Approval Summary for Bortezomib for Injection in the Treatment of Multiple Myeloma (2004)

Purpose: Multiple myeloma is a malignant plasma cell disorder accounting for about 10% of hematological malignancies. Despite treatment advances, including hematopoietic stem-cell transplantation to facilitate administration of high-dose cytotoxic chemotherapy, the median survival remains approximately 3 years and long-term remissions are rare. Bortezomib (Velcade, formerly known as PS-341; Millennium Pharmaceuticals, Cambridge MA) is a dipeptide boronic acid that inhibits the 20S proteasome involved in the degradation of intracellular proteins, including those affecting cell cycle regulation in mammalian cells. Described herein are the analyses by the United States Food and Drug Administration (FDA) of clinical and nonclinical data submitted in the New Drug Application. Chemistry manufacturing and controls, animal toxicology, and biopharmaceutical data are described. The results of Phase I and Phase II clinical studies in patients with multiple myeloma are summarized. The marketing approval and postmarketing commitments are discussed.Results: Toxicology studies in the rat and monkey identified hematological, lymphoid, cardiac, renal, gastrointestinal, and neurological toxicities of bortezomib. A steep dose-toxicity effect was 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. 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.Pharmacokinetic studies in patients with advanced malignancies demonstrated that the mean elimination half-life after the first bortezomib dose varied from 9 to 15 h at doses ranging from 1.45 to 2.00 mg/m2. The drug is metabolized by cytochrome P450–3A4, -2D6, -2C19, -2C9, and -1A2. Three Phase I studies were performed in a total of 123 patients with advanced malignancies. Dose-limiting toxicity included diarrhea and sensory neurotoxicity. No dose-limiting hematological toxicity was reported.Safety and efficacy were evaluated in an open-label, Phase II study of 202 patients with multiple myeloma who had received at least two prior therapies and had demonstrated disease progression on their most recent therapy. A smaller dose finding study of 54 patients provided additional supportive information. Bortezomib was administered by i.v. bolus on days 1, 4, 8, and 11 in a 21-day cycle for up to eight cycles. The initial dose was 1.3 mg/m2 except for 28 patients in the dose-finding study who received a 1.0 mg/m2 dose. The primary study end point in this single-arm trial was response rate, easily measured and thought to correlate with clinical benefit in patients with myeloma. One hundred eighty-eight patients who met the inclusion criteria were included in the FDA efficacy analysis population. Complete responses (CRs) were observed in 5 patients and partial responses (PRs) in 47 patients for an overall response (OR) rate (OR = CR + PR) of 28%. The dose finding study of 54 patients showed a higher response rate for patients given 1.3 mg/m2 compared with 1.0 mg/m2 twice weekly for two of the 3-week schedule, but the study was too small for statistical dose-response comparisons. The most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness) in 65%, nausea (64%), diarrhea (51%), appetite decreased (including anorexia; 43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%, including peripheral sensory neuropathy and peripheral neuropathy aggravated), pyrexia (36%), vomiting (36%), and anemia (32%).Conclusions: The FDA granted 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. Accelerated approval was based on a surrogate end point of response rate rather than clinical benefit, such as an improvement in survival. The recommended dose of bortezomib is 1.3 mg/m2 administered twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12–21). Accelerated approval was based on the results of two Phase II studies in a total of 256 patients and additional Phase I safety information. Mandated Phase IV study commitments to characterize clinical efficacy and safety more precisely are discussed.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.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 for conventional and high-dose regimens et al. published a study that complete remission by immunofixation electrophoresis is a more of survival and to progression than complete remission by response are in is thought to a in the degradation of involved in cell cycle and A first for degradation by the of multiple of The proteasome those that have been for by this The 20S proteasome, the of the proteasome is of a that has multiple on the The as this This 20S proteasome must first to other known as and are to the protein These to each with protein The most frequently proteasome is the proteasome, a by the 20S proteasome and two The proteasome cell and degradation of the regulation of that the of the proteasome multiple to an of cell of the proteasome may have other in research that the of the proteasome to the of abnormal proteins, including protein as demonstrated in cell The clinical of this protein are for that