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Current Phase II investigational proteasome inhibitors for the treatment of multiple myeloma
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DOI:10.1517/13543784.2014.920821 Terms of use:
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Bringhen, S., Gay, F., Donato, F., Troia, R., Mina, R., & Palumbo, A. (2014). Current Phase II
investigational proteasome inhibitors for the treatment of multiple myeloma. Expert Opinion on
Investigational Drugs, 23(9), 1193–1209. doi: 10.1517/13543784.2014.920821 © 2014 Informa UK,
Ltd. ISSN 1354-3784, e-ISSN 1744-7658
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Abstract
Introduction: The introduction of novel agents in multiple myeloma (MM) treatment significantly improved
outcome. Bortezomib is the first proteasome inhibitor (PI) approved for MM therapy. The efficacy and safety of bortezomib treatment provided the basis for the development of second generation PIs.
Areas Covered: This review will focus on PIs currently under evaluation in phase II trials in MM,
summarizing the mechanism of action and the available clinical data.
Expert Opinion: Second generation PIs have shown a promising activity in patients with advanced stage
myeloma, even in those refractory to bortezomib; their efficacy in the upfront setting is currently under investigation. Future directions in the development of PIs include the optimization of their schedule and the investigation of their synergistic activity with other anti-myeloma agents.
Highlights box:
• Recently, novel agents have revolutionized the treatment paradigm of MM.
• Bortezomib is the first PI approved for the treatment of MM, and is currently approved for the treatment of both relapsed and newly diagnosed patients in the transplant and non transplant setting.
• Second generation PIs with different mechanisms of action and a different toxicity profile from bortezomib are currently under evaluation in phase I/II and III studies.
• Carfilzomib and ixazomib showed promising results in the relapsed/refractory setting and are now under evaluation in in newly diagnosed multiple myeloma patients
• Excellent results in the pre-clinical setting with oprozomib and marizomib lead to their evaluation in the clinical setting in relapsed/refractory myeloma.
1. Introduction
Multiple myeloma (MM) is a plasmacell malignancy, characterized by abnormal proliferation of plasmacells in the bone marrow, presence of monoclonal immunoglobulin or light chain proteins and organ damage
including bone lesions, renal failure, hypercalcemia, or anemia.1 The introduction of novel agents, thalidomide, bortezomib and lenalidomide, significantly improved overall survival (OS) in the last decade.2 Autologous stem-cell transplantation is the gold standard as initial therapy in younger patients.3 The incorporation of novel agents into pre-transplant induction and post-transplant consolidation and
maintenance therapy improved progression free survival (PFS) and OS4–6. The current standards of care for elderly patients include novel agents combined with melphalan-prednisone (MP).7–9
Current approved treatment options for relapsed/refractory patients include bortezomib, bortezomib plus pegylated liposomal doxorubicin, or lenalidomide plus dexamethasone.7–10 New targets in MM cells have been identified. Several molecules are now under investigation in clinical trials, both as monotherapy and in combination with standard treatment. These include inhibitors of histone-deacetylase (panobinostat and vorinostat), Akt inhibitors (perifosine), mTOR-inhibitors (everolimus and temsirolimus) and monoclonal antibodies (such as elotuzumab, daratumumab and siltuximab). Furthermore, microRNAs (miRNAs) are currently regarded as possible therapeutic agents in MM.
Proteasome inhibition has been widely explored as a therapeutic strategy in MM.11,12 The ubiquitination and proteasome degradation pathway is a multistep enzymatic cascade in which ubiquitin is conjugated via a lysine residue to target proteins for degradation in the proteasome enzyme complex.13 The
ubiquitin-proteasome pathway is responsible for degradation of the majority of regulatory proteins in eukaryotic cells, including proteins that control apoptosis, cell-cycle progression, DNA repair. Therefore, it plays a critical role in preserving normal cellular homeostasis. Inhibition of the proteasome leads to accumulation of these proteasome substrates, resulting in concomitant activation of pro- and anti-proliferative signals, disruption of cell-cycle regulation, and activation of apoptotic pathways and cell death.14,15 Neoplastic cells usually have higher levels of proteasome activity compared with normal cells and, in addition, are more sensitive to the proapoptotic effects of proteasome inhibition, making the proteasome a rational therapeutic target in tumors, including MM.
