Approval Summary for Bortezomib for Injection in the Treatment of Multiple Myeloma

INTRODUCTION

Multiple myeloma (MM) is a malignant plasma cell disorder accounting for ∼10% of hematological malignancies. There are approximately 45,000 people in the United States living with multiple myeloma and an estimated 14,600 new cases of multiple myeloma are diagnosed each year.1 The reported incidence is 5 per 100,000 with a peak at age ∼70 years; rates are higher in African Americans and in men (1) . Multiple myeloma was first described in 1844; and in 1962, Bergsagel et al. (2) reported that melphalan, the phenylalanine derivative of nitrogen mustard, could induce remissions in about one-third of patients. Many cytotoxic regimens induce remissions, but effects on survival have been difficult to demonstrate despite increasing doses of conventional cytotoxic chemotherapy (3) . Median overall survival does not exceed 3 years with conventional chemotherapy (4) .

High-dose chemotherapy followed by hematopoietic stem cell rescue has been shown to increase the percentage of complete remissions to almost 50% in selected patients (versus 1–13% with conventional dose therapy), but the disease commonly recurs (5 , 6) . High-dose chemotherapy may increase the CR rate and time-to-progression; however, myeloablative therapy has not consistently shown a survival improvement (7) . Double autologous (tandem) transplantation has recently been shown to improve long-term survival in eligible patients less than 60 years old, but the majority of patients eventually relapsed even after the double transplant (8) . Subsequent treatment responses occur less frequently and are of shorter duration (9) .

Salmon et al. (10) first reported the efficacy of high-dose prednisone in this disease in 1967, and glucocorticoids are still a mainstay of myeloma therapy. Recent research has focused on other alternatives to cytotoxic chemotherapy. In 1999, Singhal et al. (11) reported durable responses with thalidomide in multiple myeloma, and subsequent studies have confirmed its activity (12, 13) . In 2003, Richardson et al. (14) reported on the efficacy results of bortezomib, an inhibitor of the 20S proteasome, in advanced multiple myeloma. This article describes the analysis of clinical and nonclinical data that led to accelerated marketing approval of bortezomib for the treatment of multiple myeloma.

RESPONSE CRITERIA IN MULTIPLE MYELOMA

Multiple myeloma is characterized by the clonal proliferation of plasma cells. Except in 1–2% of patients with nonsecretory myeloma, an abnormal monoclonal immunoglobulin heavy- and/or light-chain paraprotein, known as M protein or M component, is readily quantifiable in the serum and/or urine of patients with multiple myeloma and has been used to measure the response to therapy and progression. In 1968 and 1973, the Chronic Leukemia and Myeloma Task Force of the National Cancer Institute published guidelines for the determination of response in multiple myeloma, specifying a response parameter of 50% reduction in paraprotein measured by protein electrophoresis (PEP) of serum (SPEP) or urine (UPEP; Ref. 15 ). The Southwest Oncology Group (SWOG) subsequently refined the remission criteria to require a 75% reduction in serum and a 90% reduction in urine paraprotein (16 , 17) .

CRs were rarely reported with earlier treatment options; however, the development of newer combination and dose-intensive therapy led to new proposals for assessing treatment response. In 1989, Gore et al. reported their response evaluation in a series of patients with myeloma treated with combination chemotherapy followed by high dose-melphalan and stem cell rescue (18) . The Gore study reported a complete remission rate of 50% based on disappearance of M protein by PEP with the additional requirement of a confirmatory repeat electrophoresis finding 3 months later. Complete resolution of myeloma protein by PEP subsequently became a criterion for complete remission in the era of high-dose chemotherapy and stem-cell transplantation (7 , 19, 20, 21) .

In 1998, the European Group for Blood and Marrow Transplant (EBMT) proposed even stricter criteria for the assessment of CR in myeloma patients after high-dose therapy (22) . These criteria include the complete absence of myeloma protein by immunofixation (IF) techniques as well as by PEP, and results must be confirmed at least 6 weeks later. In addition, bone marrow plasmacytosis must be reduced to less than 5%. Absence of serum and urine paraprotein measured by IF has recently been used to define CRs for both conventional and high-dose regimens (23 , 24 , 12) . Lahuerta et al. (25) published a retrospective study suggesting that complete remission by immunofixation electrophoresis status is a more sensitive predictor of survival and time to progression than complete remission by PEP. Differences among response categories are summarized in Table 1⇓ .