could the 20S proteasome in led to the of bortezomib (Velcade, PS-341; Millennium Pharmaceuticals, a dipeptide boronic acid that inhibits the activity of the 20S proteasome of mammalian Bortezomib and in in and in and to the proteasome at than does to other In in bortezomib to cell cycle at the of and the In the National Cancer Institute of 60 cell bortezomib cell in was cytotoxic for cells. The of bortezomib the 60 cell was In with the and the bortezomib given i.v. weekly for weeks decreased by up to and 65%, to bortezomib has been noted in This is not by of such as the in of proteasome measured in from from or to in about h compared with a single dose at the after a single dose compared with almost after could be in from and but not in the or of The in the was than in is evidence of a of proteasome and clinical the degradation of cytochrome by after the of intracellular of the to may be by after Bortezomib has the to the of a of by the intracellular of cytochrome proteasome by bortezomib may a to that are metabolized by cytochrome is a dipeptide boronic The drug in its in the as a The is provided as a boronic in in with its the boronic The for the is The is and the is The of bortezomib, as the boronic in is in a of Bortezomib is for i.v. as a in bortezomib and In this the drug is and be at The drug is with to a of The is shown in and and proteasome activity were Bortezomib was administered to as a single dose and twice weekly for 2 weeks and for Bortezomib was even at studies that more regimens by a of 20S proteasome activity the subsequent dose. In the rat was observed at ≥0.9 mg/m2 (days and was to hematopoietic and with and Histopathological were observed in the and spinal in with less were observed in who were at ≥0.9 mg/m2 and who to of of including degeneration of dorsal root ganglia, peripheral nerves, and spinal including and was observed at weeks of treatment at doses a incidence of was observed after weeks of in included incidence of and was observed at dose the and of the There to be of of other at this was administered to monkeys as a single a dose for for 2 and for and cycles. In the monkey was observed at ≥0.9 mg/m2. included and There was an incidence of with in treated compared with bortezomib The of was reduced after weeks of was reported in and included degeneration of dorsal root ganglia, peripheral nerves, dorsal spinal and dorsal of the spinal cord at mg/m2 of the recommended clinical dose of 1.3 Histopathological incidence of effects in monkeys compared with that in observations included tremors and reduced activity in reduced was observed at doses ≥0.9 in to be more and/or in and In addition, and of the were observed in monkeys to and in the and in Drug with increasing dose was more in monkeys compared with rodents; the for this is multiple a in resulted in an increase in the elimination half-life and in and drug were in that a of toxicity compared with based on the and of as well as on the total of an 20S proteasome to measure of the activity in proteasome with dose and to by about h in and a single dose of was from in and of administered in and monkeys and of bortezomib and its was in the of monkeys but not of safety studies in monkeys showed that the administration of ≥3.0 mg/m2 resulted in rate and death 12–14 h postdose. studies in monkeys showed bortezomib rate decreased mean and was not reported in this however, this study is to observed in the studies monkeys were of and was to the Histopathological in monkey studies showed at doses ≥0.9 mg/m2. the observed effects are on drug and/or toxicity is activity in the in but was not in the in or the in effects were in the rat and the No evaluation of or and development I and were given bortezomib at a dose of mg/m2 and a decreased of at showed in This dose is approximately the clinical dose the of in and and the effects on primary and observed in the rat study and the monkey toxicity bortezomib is to have an adverse effect on bortezomib was not in and at the dose mg/m2 in the rat and mg/m2 in the administered These are approximately of the clinical dose. Bortezomib is of the of adverse effects on the are not to Phase I dose finding of bortezomib as were performed in a total of 123 patients with a of advanced malignancies. Phase II studies were performed in 256 patients with multiple myeloma who had not a response or who had relapsed initial therapy. patients after two or improvement after for 2 days was to each bortezomib dose. studies therapy in those patients who to The study provided safety on therapy and efficacy on response Phase I studies were performed in patients with advanced malignancies weekly and was with dose-limiting toxicities of and with doses mg/m2. The dose was to be 1.3 mg/m2 given in the first 2 weeks of a 3-week This with a dose of mg/m2 given for the first weeks in a the 1.3 mg/m2 the mean percentage proteasome measured in on 1, cycle 1, is higher than the at cycle The proteasome and dose that the bortezomib dose may be 1.0 mg/m2 and 1.3 mg/m2. The each 21-day cycle was selected more drug could be Phase II studies