Bortezomib is the first PI approved by the US Food and Drug Administration for the treatment of relapsed MM.16 In newly diagnosed MM patients, bortezomib is now currently included in the pretransplant induction regimens (in association with steroids and immunomodulatory agents [IMIDs] and/or chemotherapy); furthermore, bortezomib plus MP (MPV) is one of the approved treatment options in Europe for newly diagnosed elderly patients.Subcutaneous (SC) bortezomib approval was based on the results of a prospective randomized study showing that, in the relapse setting, subcutaneous bortezomib was as effective as intravenous bortezomib (IV). Furthermore, a significant reduction of peripheral neuropathy (PN) was reported with SC as compared to IV administration. Carfilzomib was granted approval in 2012 in the United States for relapsed or refractory MM.17 Other PIs with diverse mechanisms of action have been developed and are currently under evaluation. “Second generation” PIs representing distinct structural classes (peptidyl boronic acids, peptidyl epoxyketones, beta-lactones, and salinosporamides) are under clinical development. Those drugs have different affinities for the catalytic sites within the proteasome core, pharmacological and pharmacodynamic activity profiles, mechanisms of action (Table 1).
Briefly, PIs bind to their specific site of the proteasome with both a non-covalent, reversible manner (bortezomib, ixazomib and delanzomib) and a covalent, irreversible manner (carfilzomib, oprozomib and marizomib).Compared to the reversible bond, the irreversible binding to the catalytic area of the proteasome provides a moderately slow recovery of its normal activities (t1/2 24 h) suggesting that it is due to de novo proteasome synthesis, which is strictly related to a longer duration of action and potency.18The irreversible inactivation of proteasome by Carfilzomib could be a way to overcome the cell’s attempt at resistance by overproduction of proteasomes, which is one characteristic of cells that express primary resistance to Bortezomib.
The enzymatically active sites of the proteasome complex are located in the central inner rings which contain seven β-subunits. Specifically, the enzymatic activities are performed by chymotrypsin-like (β5), caspase-like (β1) and trypsin-like (β2) β-subunits (Fig. 1).19 All proteasome inhibitors mostly binds the chymotrypsin-like
site with both covalent and ionic/hydrogen bonds.20 Carfilzomib and Oprozomib bind to the the B5 subunit only. Some compounds exceptionally bind more than one catalytic site: Bortezomib has a good affinity even for caspase-like site; Ixazomib and Marizomib inhibit the three subunits, even if with different affinities (table 1).21 The effects promoted in the cells vary according to the binding-site. The reversible bond of Bortezomib to both sites β5 and β1 mostly modulates NF-kB pathways.22 As a consequence it decreases the
translocation of NF-kB into the nucleus, reducing cell survival. Ixazomib, binding all three catalytic sites, determines the activation of both caspase-8 and caspase-9 apoptotic pathways and induce tumor suppressor p53 activation and p53 co-related proteins NOXA and PUMA.23,24 .
The irreversible inhibitors Carfilzomib and Oprozomib, which bind the β5 subunit, activate caspase-9, caspase-8 and the common effector caspase-3 apoptotic pathways. Moreover Carfilzomib induces an increase of c-Jun-N-terminal kinase (JNK) activity in cells that augments apoptotic processes.25
Marizomib, binding the three subunits, exerts its activity on NF-kB pathway and inhibits cytokines such as Interferon-γ, mediating apoptotic activity on tumor cells.26,27
This review provides an overview of second generation PIs currently under evaluation in phase II trials in MM as monotherapy or in combination with other agents. Results from phase I studies are also briefly reported. Pis described below are firstly classified accordingly to the nature of their chemical bond to the proteasome into competitive and non-competitive inhibitors and then listed accordingly to their chemical structure (Figure 1).
2. Reversible inhibitors 2.1 Boronic acids
Boronic acids include bortezomib, and the second generation ixazomib (MLN9708) and delanzomib (CEP18770). Bortezomib is an intravenous drug; ixazomib and delanzomib have been used both as intravenous and oral agents (Table 1).
