CANCER TREATMENT REVIEWS 2003; 29 (Suppl. 1): 33–39
`doi:10.1016/S0305-7372(03)00080-X
`
`Clinical update: proteasome inhibitors in
`hematologic malignancies
`
`Paul Richardson
`
`Dana-Farber Cancer Institute, Boston, MA 02115, USA
`
`The proteasome inhibitor bortezomib (VELCADE; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid. In
`cell culture and xenograft models, bortezomib showed potent activity, enhanced the sensitivity of cancer cells to traditional
`chemotherapeutics, and appeared to overcome drug resistance. In vitro, bortzomib downregulated the NF-jB pathway. NF-
`jB is a transcription factor that enhances the production of growth factors (e.g., IL-6), cell-adhesion molecules, and anti-ap-
`optotic factors, all of which contribute to the growth of the tumor cell and/or protection from apoptosis. Phase II trials have
`been conducted in patients with relapsed and refractory multiple myeloma (SUMMIT trial, 202 patients) or relapsed my-
`eloma (CREST trial, n ¼ 54) using a 1.3 mg=m2 dose given twice weekly for 2 weeks (days 1, 4, 8, 11; rest days 12–21).
`Both trials showed responses (including complete responses) with manageable toxicities, forming the basis for an ongoing
`phase III trial comparing response to bortezomib versus high-dose dexamethasone.
`C 2003 Elsevier Science Ltd. All rights reserved.
`
`Key words: Proteasome inhibition; bortezomib; multiple myeloma; hematologic malignancies.
`
`INTRODUCTION
`
`The proteasome is a multicatalytic enzyme complex
`that degrades numerous types of proteins (reviewed
`by Adams in this issue), many of which are regula-
`tory proteins that control the cell cycle or play a role
`in survival pathways. The coordinated expression
`and degradation of these proteins are essential for
`normal cellular function. Consequently, the protea-
`some plays a central role in up- or down-regulation
`of growth signaling pathways by removing key
`signals via protein degradation. Inhibition of the
`proteasome is therefore a promising approach for
`the treatment of cancer, a disease characterized by
`defects in growth signaling pathways that promote
`the hyperproliferation of aberrant cells.
`
`The proteasome inhibitor, bortezomib (VEL-
`CADE; formerly PS-341, LDP-341, MLN341), is a
`novel dipeptide boronic acid small molecule that has
`shown antitumor activity in preclinical studies and
`is the first such agent to have progressed to clinical
`trials. A phase III trial in patients with multiple
`myeloma (MM) is ongoing and several trials in pa-
`tients with other hematologic malignancies or solid
`tumors are in progress. Here, we briefly review the
`preclinical rationale for bortezomib and the clinical
`trial status of bortezomib in patients with hemato-
`logic malignancies, with a focus on MM.
`
`PRECLINICAL RATIONALE FOR
`PROTEASOME INHIBITORS IN
`HEMATOLOGIC MALIGNANCIES
`
`Correspondence to: Paul Richardson MD, Jerome Lipper Multiple
`Myeloma Center, Division of Hematologic Oncology, Dana-Farber
`Cancer Institute, Harvard Medical School, Boston, MA 02115,
`USA. Tel.: 1-617-632-2104; Fax: 1-617-632-6624; E-mail: paul_
`richardson@dfci.harvard.edu
`
`In cell culture and in xenografted tumors, bortezo-
`mib had potent activity, enhanced the sensitivity of
`cancer cells to traditional tumoricidal chemothera-
`peutics (1–4) and appeared to overcome drug resis-
`tance (5). This activity is at least in part mediated by
`
`0305-7372/03/$ - see front matter C 2003 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED.
`
`CFAD v. Anacor, IPR2015-01776
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`34
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`P . R I C H A R D S O N
`
`the activity of bortezomib against the NF-jB path-
`way. The NF-jB pathway is constitutively active in
`some cancer cells and is associated with prolifera-
`tion, cell survival, and protection from chemothera-
`py-induced apoptosis
`(Figure
`1). Proteasome
`inhibition has also been shown to block chemother-
`apy- and radiotherapy-induced activation of NF-jB
`in laboratory studies, resulting in enhanced sensi-
`tivity to these tumoricidal agents and increased ap-
`optosis in cancer cells (1–3,6).