the safety and efficacy of bortezomib. A open-label, Phase II dose-finding and of bortezomib in the of multiple myeloma was performed in 54 patients with relapsed multiple myeloma to dose-response data The dose was compared with the dose a 21-day cycle with treatment given the first 2 The the higher dose of a higher overall response rate that included The of Multiple Myeloma with proteasome was an open-label, study of patients who had received at least two prior therapies and demonstrated disease progression on their most recent therapy were eligible had relapsed after a response to chemotherapy or or high-dose chemotherapy, and were to at least or to their most recent chemotherapy. patients were not 1.3 mg/m2 was administered by i.v. bolus on days 1, 4, 8, and 11 in a 21-day A of eight was but treatment could be for patients in a was in patients 3 or hematological toxicities resolution or was and treatment was at the dose 1.0 or mg/m2. with disease after two or who response after could be treated with the of and the bortezomib with each These patients were for efficacy and were not included in the primary performed treatment included for adverse a for neurological neurological and clinical trial 202 patients. had or myeloma and advanced disease at and had a The mean age was years; were 10% were and were had been treated with or more of the of used to myeloma or The median of therapies was had received high-dose therapy and stem-cell patients had not been treated with cytotoxic were from the efficacy In the study a less the mean of prior therapies was compared with in the The mean was higher in the the trial were and disease for studies are in primary of the Phase II studies was the determination of overall response rate + + were by an based on the criteria described in Multiple a 50% reduction in serum M protein and 90% reduction in urine M response analyses including remission by criteria and rate of complete resolution of M protein by PEP were performed to facilitate with other of therapy responses were not included in the United States Food and Drug Administration (FDA) analysis responses were less to clinical of the responses at 6 weeks by protein electrophoresis repeat IF patients were in the The response rate was in the compared with in the One in each a CR by and two additional patients in the complete resolution of myeloma M protein by responses were the + + rate was 50% in the compared with in the This of a higher response rate led the to the higher dose for the were too small for statistical dose-response the the FDA analysis identified patients of the 202 who had disease and who The study included patients with adverse including (including patients with a of age and light-chain had received high-dose chemotherapy and/or stem-cell patients with nonsecretory myeloma could not be and the FDA additional patients from the efficacy analyses had not received at least two prior therapies or had not been treated with cytotoxic chemotherapy. The studies were well and were There were in inclusion hematological criteria were not and patients received chemotherapy or 3 weeks of study in of the of patients the study of adverse and of the of 5 patients a complete remission and 47 patients a partial M protein response. In patients had or to bortezomib the 47 were patients who complete resolution of M protein by PEP but not by to the response analysis a analysis by criteria showed clinical remission criteria were by patients of were who had been from the primary FDA analysis of a and had a CR that was not confirmed by repeat The median response duration based on an analysis of response data and data from the studies was days Median survival for 202 patients was response analysis by showed that the of response was not with prior high-dose chemotherapy, of or stem-cell There was a higher response rate in patients who were years of age or who were with plasma at the bone marrow assessment had a response rate compared with a response in those with plasma in the bone with abnormal had a response rate compared with in those with marrow at however, was in response rate for patients with compared with those patients with disease after or disease after two received to bortezomib. were and patients analyses included in immunoglobulin showed an increase in mean and from the assessment to the last on study for patients. in and compared with These analyses were and were not included in the the of the dose was administered at and of the dose was administered at the dose The dose received was in the and the In the of the 202 study patients received a dose of 1.3 mg/m2. in the of the patients received 1.3 mg/m2 the of the patients who at 1.3 mg/m2 dose the and of patients had at least dose for The median of was The median treatment duration was treatment of and treatment of adverse patients in studies to the the administered dose was mg/m2 per In the the doses received with increasing cycles. The overall mean total dose received per was mg/m2 and the overall mean dose was to bortezomib is in safety included patients with treated