THE PROTEASOME PATHWAY

The ubiquitin-proteasome pathway is thought to play a critical role in the degradation of proteins involved in cell cycle control and tumor growth. A complex enzyme cascade first marks proteins destined for degradation by the covalent addition of multiple molecules of ubiquitin (26) . The proteasome hydrolyzes only those proteins that have been marked for destruction by this ubiquitin enzyme cascade (27 , 28) . The 20S proteasome, the core component of the proteasome complex, is composed of four subunits forming a hollow cylinder that has multiple proteolytic sites on the interior wall (29) . The proteasome-complex degrades proteins as it moves them through this cylinder. This 20S proteasome must first bind to various other large proteins known as activators (PA700 and PA28 are examples) to form proteasome-activator complexes before it can hydrolyze the ubiquitin-bound protein substrates. These activators can bind to form different complexes, each with different protein substrate specificity. The most frequently studied proteasome complex is the 26S proteasome, a large molecule heterotrimer formed by the 20S proteasome and two PA700 activators (30, 31, 32, 33) . The proteasome can affect cell division through ubiquination and degradation of inhibitory proteins through the regulation of nuclear transcription factors (34, 35, 36, 37, 38) . Evidence suggests that the inhibition of the proteasome can act through multiple mechanisms leading to an arrest of cell growth. Inhibition of the proteasome may also have other consequences. Limited in vitro research suggests that the inhibition of the proteasome pathway might lead to the accumulation of abnormal proteins, including prion-related protein (PrP), as demonstrated in transfected neuronal cell lines (39) . The clinical consequences of this protein accumulation are unknown.

BORTEZOMIB (PS-341, VELCADE)

The search for molecules that could inhibit the 20S proteasome in vitro led to the discovery of bortezomib (Velcade, PS-341; Millennium Pharmaceuticals, Inc., Cambridge, MA), a small, dipeptide boronic acid that reversibly inhibits the chymotrypsin-like proteolytic activity site of the 20S proteasome of mammalian cells (40) . Bortezomib exhibits cytotoxic, growth-inhibitory, and antitumor activities in several in vitro and in vivo assay systems and binds to the proteasome at lower concentrations than it does to other tested proteases. In replicating cells in vitro, bortezomib appears to cause cell cycle arrest at the transition of G₂-M, and the inhibited cells then initiate apoptosis (41) . In the standard National Cancer Institute panel of 60 human cell lines, bortezomib inhibited cell growth and, in some cases, was cytotoxic for human tumor cells. The average IC₅₀ of bortezomib across the 60 cell lines was 3.8 nm. In athymic mice implanted with both the HT-29 human colon and the PC-3 human prostate-tumor xenograft models, bortezomib given i.v. weekly for 4 weeks (3 mg/m²) decreased tumor volume by up to 50 and 65%, respectively. Resistance to bortezomib cytotoxicity has been noted over time in vitro. This resistance is probably not mediated by overexpression of transmembrane molecular pumps, such as the multidrug resistance protein.

After in vivo dosing, inhibition of proteasome activity, measured in lysate from whole blood from animals or humans, recovers to normal in about 48–72 h (42) . Repeat dosing causes greater inhibition compared with a single dose at the same level (about 30% after a single dose compared with almost 99% after seven daily doses). Inhibition could be detected in tissue from colon, muscle, prostate, and liver but not in the testes or brain of rodents. The inhibition in the liver was significantly greater than in WBCs. Thus far, there is no evidence of a relationship between ex vivo measurements of proteasome inhibition and clinical efficacy.

Bortezomib inhibited the degradation of cytochrome P450–2E1 by proteasomes after ethanol induction, thus preventing the return of intracellular expression of the enzyme to constitutive levels (43) . Other cytochromes P450 may also be degraded by proteasomes after induction (44) . Bortezomib has the potential to modify the metabolism of a broad range of chemicals by changing the intracellular concentration of cytochrome P-450 (45) . Thus, proteasome inhibition by bortezomib may modify a patient’s exposure to drugs that are metabolized by cytochrome P-450.