2.2 Ixazomib (MLN9708)
MLN9708 is an orally bioavailable PI currently under evaluation in the treatment of several cancers. It is a dipeptidilic boronic acid that is rapidly hydrolyzed in water and converts into MLN2238, the biologically active form. MLN2238 inhibits the chymotrypsin-like proteolytic siteof the proteasome. As bortezomib, ixazomib showed time-dependent reversible proteasome inhibition but the proteasome dissociation half-life for ixazomib is ∼6-fold faster than that of bortezomib (table 1). A rapid reversible inhibitor can dissociate faster from red blood cells and rapidly enter tumor (Figure 2). This can explain the greater tumor to blood ratio of proteasome inhibition of MLN2238 in comparison with bortezomib that translates into improved
pharmacodynamic response and antitumor activity in tumor xenograft models.28,29 MLN2238 inhibits growth and induces apoptosis in MM cells resistant to conventional therapies and bortezomib, without affecting the viability of normal cells. MLN2238 combined with lenalidomide, histone deacetylase inhibitors or
dexamethasone, triggers synergistic anti-MM activity.23
The preliminary PK results show that body size did not significantly impact AUC and Cmax, supporting a switch from BSA based dosing to flat dosing, that makes it very convenient for the oral administration.30 Ongoing trials are evaluating MLN9708 as single agent or in combination (Table 2 and 3).
Two phase I studies are evaluating oral MLN9708 as monotherapy in relapsed/refractory MM patients previously exposed to PIs. One has adopted a weekly administration (days 1, 8 and 15 of 28 day cycles) of the drug. The MTD was 2.97 mg/m2. Twenty-eight percent of patients had grade 3 or higher AEs including thrombocytopenia (33%), diarrhea and neutropenia (17% each), decrease appetite, fatigue and lymphopenia (each 8%). Of 41 evaluable patients, 1 achieved a very good partial response, 5 a PR, 1 a MR and 15 a SD.31,32 The second one is administering MLN9708 in a biweekly schedule (1, 4, 8 and 11 of 21 day cycles). The MTD was 2 mg/m2. Preliminary results showed 1 stringent CR, 5 PR and 1 MR. Sixty-three percent of
patients had drug-related grade 3 or higher AEs including thrombocytopenia (33%), neutropenia (14%), fatigue (9%) and rash (7%).33
In a phase II trial, single agent MLN9708 was administered at a flat dose of 5.5 mg weekly for three out of four weeks in patients relapsed but not refractory to bortezomib. Dexamethasone (20 mg on the day of and the day after MLN) was added for suboptimal response (lack of MR after 2 cycles or lack of PR after 4 cycles). Most frequent AEs included thrombocytopenia, fatigue, nausea and diarrhea. At least PR was seen in 5 patients including 2 stringent CR; median EFS was 12.4 months.34
Other trials are currently evaluating MLN9708 in combination with other drugs (Table 2 and 3). A phase I/II study evaluated weekly MLN9708 (days 1, 8, 15 escalating doses) in combination with
lenalidomide (25 mg/day days 1-21) and weekly dexamethasone in previously untreated MM patients for up to twelve 28-day cycles, followed by maintenance with MLN9708 alone. The MTD was 2.97 mg/mq and the recommended dose for the phase 2 portion of the trial was 2.23 mg/mq, converted then to a 4 mg/day flat dose. Most frequent all grade AEs were fatigue (32%), nausea (31%) and vomiting (25%). Grade 3-4 AEs included cutaneous rash, nausea and vomiting (5% each). PR or better was reported in around 90% of patients including 40% VGPR and 18% CR.35
Another phase I/II trial in newly diagnosed MM patients evaluated twice weekly MLN9708 (days 1,4,8,11 escalating doses) plus lenalidomide (25 mg/day days 1-14) and dexamethasone for up to sixteen 21-day cycles, followed by MLN9708 maintenance. No DLTs were seen and the recommended phase II dose was 3 mg. Drug related grade 3 AEs were reported in 56% of patients and included rash (16%), hyperglycemia (8%), pneumonia (6%) and peripheral neuropathy (5%). Al least a PR was reported in 96% of patients including 67% VGPR and 24% CRs.36
A phase II trial is ongoing to establish the safety and efficacy of MLN and lenalidomide in the maintenance setting post ASCT.37
2.3 Delanzomib (CEP-18770)
CEP-18770 is a new reversible inhibitor of the chymotrypsin-like activity of the proteasome subunit..38,39 Delanzomib showed a greater and more sustained dose-related proteasome inhibition than bortezomib in severe combined immunodeficient (SCID) mice and single-agent antitumor activity similar to bortezomib in primary MM plasma cells in vitro.39 In preclinical models, it was also able to overcome bortezomib resistance. Synergistic cell death was detected when delanzomib was combined with doxorubicin, melphalan and arsenic trioxide in MM cell lines, and with melphalan in a MM mouse model.40 Delanzomib combined with dexamethasone and/or lenalidomide results in increased tumor reduction and extended tumor growth delays when compared to these drugs without delanzomib.41
The major target organs of toxicity in rats and monkeys were bone marrow, liver and kidney. PK in plasma was linear. Proteasome inhibition in peripheral blood mononuclear cells was dose-related in MM patients. Intravenous delanzomib in a twice-weekly schedule (days 1, 4, 8 and 11 in 21-day cycle) has been
investigated in patients with solid tumors and MM. The MTD was 1.5 mg/m2. Skin rash was dose-limiting and occurred in 53% of patients; other common toxicities were asthenia (29%), stomatitis (21%) and pyrexia (16%).42 A phase I/II trial in relapsed/refractory MM evaluated delanzomib administered at escalating doses in a weekly schedule (days 1, 8, 15 in 28-day cycles). In the phase I portion of the trial, the MTD was 2.1 mg/m2 and two patients achieved SD that lasted more than 6 months but the phase II portion of the study was prematurely stopped because of lack of efficacy.43
3. Irreversible inhibitors 3.1 Epoxyketones
Epoxyketones are selective inhibitors of chymotrypsin-like activity and induce irreversible inhibition.