malignancies from of bortezomib and study that used a combination of bortezomib with observed in the two Phase II studies are in In the study of 1.0 1.3 and peripheral neuropathy were more frequently reported in patients to the 1.3 mg/m2 dose increasing of peripheral neuropathy was with increasing of treatment at the 1.3 mg/m2 dose. One in the and patients in the bortezomib of peripheral studies were performed in patients with the results axonal sensory In the neuropathy was a peripheral was observed after dose reduction or additional data on the and of neuropathy are from the toxicities were at of 1.0 or 1.3 mg/m2. There was in the reported incidence of adverse events or study to adverse events for those patients to years of age and those years In the two Phase II observations of the patients who received the 1.3 mg/m2 dose were to adverse events at the dose. The most commonly reported adverse events for of the patients to the dose are in These nausea (64%), diarrhea (51%), (43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy pyrexia (36%), vomiting (36%), and anemia events of or included thrombocytopenia peripheral neuropathy anemia and vomiting is to plasma at Bortezomib is metabolized cytochrome and is a of cytochrome The to be results in the of two of a single and of the have been data to the of in The mean elimination half-life of bortezomib from 9 to 15 h at doses of 1.45 to 2.00 mg/m2 in patients with advanced malignancies. i.v. administration of the the median plasma of bortezomib was in eight patients with multiple myeloma and ranging from studies are to bortezomib is with that are or of No clinical studies were to the in or or or to the for with The of bortezomib as a single agent has not been characterized at the recommended dose of 1.3 mg/m2 in multiple myeloma trial included patients with multiple myeloma who had received at least two prior to initial and demonstrated disease progression on their last therapy. The study included patients with adverse In the FDA efficacy were patients who a CR the (EBMT) are rarely with therapy in this except with the use of high-dose chemotherapy and stem cell rescue In addition, were 47 patients who met criteria for including patients with complete resolution of myeloma protein by The overall response rate was and the median response duration was the clinical remission were complete of monoclonal protein may correlate with more complete reduction of the myeloma cell and with but this remains to be clinical observed included of hematological and reduction of in patients. The drug was well with fatigue, thrombocytopenia and peripheral neuropathy the most commonly reported adverse The median of received was and the overall dose was for patients the studies in monkeys and for 2 weeks followed by rest demonstrated gastrointestinal, and as well as and in 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 A small dose doses ≥0.9 and the dose or dose mg/m2 was observed in monkeys and There was a steep dose-toxicity effect noted at doses ≥0.9 administration of doses ≥3.0 mg/m2 to monkeys resulted in cardiovascular collapse and death 12–14 h postdose. These observations in a drug led to the inclusion of animal toxicity in the of the FDA may marketing approval for a new drug the the drug benefit therapy for the treatment of or Accelerated approval and clinical that the drug has an effect on a surrogate end point that is to be to clinical benefit based on or other evidence The efficacy and safety results of the bortezomib Phase II studies were evaluated by the FDA and thought to an improvement therapy for relapsed multiple myeloma and to clinical benefit in this population. The 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 from the initial New Drug to of the New Drug was 54 and the New Drug was by the FDA in recommended dose of bortezomib is 1.3 mg/m2 administered as a bolus i.v. twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a rest period (days each This 3-week period is a treatment least h doses of bortezomib. for neuropathy are in and are included in the to be with increasing dose as well as after drug is not well and cardiovascular could patients to and is not the other toxicities may dose The and of and neuropathy to be dose are to safety in or or in combination with other The be on the FDA drug approval accelerated the must complete additional studies IV to clinical Millennium Pharmaceuticals has a study of in with or Multiple The primary is the of in progression. A trial of bortezomib in the initial treatment of multiple myeloma be data characterize the and of the peripheral studies characterize the of bortezomib at 1.0 mg/m2 and at 1.3 as well as in patients with of and studies the of cytochrome in the of bortezomib and the for of the cardiovascular effects observed in multiple animal studies and clinical cardiovascular adverse the the with in Millennium Pharmaceuticals additional in studies to administration of bortezomib results in the of in the of with a to the effects of other proteasome for United States Food and Drug of of of United States