CHEMISTRY

Bortezomib is a modified dipeptide boronic acid. The drug substance exists in its cyclic anhydride form in the solid state as a trimeric boroxine. The product is provided as a mannitol boronic ester that, in reconstituted form, exists in equilibrium with its hydrolysis product, the monomeric boronic acid. The chemical name for the monomeric form is [(1R)-3-methyl-1-{[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]- amino}butyl]boronic acid. The molecular weight is 384.24, and the molecular formula is C₁₉H₂₅BN₄O₄. The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3–3.8 mg/ml in a pH range of 2–6.5. Bortezomib is available for i.v. injection as a sterile lyophilized powder in single-dose vials containing 3.5 mg bortezomib and 35 mg mannitol, USP. In this form, the drug product is stable and can be stored at controlled room temperature. The lyophilized powder drug product is reconstituted with 0.9% NaCl to a final concentration of 1 mg/1 ml before injection. The chemical structure is shown in Fig. 1⇓ .

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Fig. 1.

Bortezomib structure. Bortezomib is a modified dipeptide boronic acid derived from leucine and phenylalanine.

TOXICOLOGY

Traditional toxicological and toxicokinetic parameters, neuropathological evaluations, and proteasome activity determinations were examined. Bortezomib was administered to rats as a single dose and twice weekly for 2 weeks and for 26 weeks. Bortezomib was poorly tolerated when administrated daily, even at very low doses. Nonclinical tolerability studies suggested that intermittent dosing permitted more prolonged dosing regimens by allowing a return toward baseline of 20S proteasome activity before the subsequent dose. In the 9-cycle 26-week rat study, drug-related mortality was observed at ≥0.9 mg/m² (days 23–180) and was due primarily to hematopoietic and lymphoid system depletion, along with gastrointestinal hyperplasia and necrosis. Histopathological changes were observed in the heart, liver, lung, kidney, sciatic nerve (necrosis), and spinal cord; in general, similar findings albeit with less severity were observed in scheduled-death animals. Animals who were dosed at ≥0.9 mg/m² and who survived to week 26 (end of treatment) exhibited various forms of neurotoxicity including degeneration of dorsal root ganglia, peripheral nerves, and spinal cord. Nephrotoxicity, including eosinophilic casts, inflammation, hypertrophy, tubular dilation, and glomerulonephritis was observed at 26 weeks of treatment at doses ≥0.6 mg/m²; a comparable incidence of tubular dilation was observed after 8 weeks of recovery in males. Cardiac histopathological changes included increased incidence of perivascular necrosis, myocardial degeneration, hemorrhage, and inflammation. Thrombocytopenia was observed at all dose levels. After the 8-week recovery interval, myocardial inflammation, cardiac necrosis, and tubular dilation of the kidney (males only) persisted. There appeared to be some indication of reversibility of other findings at this time.

Bortezomib was administered to monkeys as a single dose, a daily dose for 13 days, twice-weekly for 2 weeks, and twice-weekly for 4- and 13-three week cycles. In the 13-cycle monkey study, bortezomib-related mortality was observed at dosages ≥0.9 mg/m². Findings included severe anemia, dehydration, gastrointestinal diffuse mucosal hyperplasia, thrombocytopenia, neurotoxicity, and cardiotoxicity. There was an increased incidence of clinically observable findings, typically associated with neurotoxicity, in treated animals when compared with controls during bortezomib administration. The frequency of histopathological findings demonstrating neurotoxicity was reduced after 8 weeks of recovery.

Clinical neurotoxicity was reported in monkeys, rats, and mice; findings included nerve degeneration of dorsal root ganglia, peripheral nerves, dorsal spinal roots and dorsal tracts of the spinal cord at ≥0.6 mg/m² (one-half of the recommended clinical dose of 1.3 mg/m²). Histopathological incidence of neurotoxic effects in monkeys appeared greater compared with that in rodents. Clinical observations included tremors and reduced activity in monkeys; rats also exhibited reduced activity. Nephrotoxicity was observed at doses ≥0.9 g/m² in monkeys; males appeared to be more susceptible. Lymphoid atrophy and/or necrosis occurred in thymus, spleen, lymph nodes, and gut-associated lymphoid tissue. In addition, necrosis, atrophy, and hyperplasia of the gastrointestinal tract were observed in monkeys surviving to 38 weeks.