Epoxyketones include carfilzomib (PR-171), an intravenous drug, and oprozomib (ONX-0912 or PR-047) that is orally bioavailable.
3.2 Carfilzomib
Carfilzomib, is a tetrapeptide epoxyketone analogue of epoxomicin.44,45 Carfilzomib primarily inhibits chymotripsin-like site of the proteasome; it forms a stable and irreversible adduct with the proteasome.46 In vitro, carfilzomib can directly inhibit osteoclast formation and bone resorption, and increases trabecular bone formation. Carfilzomib is rapidly and extensively distributed, except for the brain because it cannot cross the blood-brain barrier.47,48 Carfilzomib is cleared from the circulation by biliary and renal excretion; however renal impairment does not appear to involve pharmacokinetic and safety of Carfilzomib.49,50
Based on the data obtained in two phase I studies,48,51 phase II trials evaluated Carfilzomib as single agent in relapsed/refractory MM (PX-171-003-A0 and PX-171-004), (Table 2 and 3). The first trial enrolled 46 MM patients relapsed after at least two prior lines of therapy and refractory to the last line of therapy.52
Carfilzomib was administered at the dose of 20 mg/m2 on days 1, 2, 8, 9, 15, 16 of a 28-day cycle for up to 12 cycles. The overall response rate (ORR) was 17% and the clinical benefit rate including MR was 24%. These results prompted the expansion into the PX-171-003-A1, which included 266 patients previously treated with bortezomib, IMiDs, and an alkylator.53 Patients received carfilzomib 20 mg/m2 in the first cycle and 27 mg/m2 from cycle 2, as in the PX-171-003-A0 trial. Twenty-four percent of patients achieved at least PR; the median duration of response was 7.8 months and the median OS 15.6 months. In the PX-171-004 trial, 164 relapsed/refractory patients were stratified into bortezomib-naïve (n=129) and bortezomib-treated (n=35) and included in 2 different carfilzomib dose cohorts (the first cohort received 20 mg/m2 for up to 12 cycles and the second 20 mg/m2 in the first cycle and 27 mg/m2 from cycle 2). In the bortezomib-naıve group, 42% of patients in the 20 mg/m2 cohort and 52% in the 27 mg/m2 cohort achieved at least PR. The median TTP was 8.3 months in cohort 1 and have not been reached in cohort 2.54 These data highlighted a dose-response relationship, and were confirmed in a pooled multivariate analysis on 430 patients; the odds of a response increased by 1.28-fold for each 1 mg/m2 increase in Carfilzomib dose.55 In the bortezomib-treated group, 17% of patients achieved a PR or better.56 Pooled analysis of the PX-171-003 and PX-171-004 trials, showed that ORR was almost identical in patients with standard- and high-risk cytogenetic abnormalities, showing a trend towards a higher ORR for t(4;14) but a lower rate for t(14;16), as well as a shorter duration of response for the subgroup of patients with del 17p13.57
The PX-171-005 trial evaluated carfilzomib in patients with renal insufficiency. Carfilzomib was administered at a dose of 15 mg/m2 intravenously on days 1, 2, 8, 9, 15, 16 every 28 days for cycle 1, 20 mg/m2 in cycle 2 and 27 mg/m2 from cycle 3, with the possibility of adding dexamethasone in case of suboptimal response (failure to achieve PR by cycle 2 or CR by cycle 4). PR or better was achieved in 25% of patients.58 In a pooled analysis of PX-171-003, 004, and 005 trials the most frequent AEs were fatigue (55%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%). The grade 3 AEs present in ≥10% of patients were mainly hematological: thrombocytopenia (23%), anemia (22%), lymphopenia (18%), and neutropenia (10%). Dose modifications were required in 10% of patients. Renal AEs (mainly grade 2) were reported in 33% patients, but drug discontinuation for a renal AE occurred in 4% of patients only. Cardiac failure was reported in 7% of patients regardless of causality; treatment discontinuation for cardiac events included congestive heart failure (2%), cardiac arrest (1%), and
myocardial ischemia (1%). Rates and causes of death were consistent with those observed in patients with end-stage MM.59 Therefore, single-agent carfilzomib has an acceptable safety profile in heavily pretreated relapsed/refractory MM. Based on these data, a phase III randomized trial (FOCUS) is comparing
carfilzomib versus best supportive care in patients with relapsed/refractory MM who have received three or more prior therapies.