`Activation of NF-jB signaling appears to be par-
`ticularly important for the survival of multiple my-
`eloma cells (MMCs): MMCs isolated from patients
`had constitutive NF-jB activity, MMCs and BMSCs
`showed enhanced NF-jB activity, and chemoresis-
`tant MMCs had increased NF-jB activity compared
`with chemosensitive lines (5,7). Bortezomib ap-
`peared not only to have activity against MMCs, but
`also to downregulate protective interactions with
`bone marrow stromal cells (BMSCs) in the bone
`marrow microenvironment (4), and to inhibit blood
`vessel development
`(8). Thus, bortezomib acts
`against MMCs by antagonizing the activation of
`protective NF-jB functions in not only MMCs but
`BMSCs.
`Myeloma growth and resistance pathways be-
`come activated when MMCs bind to normal BMSCs.
`Myeloma cells express VLA-4 and VLA-5, which are
`receptors that allow myeloma to bind to the VCAM-
`1 receptor on BMSCs. Damiano and colleagues
`
`demonstrated that binding VLA receptors with fi-
`bronectin conferred protection against apoptosis,
`and Chauhan and colleagues have shown that the
`binding of myeloma cells to BMSCs resulted in the
`NF-jB-dependent secretion of
`IL-6 from BMSCs
`(9,10). These studies suggested that the interactions
`between myeloma cells and normal cells in the
`bone marrow microenvironment are important for
`the activation of resistance or growth-promoting
`mechanisms.
`Preclinical studies with bortezomib showed direct
`cytotoxic activity against MMCs in vitro. In addition,
`bortezomib inhibited growth of dexamethasone-,
`doxorubicin-, and melphalan-resistant myeloma
`cells lines (4), reduced the expression of the BMSC
`adhesion receptor VCAM-1 (11), decreased adher-
`ence of myeloma cells to BMSCs (presumably due to
`downregulation of adhesion molecules), suppressed
`the NF-jB-dependent expression of IL-6 (a myeloma
`growth factor) (4), and had in vivo activity against
`human myeloma xenografts
`(8). Synergy with
`doxorubicin and melphalan but not dexametha-
`sonewas observed in sensitive MMCs since low
`concentrations of bortezomib significantly reduced
`the LD50 of either of these chemotherapies (12). In
`addition, MMCs from a heavily treated patient prior
`regimens included conventional and high dose
`chemotherapy, interferon-a, thalidomide, liposomal
`doxorubicin, and bortezomib as a single agent and in
`combination with dexamethasonedid not respond
`
`Figure 1 Downregulation of the NF-jB pathway by bortezomib. NF-jB activation leads to phosphorylation and ubiquitination of IjB.
`Once ubiquitinated, IjB is bound by the proteasome and degraded, releasing NF-jB. Free NFjB readily enters the nucleus where it
`activates the transcription of promoters containing jB response elements. Some of the genes activated by NF-jB encode anti-apoptotic
`factors, cell adhesion molecules, cytokines, and cell cycle regulators. Bortezomib prevents IjB degradation, maintaining NF-jB in an
`inactive complex with IjB and preventing the downstream effects of NF-jB activation. Consequently, cancer cells that require NF-jB for
`survival or to prevent apoptosis following cytotoxic treatments experience a downregulation in NF-jB-activated gene expression.
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`35
`
`well to bortezomib or doxorubicin monotherapy in
`vitro. However, combined treatment led to a 4–5-fold
`increase in cell killing. Further studies from this lab
`show that bortezomib can interfere with DNA repair
`pathways by promoting the cleavage of DNA PKcs
`(DNA protein kinase catalytic subunit) and/or ATM
`(13). In addition, bortezomib could increase MDM2
`expression, thereby reducing the degradation of p53.
`Thus, while NF-jB may be a key target for bort-
`ezomib,
`inhibition of the proteasome affects nu-
`merous cellular pathways, thereby sensitizing the
`cell to apoptosis through several mechanisms.