Dose- and schedule-dependent changes in AUC (area under the curve) and C_max (maximum concentration) occurred in both species. Drug exposure with increasing dose was more linear in monkeys compared with rodents; the explanation for this difference is unknown. After multiple doses, a decrease in clearance resulted in an increase in the terminal elimination half-life (t_1/2) and AUC (3–4-fold) in rats and cynomolgus monkeys, suggesting drug accumulation. Even though there were no gender differences in systemic exposure, it appears that female decedent rats exhibited a greater degree of toxicity compared with males based on the number and types of lesions, as well as on the total number of unscheduled deaths. Using an ex vivo 20S proteasome assay to measure inhibition of the chymotrypsin-like proteolytic activity in whole blood cells, proteasome inhibition increased with dose and returned to baseline by about 72 h in rats and monkeys. After a single dose of [¹⁴C]bortezomib, bortezomib-related radioactivity was eliminated slowly from tissues (with highest concentrations in liver and kidneys); incomplete recovery of administered radioactivity in rats and monkeys suggests extensive tissue distribution and retention of bortezomib and its metabolites. Radioactivity was detected in the brain of monkeys but not of rats.

Cardiovascular safety pharmacology studies conducted in cynomolgus monkeys showed that the administration of dosages ≥3.0 mg/m² resulted initially in physiologically significant heart rate elevations, then profound progressive hypotension, bradycardia, and death 12–14 h postdose. Additional studies in monkeys showed bortezomib increased heart rate (≥1.2 mg/m²), decreased mean arterial pressure (≥2.4 mg/m²), increased ventricular contractility (≥3.6 mg/m²), and increased cardiac output (≥3.6 mg/m²). Mortality was not reported in this study; however, this study is inadequate to address drug-associated mortality observed in the previous studies because these monkeys were sacrificed before signs of terminal hypotension and imminent mortality occurred. Bortezomib-related radioactivity was distributed to the myocardium. Histopathological findings in repeat-dose monkey studies showed cardiac necrosis at doses ≥0.9 mg/m². Whether the observed cardiac effects are dependent on local drug disposition and/or direct drug-myocardial toxicity is unknown.

Bortezomib exhibited clastogenic activity in the in vitro chromosomal aberration assay using Chinese hamster ovary cells but was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) or the in vivo micronucleus assay. Teratological effects were examined in the rat and the rabbit. No formal evaluation of fertility or peri- and postnatal development (Segments I and III, respectively) were conducted. Pregnant rabbits given bortezomib during organogenesis at a dose of 0.6 mg/m² experienced significant postimplantation loss and a decreased number of live fetuses at minimally maternally toxic doses. Live fetuses also showed significant decreases in fetal weight. This dose is approximately one-half the clinical dose (1.3 mg/m²). On the basis of embryo lethality findings in rats and rabbits, and the effects on primary and secondary sex organs observed in the 6-month rat study and the 9-month monkey toxicity studies, bortezomib is likely to have an adverse effect on pregnancy. However, bortezomib was not teratogenic in rats and rabbits at the highest dose tested, 0.5 mg/m² in the rat and 0.6 mg/m² in the rabbit, when administered during organogenesis. These dosages also are approximately one-half of the human clinical dose. Bortezomib is labeled “Pregnancy category D;” because of the potential of significant adverse effects on the developing fetus, women are strongly advised not to become pregnant while taking bortezomib.

CLINICAL STUDIES SUPPORTING APPROVAL

Three Phase I dose finding trials of bortezomib as monotherapy were performed in a total of 123 patients with a variety of advanced malignancies. Two Phase II studies were performed in 256 patients with multiple myeloma who had not achieved a response to, or who had relapsed after, initial therapy. If patients progressed after two cycles or experienced no improvement after four cycles, dexamethasone 20 mg daily p.o. for 2 days was added to each bortezomib dose. An extension studies allowed continued therapy in those patients who appeared to benefit. The extension study provided safety information on longer-term therapy and efficacy information on response duration.

PHASE I STUDIES

The Phase I studies were performed in patients with advanced malignancies using weekly and twice-weekly dosing schedules. Weekly dosing was associated with dose-limiting toxicities of diarrhea, hypotension, tachycardia, and syncope with doses >1.6 mg/m². The maximum tolerated dose was found to be 1.3 mg/m² when given twice-weekly in the first 2 weeks of a 3-week cycle. This compares with a maximum tolerated dose of 1.04 mg/m² when given twice-weekly for the first 4 weeks in a 6-week cycle. At the 1.3 mg/m² dose, the 1-h mean percentage proteasome inhibition measured in patients’ WBCs on day 1, cycle 1, is higher than the corresponding value at cycle 7 (70.5 versus 55%). The relationship between proteasome inhibition and dose suggests that the optimal bortezomib dose may be between 1.0 mg/m² and 1.3 mg/m². The twice-weekly dosing each 21-day cycle was selected because ∼25% more drug could be tolerated.