The MTD for single-agent carfilzomib has not been defined yet and the drug is being tested in a dose-escalation trial with doses up to 56 mg/m2.60 Preliminary results demonstrated that weekly carfilzomib at doses ≥45 mg/m2 combined with dexamethasone in relapsed or refractory MM is well tolerated, showing an ORR of 67%.61
Several carfilzomib-based combinations are being explored. In the upfront setting, 53 patients have been treated with carfilzomib-lenalidomide-dexamethasone in a phase I/II study. Successful stem cell harvest was achieved when attempted. CR was achieved in 64%, including a sCR in 55%; the 3-year PFS was 79% and the 3-year OS 96%. Using highly sensitive minimal residual disease assays, a consistently high rates of deep remission and minimal residual disease negativity were reported. Low rates of neutropenia (grade 3–4,
12%) were observed; 24% of patients had peripheral neuropathy, limited to grade 1-2 in all cases.62 The PX-171-006 trial evaluated the combination of carfilzomib-lenalidomide-low dose dexamethasone in
relapsed/refractory patients showing excellent tolerability that allowed the continued administration of the combination for up to 18 cycles. ORR was 69% including 5% sCR/CR, 36%VGPR, and 29% PR.63
The combination carfilzomib plus thalidomide-dexamethasone was evaluated as pre-transplant induction and post-transplant consolidation in untreated patients; after induction 19% of patients achieved CR/sCR, 60% at least VGPR and 93% at least ≥ PR. The CR/sCR rate increased to 30% after transplant and to 49% after consolidation. Grade 3-4 non hematologic AEs were reported in less than 5% (mainly infections and skin lesions).64
Preliminary results from a phase I/II trial exploring cyclophosphamide-thalidomide-dexamethasone plus carfilzomib as pretransplant induction in newly diagnosed patients showed at least a PR in 91% of patients including 18% CR and 58% VGPR. Most commonly reported non hematological toxicities (all grades) included fatigue (63%), constipation (46%), elevated creatinine (27%), hyperglycemia (27%), lethargy (25%) peripheral sensory neuropathy (25% - all grade 1), and somnolence (21%); however, grade 3/4 toxicities occurring in >5% were uncommon: hypertension (8%), thromboembolic event (6%) and hyperglycemia (6%). Cardiac events occurred in less than 5% of patients. All patients successfully collected stem cells.65
In elderly newly diagnosed non-transplant eligible patients 2 combinations were investigated. In a phase II study cyclophosphamide-dexamethasone and carfilzomib showed a PR rate of 96%, including 71% at least VGPR, and 20% stringent CR. After a median follow-up of 18 months, the 1-year PFS and OS rates were 76% and 87%, respectively. The most frequent grade 3–5 toxicities were neutropenia (20%), anemia (11%), cardiopulmonary adverse events (7%) and infections (5%). Peripheral neuropathy was limited to grade 1–2 (9%).66 In another phase I/II dose-escalation study, melphalan-prednisone plus carfilzomib showed a PR rate of 91%, including 55% VGPR; median event-free survival was 21.8 months.67
A randomized phase III trial (ASPIRE) comparing lenalidomide plus low-dose dexamethasone with or without carfilzomib in patients with relapsed or progressive MM has completed enrollment.68
3.3 Oprozomib
Oprozomib (ONX-0912 and previously PR-047) is another second-generation PI that is a structural analog of carfilzomib and is orally bioavailable.69 It showed high levels of proteasome inhibition; the safety profile was acceptable in a phase 1 trial in patients with advanced solid tumors.70 An open-label, phase 1b/2 study is enrolling patients with relapsed MM or Waldenström's macroglobulinemia. The schedule was once daily on days 1, 2, 8, 9 of a 14-day cycle or on days 1–5 of a 14-day cycle. There were 2 dose-limiting toxicities (renal failure [180 mg/d] and tumor lysis syndrome [240 mg/d]; both occurred on the second schedule), but the dose escalation is still ongoing. The most common grade 3–4 AEs included diarrhea (n=9); anemia, nausea, and neutropenia (n=4 each); hypophosphatemia, thrombocytopenia, and vomiting (n=3 each);dehydration and fatigue (n=2 each). Two patients experienced grade 1 peripheral neuropathy (both reported grade 2 at baseline). The clinical benefit response rate was 23% in MM patients and 80% in Waldestrom patients. In 14 patients refractory to bortezomib, 3 had a PR, 1 had a MR, 9 had SD, and 1 had PD.71