`Proteasome inhibitors have also demonstrated
`activity against other B-cell malignancies in labora-
`tory studies, including mantle cell lymphoma (MCL)
`and Hodgkin’s disease. An in vitro study of MCL
`cells treated with bortezomib resulted in stabiliza-
`tion of IjB and reduced binding of activated NF-jB
`to its promoter. In addition, bortezomib treatment in
`vitro led to cell growth inhibition and rapid induc-
`tion of apoptosis of MCL cells. Bortezomib also
`exhibited activity in a xenograft model with MCL-
`xenografted, severe combined immunodeficiency
`mice evincing little or no gross MCL tumor in-
`volvement post-treatment compared to controls (14).
`Other preclinical studies in diffuse large B-cell
`lymphoma (DLBCL) provide indirect evidence that
`proteasome inhibition may be a potential treatment
`approach in this tumor type as well (15). Research
`has indicated that DLBCL is composed of two sub-
`groups – germinal center B-like (GCB) and activated
`B cell-like (ABC) – each of which present distinct
`pathogenetic mechanisms and clinical outcomes.
`Patients with ABC DLBLC have a poorer prognosis
`and ABC-type DLBCL is frequently refractory to
`chemotherapy. In vitro, ABC DLBCL cell lines had
`higher NF-jB activation, constitutive IjB kinase
`(IKK) activity, and IjBa degradation compared to
`GCB lines. Furthermore, ABC DLBCL cell
`lines
`treated with a ‘‘super-repressor’’ IjBa (unphosph-
`orylatable by IKK and therefore non-degradable)
`showed cell death and G1-phase growth arrest.
`These results suggest that proteasome inhibition, via
`its downregulation of the NF-jB pathway, is a po-
`tential mechanism of action in DLBCL treatment (16).
`While NF-jB is clearly important in bortezomib’s
`mechanism of action, several studies suggest that
`other mechanisms act in parallel to NF-B to induce
`apoptosis in MMCs and other cancer cells. In early
`experiments, cell culture experiments uncovered
`evidence that proteasome inhibition altered the ex-
`pression of proteins that control cell cycle and ap-
`optosis (4,17,18). More recently, Hideshima et al. (12)
`used a specific inhibitor of the NF-jB pathway to
`investigate non-NF-jB-mediated mechanisms of cell
`killing by proteasome inhibitors.
`In contrast
`to
`bortezomib, PS-1145 specifically prevents NF-jB
`
`activation by preventing the phosphorylation of IjB.
`Specific pathways activated by NF-j B were blocked
`by PS-1145: ICAM-1 and VCAM-1 expression were
`prevented in MMCs and IL-6 expression in BMSCs
`was eliminated. However, DNA synthesis in MMCs
`was incompletely blocked and PS-1145 was only
`capable of inhibiting cell growth in 20–50% of trea-
`ted MMCs (compared to nearly 100% of bortezomib-
`treated cells). Since a specific NF-jB-inhibitor is not
`as potent an inducer of apoptosis as bortezomib,
`other mechanisms tied to proteasome inhibition
`must be involved in bortezomib-induced apoptosis.
`
`PHASE I: TRIAL OF BORTEZOMIB IN
`PATIENTS WITH HEMATOLOGIC
`MALIGNANCIES
`
`Orlowski et al. conducted a phase I trial to determine
`the maximum-tolerated dose (MTD), dose-limiting
`toxicity (DLT), and phamacodynamics (PD) of bort-
`ezomib in patients with refractory hematologic ma-
`lignancies (19) (Table 1). Patients (N ¼ 27) were
`enrolled at 0.40 mg/m2 (n ¼ 3), 1.04 mg/m2 (n ¼ 12),
`1.20 mg/m2 (n ¼ 7), or 1.38 mg/m2 (n ¼ 5). Bortezo-
`mib was administered twice weekly for 4 weeks
`followed by a 2-week rest. Participants received a
`total of 293 doses of bortezomib, including 24 com-
`plete cycles.
`The MTD was determined to be 1.04 mg/m2. DLTs
`possibly related to bortezomib included thrombo-
`ctyopenia, malaise and fatigue, and electrolyte dis-
`turbances such as hyponatremia and hypokalemia.
`Ten patients developed grade 3 thrombocytopenia
`during cycle 1. Although the study protocol did not
`define thrombocytopenia as dose-limiting, it did in-
`fluence dosing behavior. In the majority of cases,
`grade 3 thrombocytopenia occurred in patients who
`entered the trial with thrombocytopenia. Only 1 of 9
`patients who entered the trial with normal platelet
`counts had dose withheld because of grade 3
`thrombocytopenia. No episodes of febrile neutrope-
`nia were reported. Nor were any major bleeding
`events reported during this trial. Five patients de-
`veloped a treatment-emergent peripheral neuropa-
`thy. Of the four grade 2 cases, three were thought to
`be related to bortezomib but were not dose-limiting;
`the sole grade 3 event was due to progressive disease.