PHASE II CLINICAL STUDIES

Two Phase II studies assessed the safety and efficacy of bortezomib. A small, open-label, randomized Phase II dose-finding study, Clinical Response and Efficacy Study of bortezomib in the Treatment of relapsing multiple myeloma (CREST) was performed in 54 patients with relapsed multiple myeloma to provide some dose-response data (46) . The 1.3-mg/m² dose was compared with the 1.0-mg/m² dose using a 21-day cycle with treatment given during the first 2 weeks. The sponsor chose the higher dose because of a somewhat higher overall response rate that included minimal responders. The larger Study of Uncontrolled Multiple Myeloma managed with proteasome Inhibition Therapy (SUMMIT) was an open-label, single-arm, multicenter study of patients who had received at least two prior therapies and demonstrated disease progression on their most recent therapy (15) . Patients were eligible if they had relapsed after a response to standard first-line chemotherapy (e.g., vincristine-doxorubicin-dexamethasone or melphalan-prednisone) or high-dose chemotherapy, and were refractory (i.e., failure to achieve at least CR, PR, or stable disease) to their most recent chemotherapy. Primary refractory patients were not enrolled.

Bortezomib 1.3 mg/m² was administered by i.v. bolus over 3–5 s on days 1, 4, 8, and 11 in a 21-day cycle. A maximum of eight cycles (24 weeks) was planned, but treatment could be continued for responding patients in a continuation study. Treatment was withheld in patients experiencing ≥ grade 3 nonhematological or grade 4 hematological toxicities until resolution or grade 1 was attained, and treatment was then resumed at the next lower dose level, either 1.0 or 0.7 mg/m². Patients with progressive disease after completing two cycles or who experienced no response after four cycles could be treated with the addition of dexamethasone, 20 mg p.o. (each day of, and the day after, bortezomib administration, i.e., 40 mg with each dose). These patients were analyzed separately for efficacy and were not included in the primary analysis. Safety assessments performed during treatment included monitoring for adverse events, a directed questionnaire for neurological toxicities, specialized neurological testing, and clinical examinations.

The SUMMIT trial enrolled 202 patients. Eighty-four % had IgG or IgA myeloma and advanced disease at diagnosis, and 80% had a Karnofsky performance-status score ≥80. The mean age was 59 years; 81% were white, 10% were black, and 60% were male. Ninety-two % had been treated with three or more of the major classes of agents used to treat myeloma (steroids, alkylating agent, thalidomide, or anthracyclines). The median number of previous therapies was six (range, 2–15). Sixty-four % had received high-dose therapy and stem-cell transplantation. Five patients had not been treated with cytotoxic chemotherapy; these were excluded from the efficacy analysis. In comparison, the CREST study enrolled a less heavily pretreated population; the mean number of prior therapies was three, compared with six in the larger study. The mean Karnofsky performance-status score was also higher in the CREST study; otherwise, the trial characteristics were similar. Baseline patient and disease characteristics for both studies are summarized in Table 2⇓ .

RESULTS

The primary objective of the Phase II studies was the determination of overall response rate (CR + PR + minimal response). Responses were assigned by an Independent Review Committee based on the EBMT criteria described above (section “Response Criteria in Multiple Myeloma”). PRs required a 50% reduction in serum M protein and 90% reduction in urine M protein. Additional response analyses including remission by SWOG criteria and rate of complete resolution of M protein by PEP were performed to facilitate comparison with other reports of available therapy (see Table 1⇓ .) Minimal responses were not included in the United States Food and Drug Administration (FDA) analysis because these responses were deemed less likely to predict clinical benefit. All of the responses required confirmation at 6 weeks by protein electrophoresis (CRs required repeat IF also.)

Fifty-four patients were enrolled in the CREST study. The response rate (CR+PR) was 38% in the 1.3-mg/m² group compared with 30% in the 1.0-mg/m² group. One patient in each group experienced a CR by EBMT criteria, and two additional patients in the 1.0-mg/m² group experienced complete resolution of myeloma M protein by PEP. If minimal responses were included, the (CR + PR + minimal response) rate was 50% in the 1.3-mg/m² group compared with 33% in the 1.0-mg/m² group. This observation of a higher response rate led the sponsor to recommend the higher dose for further study, although the numbers were too small for statistical dose-response comparisons.