3.4 B-lactone
NPI-0052 (Marizomib)
Marizomib (Salinosporamide A) is a non-pepditic PI isolated from the marine actino-mycetes Salinispora tropica.72 It covalently bounds to all proteolytic subunits of the proteasome.73 Marizomib differs structurally from other proteasome inhibitors by possessing chloroethyl and cyclohexenyl carbinol substitutions.26,74 The chlorine confers irreversible binding properties.74,75 Experiments revealed that the irreversible binding of Marizomib to the proteasome is responsible for its slow efflux, long duration of action, and high cytotoxicity.18 Marizomib has been shown to potently overcome bortezomib resistance in vitro.72,73,76 and exhibited
synergistic activities in tumor models in combination with bortezomib, lenalidomide, and histone deacetylase inhibitors.27,77–83
Marizomib is being evaluated in several phase 1 trials in patients with hematologic and solid tumors, including patients relapsed/refractory after other PIs.84–87
Efficacy and safety data for Marizomib are available from phase 1 trials only. Although it is orally active, the trials performed to date used the iv formulation. In 2 parallel, phase 1, dose-escalation studies in patients with relapsed/refractory MM, Marizomib was given iv over 1-120 minutes on day 1,4,8,11 of a 21-day cycle. Dexamethasone (20 mg) was given the day prior to and the day of treatment in one study and could be added in patients who did not achieve a MR after 2 cycles in the other study. The MTD of Marizomib was 0.4 mg/m2 over a 60-min infusion or 0.5 mg/m2 over a 120-min infusion. DLTs included reversible cognitive changes, transient hallucinations, and loss of balance. The most common drug-related AEs included fatigue, gastrointestinal AEs, dizziness, and headache. Of 15 patients treated in the active dose range (0.4–0.6 mg/m2), 3 bortezomib-refractory demonstrated a PR.88
4. Conclusions
The development of novel agents is necessary to overcome drug resistance and increase survival of MM patients. The positive results obtained with bortezomib treatment in MM patients provided the basis for the development of second generation PIs, with the aims of enhancing anti-tumor activity, reducing toxicity, and improving patient compliance. These emerging drugs have exhibited promising antitumor activity in
relapsed/refractory MM, thus creating an alternative, particularly for patients who are refractory to approved agents.
Expert opinion
The proteasome is an extremely sensitive target in cancer cells. It is involved in multiple cellular processes both in healthy and neoplastic cells. Bortezomib is the first PI approved by the FDA and the EMA for the treatment of MM. It represented a turning point in the treatment of MM, showing a great efficacy both in relapsed/refractory and newly diagnosed patients. Peripheral neuropathy is the main extra-hematologic toxic effect associated with this agent; however, bortezomib has been used for approximately 10 years now, and the long experience with this agent has led to the definition and the optimization of its schedule, once-weekly administration, and its route of administration, subcutaneous. These improvements translated into a relevant safety benefit without affecting the efficacy of this drug.89,90 The new route of administration and the better safety profile may facilitate the use of bortezomib in the maintenance setting, further improving its long term efficacy , as demonstrated with other anti-MM agents.91–95
The second generation PI ixazomib showed a greater anti-tumor activity than bortezomib in preclinical models and a promising clinical efficacy in ongoing studies. Moreover, ixazomib is orally available, and this route of administration can further improve patient’s compliance and facilitate a long term treatment in the maintenance setting. The availability of an oral formulation for both IMiDs and PIs and the evidence of the advantage on survival outcomes with both drugs allow their experimental use in a continuous fashion to further improve survival. The combination of ixazomib and lenalidomide, currently under investigation in a phase III trial in relapsed patients, is a promising orally available therapy. Future studies are needed to evaluate the combination of the drug with chemotherapy and steroids, as well as to explore the role of ixazomib in the maintenance setting.