`Adverse events were reported in patients at all
`dose levels with cytopenias as the most common
`events (Table 2); these included thrombocytopenia
`(74% of patients), anemia and leukopenia (48%), and
`neutropenia (37%). Gastrointestinal events were also
`seen in many patients including nausea (52%) and
`constipation (30%). Fatigue was reported in 59% of
`patients.
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`36
`
`
`
`TA B L EA B L E 1 Phase I patient demographics
`
`Characteristics
`
`Number of patients
`MSKCC
`UNC
`
`Sex
`Male
`Female
`
`Age (years)
`Mean
`Range
`
`Race
`Native American
`African American
`White
`
`Diagnoses
`Hodgkin’s disease
`Non-Hodgkin’s lymphoma
`SLL/CLL
`DLCL
`Mantle cell
`Plasma cell dycrasias
`Waldenstrom’s
`Multiple myeloma
`MDS with excess blasts and POEMS
`
`ECOG performance scale
`0
`1
`2
`
`Number
`
`Percent
`
`27
`7
`20
`
`17
`10
`
`56
`22–77
`
`1
`7
`19
`
`4
`10
`2
`2
`3
`12
`1
`11
`1
`
`6
`16
`5
`
`63
`37
`
`4
`26
`70
`
`22
`59
`19
`
`Prior therapy
`Chemotherapy
`Median no. regimens
`Range
`Radiation therapy
`Marrow or stem-cell transplantation
`
`27
`3
`1–12
`13
`10
`
`Reprinted with permission from: Orlowski RZ, Stinchcombe TE,
`Mitchell BS et al. Phase I trial of the proteasome inhibitor PS-341 in
`patients with refractory hematologic malignancies.
`J Clin Oncol
`2002; 20: 4420–4427.
` Memorial Sloan-Kettering Cancer Center.
` University of North Carolina.
`
`Twelve patients with heavily pre-treated plasma
`cell dyscrasias were enrolled in the study, nine of
`whom completed at least one full cycle and were
`assessable for response. One patient who received a
`total of 4 cycles showed by the end of cycle 3 an
`immunofixation-negative complete response. There
`was also evidence of antitumor activity among the
`eight remaining patients, with reduction of para-
`protein levels and/or marrow plasmacytosis.
`In
`addition, one patient with mantle cell lymphoma
`and another with refractory follicular lymphoma
`achieved a partial response with treatment at the
`1.38 mg/m2 level.
`
`P . R I C H A R D S O N
`
`Orlowski et al. concluded that bortezomib can be
`administered at 1.04 mg/m2, using a dose-intensive,
`twice-weekly administration for 4 weeks, followed a
`by a 2-week rest with concomitant monitoring for
`electrolyte abnormalities and late toxicities (19).
`However, induction of toxicity requiring the inter-
`ruption of therapy in patients during their first cycle
`of therapy most commonly occurred during the
`third week of treatment. Twice-weekly therapy for
`2-weeks with a third week off, delivering the same
`total dosage of over 6 weeks, was predicted to be
`better
`tolerated. Pharmacodynamic studies sug-
`gested that bortezomib induced 20S proteasome in-
`hibition in a time- and dose-dependent manner. This
`study provided the first evidence of potential activ-
`ity in myeloma and established the rationale for
`more comprehensive assessment in phase II (19).
`
`PHASE II: TRIALS OF BORTEZOMIB IN
`PATIENTS WITH MULTIPLE MYELOMA
`
`The safety and efficacy of bortezomib have been
`assessed in two phase II trials of patients with re-
`lapsed and refractory MM. Patients in Study 025
`(SUMMIT) were relapsed and refractory to their
`most recent therapy; those in Study 024 (CREST)
`were relapsed or refractory after front-line therapy.
`Patients in Study 025 thus had more advanced
`disease.