In the SUMMIT study, the FDA analysis identified 188 patients of the 202 enrolled who had evaluable disease and who fulfilled all eligibility criteria. The study population included patients with numerous adverse prognostic features including β₂ microglobulin levels above 4 mg/liter, cytogenetic abnormalities (including 26 patients with a deletion of chromosome 13), age over 60, and light-chain disease. Sixty-nine % had received high-dose chemotherapy and/or stem-cell transplantation. Nine patients with nonsecretory myeloma could not be evaluated, and the FDA excluded five additional patients from the efficacy analyses because they had not received at least two prior therapies or had not previously been treated with cytotoxic chemotherapy. The studies were generally well conducted, and protocol violations were relatively minor. There were 10 instances in which specified inclusion laboratory hematological criteria were not met, and 13 patients received either chemotherapy or corticosteroids within 3 weeks of study entry, in violation of the protocol. Twenty-two % of patients discontinued the study because of adverse events, and 27% discontinued because of the lack of efficacy.

By EBMT criteria, 5 patients experienced a complete remission and 47 patients achieved a partial (50% M protein reduction) response. In total, 52 patients (27.7%) had EBMT CRs or PRs to bortezomib monotherapy (see Table 3⇓ .) Among the 47 PRs, there were 12 patients who exhibited complete resolution of M protein by PEP but not by IF.

In addition to the protocol-specified response analysis (EBMT), a separate analysis by SWOG criteria showed clinical remission criteria were fulfilled by 33 patients (17.6%), all of whom were also EBMT responders. Additionally, one patient who had been excluded from the primary FDA analysis because of minimal pretreatment also experienced a CR, and one patient had a CR that was not confirmed by repeat IF. The median Kaplan-Meier response duration (CR+PR), based on an analysis of Independent Review Committee response data and data from the extension studies (see Fig. 2⇓ ), was 365 days (95% confidence interval, 224-not estimable). Median survival for all 202 patients was 16 months.

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Fig. 2.

Kaplan-Meier duration of response [complete response and partial response (CR+PR)]. Fifty-two patients (28%) had responses (CR or PR) to bortezomib as monotherapy. The Kaplan-Meier median duration of response (CR+PR) was 365 days, including data from extension studies.

Exploratory response analysis by subgroup showed that the likelihood of response was not correlated with gender, performance status, prior high-dose chemotherapy, number of previous therapeutic regimens, or stem-cell transplantation. There was a marginally higher response rate in patients who were under 65 years of age or who were black. Patients with >50% plasma cells at the screening bone marrow assessment had a 20% response rate compared with a 35% response in those with ≤50% plasma cells in the bone marrow. Patients with abnormal cytogenetics had a 19% response rate compared with 35% in those with normal marrow cytogenetics at screening; however, there was no apparent difference in response rate for patients with chromosome 13 abnormalities (24%) compared with those without abnormalities (28%).

Seventy-eight patients with stable disease after four cycles or progressive disease after two cycles received dexamethasone added to bortezomib. Among these patients, there were no CRs, and only five patients achieved PRs. Additional secondary analyses included changes in immunoglobulin levels, which showed an increase in mean IgM, IgA, and IgG levels from the screening assessment to the last value obtained on study for responding patients. Responders also experienced improvements in platelet counts, hemoglobin, renal function, and performance status compared with nonresponders. These analyses were considered exploratory and were not included in the product label.

DOSE INTENSITY

In the CREST study, 97% of the planned dose was administered at 1.0-mg/m², and 85% of the planned dose was administered at the 1.3-mg/m² dose level. The actual dose received was similar in the 1.3-mg/m² group and the 1.0-mg/m² group. In the SUMMIT study, 98% of the 202 study patients received a starting dose of 1.3 mg/m². Also, in the SUMMIT study, 29% of the patients received 1.3 mg/m² throughout the study, whereas 34% of the patients who started at 1.3 mg/m² required dose reductions during the study, and 64% of patients had at least one dose held for toxicity. The median number of cycles was six. The median treatment duration was 3.8 months. Fifty-four (27%) discontinued treatment early because of progressive disease, and 45 (22%) discontinued treatment early because of adverse events. For patients in both studies assigned to the 1.3-mg/m² dose, the actual administered dose intensity was 85% (or 1.1 mg/m² per dose). In the SUMMIT study, the doses received declined with increasing cycles. The overall mean total dose received per patient was 22.9 mg/m² and the overall mean dose intensity was 80%. Patient exposure to bortezomib is summarized in Table 4⇓ .