As far as PIs with an irreversible bond to the proteasome are concerned, carfilzomib has shown a great efficacy both in young and elderly patients. The safety profile differs from that of bortezomib: in patients treated with carfilzomib no relevant peripheral neuropathy was reported but particular attention must be paid to cardiovascular toxicity. However, this side effect might be, at least partially, related to the high fluid intake during carfilzomib infusion and to the concomitant administration of steroids. Several carfilzomib-based combinations are currently under evaluation in phase I/II trials. Ongoing phase III trials are comparing carfilzomib with the milestone PI, bortezomib, in both upfront and in the relapse settings. Carfilzomib is currently used in a bi-weekly schedule; ongoing studies will evaluate once-weekly administration in order to optimize its schedule and improve safety and patient’s compliance, as previously obtained with bortezomib.
Carfilzomib has demonstrated to overcome bortezomib refractoriness, thus representing a valid therapeutic option in patients previously exposed to bortezomib; however, no information about cross-resistances to other Pis in patients primarily exposed to carfilzomib is currently available; these data are essential in order to establish in which sequence PIs should be administered so as to optimize their use. Recently, oprozomib, a carfilzomib structural analogue orally available, has been tested in phase I/II trials; future data about its safety and efficacy are awaited.
To date, a comparison between first and second generation PIs (bortezomib versus carfilzomib) is under investigation in the upfront treatment of newly diagnosed patients; however, no formal comparison between second generation PIs has been made yet. The different toxicity profiles showed by second generation PIs will probably guide clinician’s choice accordingly to patients’ comorbidities.
The proteasome is only one of the many targets in MM cells. A complex pathophysiology lies under the development of MM and several mechanisms contribute to the growth of the tumor and its effects on the host. Several pathways have been targeted by agents belonging to other classes, such as alkylators, IMiDs and monoclonal antibodies. IMiDs have already proved their efficacy in MM and their synergistic activity with corticosteroids, alkylators and proteasome inhibitors. Thalidomide and lenalidomide have been associated with bortezomib and other drugs in the upfront treatment and in the treatment of relapsed patients; the third generation IMiD pomalidomide is an effective option in the relapse setting; no data are available on its use in the upfront setting. The combination of pomalidomide and second generation PIs may be an effective option for heavily pretreated patients. Among the different monoclonal antibodies, the anti-CS1 Elotuzumab is currently under evaluation with either PIs or IMiDs in both newly-diagnosed and relapsed MM patients. Daratumumab is directed against CD38 expressed on the surface of myeloma cells while siltuximab targets IL6: their role in the treatment of MM still needs to be elucidated. Recently, microRNAs (miRNA) have been studied in this setting. A deregulated expression of miRNAs has been proven in MM cells: hence they may represent targeted therapeutic agents.96 A major limitation for their use is the unstable nature of their molecular structure; lipid-based vesicles nano-carriers, specifically stable nucleic acid lipid particles (SNALPs), have been used to vehicle small interfering RNAs in non-human primates and clinical trials are currently ongoing. Recently, various murine models, such as human (SCID-hu) or humanized (SCID-synth-hu) murine models, have been developed and successfully tested as platforms that better recreate the human bone marrow microenvironment in which MM cells grow and anti-MM agents exert their activity.97 Lipidic-formulated miR-34a has anti-MM activity in vivo in SCID mice bearing human MM cells; SNALPs can be successfully used to deliver miR-34a both in vitro and in vivo.98,99 Interestingly, the pro-apoptotic effect of miRNA 29b is positively modulated by bortezomib in MM cells, suggesting a possible synergic activity between miRNA and PI.100,101
To date, the ultimate goal of therapy against myeloma is to obtain the deepest response with the longest duration translating into a long disease-free survival. In order to achieve this goal, a combination of multiple drugs active on different targets may be the best strategy to induce a long-lasting remission and prolong survival. However, to date, which is the best combination and whether a sequential approach with the available agents may succeed in improving outcomes are open matters that need to be clarified.
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Figure 1 Chemical structure of novel Proteasome inhibitors compared to Bortezomib.