`This study enrolled patients in two cohorts: the
`first cohort filled rapidly ðN ¼ 78Þ, and, at the re-
`quest of the investigators, enrollment continued to
`eventually enroll a total of 202 patients. The first
`phase I trials (19,20) were designed to test several
`dosing schedules for bortezomib of varying dose
`intensities (Table 3). These studies were still in pro-
`gress at the initiation of Study 025 and preliminary
`indications from the study testing the 3-week cycle
`suggested this regimen offered a reasonable balance
`between toxicity and adequate dosing. At the time,
`dose-limiting diarrhea and peripheral neuropathy
`had been observed at 1.56 mg/m2 on the 3-week
`cycle. Thus, 1.3 mg/m2 bortezomib the previous
`dose level was administered by IV push on days 1, 4,
`8, and 11 of a 21 day treatment cycle in Study 025. A
`total of eight treatment cycles were allowed. Patients
`with a suboptimal response were allowed to add
`dexamethasone to bortezomib after 2 (patients with
`progressive disease) or 4 cycles (patients with stable
`disease).
`response criteria
`trial employed strict
`This
`[adapted from SWOG criteria and Blade et al. (21)]
`assessed by an independent review committee, and
`the population was heavily pretreated (the median
`number of prior treatments was 6) (22). For a com-
`
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`37
`
`
`
`TA B L EA B L E 2 Bortezomib-related adverse events (Pgrade 3) during cycle 1
`
`Adverse event
`
`Bortezomib dose level (mg/m2)
`
`0.40
`(n ¼ 3)
`
`1.04
`(n ¼ 12)
`
`1.20
`(n ¼ 7)
`
`1.38
`(n ¼ 5)
`
`Total
`(N ¼ 27)
`
`P 1 adverse event
`Blood and lymphatic system
`Thrombocytopenia
`Anemia
`Neutropenia
`Leukopenia
`Metabolism and nutrition
`Hyponatremia
`Hypokalemia
`Other
`Malaise
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`7
`5
`4
`1
`2
`2
`4
`2
`1
`0
`0
`
`6
`6
`4
`3
`1
`1
`1
`0
`1
`1
`1
`
`4
`4
`2
`1
`1
`0
`2
`2
`0
`0
`0
`
`17
`15
`10
`5
`4
`3
`7
`4
`2
`1
`1
`
`Reprinted with permission from: Orlowski RZ, Stinchcombe TE, Mitchell BS et al. Phase I trial of the proteasome inhibitor PS-341 in
`patients with refractory hematologic malignancies. J Clin Oncol 2002; 20: 4420–4427.
`
`
`
`TA B L EA B L E 3 Dosing schedules in phase I bortezomib trials
`
`Treatment schedule
`1/wk 4
`2/wk 2
`2/wk 4
`
`Cycle length (days)
`
`Dose-limiting toxicities (mg/m2)
`
`Maximum tolerated dose (mg/m2)
`
`35
`21
`42
`
`NDa
`1.56b
`1.38b
`
`NDa (25)
`1.3 (20)
`1.04 (19)
`
`Reprinted with permission from Adams J. Potential for proteasome inhibition in the treatment of cancer. Drug Discovery Today, 2003; in
`press.
`a Not determined. MTD not reached at time of report.
`b Enrollment suspended due to DLT; maximum dose reached.
`
`plete response, no M protein was visible by immu-
`nofixation, fewer than 5% plasma cells were present
`in the bone marrow, and no new bone disease or
`plasmacytomas were present; responses were con-
`firmed after 6 weeks. Preliminary data from the first
`cohort showed significant biologic activity with
`manageable toxicities, as demonstrated by reduc-
`tions in M protein (23). A preliminary analysis of the
`full cohort ðn ¼ 202Þ confirming and extending these
`results was recently presented and is being prepared
`for publication (22). An integral component of Study
`025 was the collection of bone marrow samples for
`pharmacogenomic analysis. Prior to treatment, bone
`marrow samples were collected from 126 consenting
`patients, and RNA from myeloma cells was purified
`from 64 of these. The gene expression profiles of
`responding patients are now being compared to the
`expression profiles of non-responders to identify
`expression patterns that are predictive of a response
`to bortezomib.