SAFETY

The safety population included 379 patients with advanced, previously treated malignancies from six studies: five of single-agent bortezomib and one study that used a combination of bortezomib with gemcitabine. Toxicities observed in the two Phase II studies are summarized in Table 5⇓ . In the CREST study of 1.0 versus 1.3 mg/m², diarrhea, nausea, vomiting, and peripheral neuropathy were more frequently reported in patients assigned to the 1.3 mg/m² dose level. An increasing prevalence of peripheral neuropathy was associated with increasing number of treatment cycles, especially at the 1.3 mg/m² dose. One patient in the 1.0-mg/m² group and four patients in the 1.3-mg/m² group discontinued bortezomib because of peripheral neuropathy. When nerve conduction studies were performed in patients with neuropathy, the results suggested axonal sensory polyneuropathy. In some patients, the neuropathy was a painful, peripheral dysesthesia. Limited reversibility was observed after dose reduction or discontinuation; additional data on the time course and reversibility of neuropathy are expected from the continuation study. Other toxicities were similar at twice-weekly dosing of 1.0 or 1.3 mg/m². There was no difference in the reported incidence of serious adverse events or study discontinuation attributable to adverse events for those patients 51 to 65 years of age and those >65 years old. In the two Phase II studies, observations among all of the 228 patients who received the 1.3 mg/m² dose were combined to describe adverse events at the labeled dose. The most commonly reported (≥10%) adverse events for all of the 228 patients assigned to receive the labeled dose are presented in Table 6⇓ . These included: nausea (64%), fatigue (52%), diarrhea (51%), anorexia (43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%), pyrexia (36%), vomiting (36%), and anemia (32%). Adverse events of grade-3 or -4 severity included thrombocytopenia (29%), peripheral neuropathy (11%), neutropenia (15%), anemia (9%); diarrhea, nausea, and vomiting (each, 7%).

CLINICAL PHARMACOLOGY

Bortezomib is 83% bound to human plasma proteins at therapeutic concentrations. Bortezomib is oxidatively metabolized via cytochrome P-450 enzymes 3A4, 2D6, 2C19, 2C9, and 1A2. It is primarily a substrate of cytochrome P450–3A4. The major metabolic pathway appears to be deboronation, which results in the production of two isomeric forms of a single metabolite. Additional hydroxylation and deamidation of the deboronated species have also been identified, although no data exist to support the stepwise production of these metabolites in vivo. The mean elimination half-life of bortezomib ranged from 9 to 15 h at doses of 1.45 to 2.00 mg/m² in patients with advanced malignancies. After i.v. administration of the 1.3-mg/m² dose, the median maximum plasma concentration of bortezomib was 509 ng/ml (range, 109-1300 ng/ml) in eight patients with multiple myeloma and creatinine clearance values ranging from 31–169 ml/min. Postmarketing studies are planned to determine whether bortezomib clearance will change when it is coadministered with drugs that are potent inhibitors or inducers of 3A4 (e.g., ketoconazole, rifampin). No clinical pharmacology studies were conducted to examine the pharmacokinetics in pediatric, geriatric, or severely renal- or hepatic-compromised populations or to evaluate the potential for drug–drug interactions with concomitant medications. The pharmacokinetics of bortezomib as a single agent has not been fully characterized at the recommended dose of 1.3 mg/m² in multiple myeloma patients.

CONCLUSIONS

The SUMMIT trial included patients with multiple myeloma who had received at least two prior therapies, responded to initial therapy, and demonstrated disease progression on their last therapy. The study population included many heavily pretreated patients with adverse prognostic factors. In the FDA efficacy analysis, there were five patients who achieved a CR using the strictest (EBMT) criteria. CRs are rarely achieved with available therapy in this population, except with the use of high-dose chemotherapy and stem cell rescue (37 , 47, 48, 49, 50) . In addition, there were 47 patients who met EBMT criteria for PR, including 12 patients with complete resolution of myeloma protein by PEP. The overall EBMT response rate (CR+PR) was 27.7% and the median response duration (CR+PR) was 365 days. By the SWOG clinical remission criteria, there were 33 responders (17.6%.) More complete suppression of monoclonal protein levels may correlate with more complete reduction of the myeloma cell mass and with longer survival, but this assertion remains to be validated. Additional clinical benefits observed included normalization of hematological parameters and reduction of transfusion requirements in some patients. The drug was reasonably well tolerated, with gastrointestinal distress, fatigue, thrombocytopenia and peripheral neuropathy the most commonly reported adverse events. The median number of cycles received was five, and the overall dose intensity was 85% for patients assigned the 1.3-mg/m² dose.

