patients mentani having received lecture fees from Aventis and grant support from Aventis, Novartis, GlaxoSmithKline, and Millennium; Dr. Lee with relapsed multiple myeloma is ongoing. The re- having served as a paid consultant for Millennium; Dr. Hideshimasults of this trial and other ongoing studies should having received grant support from Millennium; Dr. Kauffmanprovide clinical guidance as to how to use this agent owning stock in Millennium and is the chief executive officer of Pre- dix Pharmaceuticals; and Drs. Adams, Esseltine, and Schenkein are employees of and report having equity ownership in Millennium.
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