`Study 024 allowed the assessment of a patient
`population with earlier stage disease (median prior
`therapies was 3) and applied the same treatment
`schedule and response criteria as in Study 025. A
`total of 54 patients were randomized to receive ei-
`
`ther 1.0 (28 patients) or 1.3 (26 patients) mg/m2
`bortezomib. Dexamethasone was also allowed for
`patients who had progressive (after cycle 2) or stable
`disease (after cycle 4). Preliminary results of this trial
`were recently reported and the analysis is ongoing
`(24).
`
`FUTURE DIRECTIONS
`
`A phase III study comparing response to bortezomib
`versus high-dose dexamethasone is in progress. The
`multicenter Assessment of Proteasome Inhibition for
`Extending Remissions (APEX)
`trial will be con-
`ducted at more than 60 centers in the United States,
`Canada, and Europe. Over 600 patients with re-
`lapsed or refractory MM will be enrolled and ran-
`domize to either bortezomib or dexamethasone
`treatment arms. Response will be assessed by pro-
`longation of
`time-to-disease progression and se-
`lected measures of clinical benefit. APEX will also
`study the potential of bortezomib as maintenance
`therapy. Survival, response rates, quality of life, and
`safety and tolerability in the two treatment arms will
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`38
`
`P . R I C H A R D S O N
`
`Figure 2 Treatment regimens in the phase III APEX trial. Bortezomib is being compared to high dose dexamethasone treatment in
`an international phase III study. Both arms have a treatment phase followed by a maintenance phase.
`
`also be compared. In addition, bone marrow sam-
`ples are being collected for validation of candidate
`drug response markers identified in Study 024 and
`Study 025.
`In the APEX trial, bortezomib 1.3 mg/m2 will be
`administered as injection for eight 3-week induction
`cycles followed by three 5-week maintenance cycles
`(Figure 2). The 3-week cycles include twice-weekly
`administration (Days 1, 4, 8, and 11) for 2 weeks
`followed by a 10-day rest period (Days 12–21); the
`5-week cycles include once-weekly administration
`(Days 1, 8, 15, and 22) for 4 weeks followed by a
`13-day rest period (Days 23–35). In the comparator
`arm, patients will receive oral administration of
`dexamethasone 40 mg/day for four 5-week cycles
`followed by three 4-week cycles. Dosing will be
`administered in the 5-week cycles on Days 1–4, 9–12,
`and 17–20 followed by a 15-day rest period. The
`4-week cycles include doses on Days 1–4 followed
`by a 24-day rest period.
`Depending on response, patients in either treat-
`ment arm may receive up to 10 months of treatment.
`In addition, patients in the dexamethasone cohort
`who experience progressive disease may be eligible
`for participation in a bortezomib extension trial
`(Study 040). The objective of Study 040 is to deter-
`mine rate and duration of response in patients with
`relapsed or refractory MM.
`Additional clinical trials for hematologic malig-
`nancies are currently under consideration. These
`trials will assess bortezomib’s safety and efficacy
`when used as a single agent or in combination with
`other chemotherapeutics. There are currently ten
`additional clinical trials either open or in develop-
`ment to further explore the role of bortezomib in
`myeloma. In addition, there are ten early clinical
`trials open or in development that will evaluate
`bortezomib therapy for lymphomas (non-Hodgkins’
`lymphoma and mantle cell lymphoma) and eight
`clinical
`trials open or in development for other
`hematologic malignancies
`(myelodysplastic syn-
`drome, Waldenstrom’s macroglobulinaemia, acute
`myelogenous leukemia, and chronic myelogenous
`leukemia).
`
`CONCLUSIONS
`
`The NF-jB signaling pathway appears to be a
`promising target for the treatment of hematologic
`malignancies. Activation of NF-jB is an important
`step in transformation and can provide protection
`from cytotoxic treatments, while inhibition of this
`pathway with proteasome inhibitors results in ap-
`optosis or sensitizes cancer cells to cytotoxic drugs.
`Phase I trials demonstrated responses in several
`hematologic malignancies,
`including MM; other
`phase I trials showed that this agent was relatively
`well tolerated. Several phase II studies have further
`examined the safety and activity of bortezomib in
`MM, and the findings in these trials have been en-
`couraging. Bortezomib appears to have antitumor
`activity in MM and the adverse effects associated
`with treatment are manageable. A phase III trial is
`now in progress comparing the safety and efficacy of
`bortezomib treatment to high dose dexamethasone
`in patients with advanced MM.
`
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