Toxicological studies in monkeys and rats using twice-weekly dosing for 2 weeks followed by 1-week rest demonstrated hematopoietic, gastrointestinal, and lymphoid system debilitation, as well as glomerulonephropathy and cardiac changes in both species. Histopathological evidence of axonal and myelin degeneration of dorsal root ganglia, peripheral nerves, and spinal cord were observed in monkeys and rodents; concurrent clinical observations included tremors and decreased activity. A small dose margin between lethality (at doses ≥0.9 mg/m²) and the maximum tolerated dose or highest non-severely toxic dose (0.6 mg/m² bortezomib) was observed in both monkeys and rodents. There was a steep dose-toxicity effect noted at doses ≥0.9 mg/m²; administration of doses ≥3.0 mg/m² to monkeys resulted in cardiovascular collapse and death 12–14 h postdose. These observations in a first-in-class drug led to the inclusion of animal toxicity findings in the PRECAUTIONS section of the approved labeling.

The FDA may grant marketing approval for a new drug under the “accelerated approval” regulations (21 CFR§314.510, Subpart H)2 if the drug provides benefit over available therapy for the treatment of serious or life-threatening diseases. Accelerated approval requires adequate and well-controlled clinical trials establishing that the drug has an effect on a surrogate end point that is considered to be “reasonably likely” to predict clinical benefit based on epidemiological, therapeutic, pathophysiological, or other evidence (51) . The efficacy and safety results of the bortezomib Phase II studies were evaluated by the FDA and thought to represent an improvement over available therapy for relapsed multiple myeloma and reasonably likely to predict clinical benefit in this population. The FDA, therefore, granted accelerated marketing approval to Millennium Pharmaceuticals on May 13, 2003, for bortezomib for use as a single agent for the treatment of multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. The time from the initial Investigational New Drug filing to submission of the New Drug Application was 54 months, and the New Drug Application review was completed by the FDA in 3.7 months.

The recommended dose of bortezomib is 1.3 mg/m² /dose, administered as a bolus i.v. injection twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10- day rest period (days 12–21) each 21 days. This 3-week period is considered a treatment cycle. At least 72 h should elapse between consecutive doses of bortezomib. Dose modifications for symptomatic neuropathy are summarized in Table 7⇓ and are included in the product label. Neuropathy appears to be associated with increasing cumulative dose as well as preexisting neuropathy; reversibility after prolonged drug exposure is not well characterized. Dehydration and impaired cardiovascular reserve could predispose patients to hypotension and syncope. Because myelosuppression is not the predominant toxicity, other organ toxicities may become dose limiting. The frequency and severity of nausea, vomiting, diarrhea, and neuropathy appear to be dose dependent. Data are limited to describe safety in special populations (hepatic or renal impairment patients) or in combination with other drugs. The approved product label can be found on the FDA drug approval web page.3

PHASE IV POSTMARKETING COMMITMENTS

Under accelerated approval, the sponsor must complete additional studies (Phase IV commitments) to confirm clinical benefit. Millennium Pharmaceuticals has initiated a randomized study entitled, “An International, Multi-center, Randomized, Open-Label Study of PS-341 Versus High-Dose Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma.” The primary objective is the demonstration of superiority in time-to-disease progression. A randomized trial of bortezomib in the initial treatment of multiple myeloma also will be initiated. Additional data will characterize further the frequency, severity, and reversibility of the peripheral neuropathy. Additional studies will characterize the pharmacokinetics of bortezomib at 1.0 mg/m² and at 1.3 mg/m², as well as in patients with various degrees of hepatic and renal impairment. Also, studies will evaluate the role of cytochrome P-450 enzymes in the metabolism of bortezomib and the potential for drug–drug interactions. Because of the cardiovascular effects observed in multiple animal studies and clinical cardiovascular adverse events, the sponsor will investigate further the factors associated with bortezomib-induced lethality in animals. Millennium Pharmaceuticals will also conduct additional in vitro studies to determine whether administration of bortezomib results in the accumulation of prion-related proteins in the cytosol of cells transfected with a normal PrP gene, similar to the effects of other proteasome inhibitors.