Bortezomib (PS-341)
Peptide boronic acid
Carfilzomib (PR-171)
Peptide epoxyketone
Ixazomib (MLN-9708/MLN-2238)
Peptide boronic acid
Marizomib (NPI-0052) ß-lactone Oprozomib (PR-047/ONX-0912) Peptide epoxyketone Delanzomib (CEP18770)
Table 1. Novel proteasome Inhibitors: chemical and biological features and clinical implications.
Drug Name Chemical
class Binding kinetics Proteasome 20S ß5/ß2/ß1 (nM) IC50S Phase Half-life of Proteasome Maximal % inhibition
at MTD
Route of
administration Therapeutic Use
Bortezomib
(PS-341)23,28,46 Boronate Reversible ß5;ß5i 2.4;7.9/590;4200/24;74 Approved by FDA as first line treatment for MM and
MCL
110 min 65%-75% IV, Sc ND/RRMM, MCL. Under clinical investigation for metastatic solid tumors.
Carfilzomib
(PR-171)46 Epoxyketone Irreversible ß5;ß5i 6/3600/2400 Approved by FDA for RRMM
<30 min >80% IV ND/RRMM, refractory lymphoma and advanced
solid tumors (renal cancer, ovarian cancer)
Ixazomib
(MLN-9708)28 Boronate Reversible ß5 3.4/3500/31 III 18 min 73 to 99% IV, Oral (including HL). Adavnced ND/RRMM, Lymphoma solid malignancies (head and neck neoplasms, soft tissue sarcoma, prostatic
cancer)
Marizomib
(NPI-0052)23 β-lactone Irreversible ß5;ß2 3.5/28/430 I <10-15 min 100% IV, Oral lymphoma and advanced RRMM, refractory solid tumors (including
pancreatic cancer and melanoma)
Oprozomib
(PR-047/ONX-0912)69 Epoxyketone-based Irreversible ß5;ß5i 36;82/NR/NR Ib/II 4 hours dependent Dose >80% (210 mg/die)
Oral Under clinical investigation for advanced refractory or recurrent solid tumors,
Delanzomib
(CEP18770)39 Boronate Reversible ß5 3.8/>100/<100 I/II 9 hours 45 ± 11% IV, Oral RRMM, refractory solid tumors, NHL.
MM: Multiple Myeloma, MCL: Mantle Cell Lymphoma, HL: Hodgkin Lymphoma, NHL: Non-Hodgkin Lymphoma, NDMM; Newly diagnosed Multiple Myeloma, RRMM: Relapsed/Refractory Multiple Myeloma; IV: intra-venous; Sc: subcutaneous
Table 2 Efficacy of proteasome inhibitors
DRUG PHASE PATIENTS TREATMENT SCHEMA ORR (≥PR)
MLN9708 IXAZOMIB
single agent32 I 60 RRMM MLN9708 MTD: 2.97 mg/mq on days 1,8,15 every 28 days 15% single agent33 I 57 RRMM MLN9708 MTD: 2 mg/mq on days 1,4,8,11 every 21 days 13% single agent34 II 33 RRMM° MLN9708: 5.5 mg on days 1,8,15; dexamethasone 20 mg on
days 1,2,8,9,15,16§ every 28 days 15%
combination35 I/II 65 NDMM MLN9708: 4 mg on days 1,8,15; lenalidomide 25 mg on days
1-21; dexamethasone 40 mg on days 1,8,15,22 every 28 days 88% combination36 I/II 64 NDMM MLN9708 3 mg on days 1,4,8,11; lenalidomide 25 mg on days
1-14; dexamethasone 20/10 mg on days 1,2,4,5,8,9,11,12 every 21 days
93%
CARFILZOMIB
single agent48 I 29 RRMM Carfilzomib: MTD 15 mg/mq on days 1-5 every 14 days NA single agent51 I 48 RRMM Carfilzomib: MTD 27 mg/mq days 1, 2, 8, 9, 15 and 16 every 28
days NA
single agent52 II 46 RRMM Carfilzomib 20 mg/mq on days 1, 2, 8, 9, 15 and 16 every 28
days 17%
single agent53 II 266 RRMM Carfilzomib 20-27 mg/mq on days 1, 2, 8, 9, 15 and 16 every 28
days 24% single agent54 II 164 RRMM (Cohort 1=94; Cohort 2=70)
Carfilzomib: 20 (cohort 1) mg/mq or 20/27 mg/mq (cohort 2)
on days 1, 2, 8, 9, 15 and 16 every 28 days Cohort 1: 42% in bortezomib naive and 17% bortezomib pre-treated patients; Cohort 2: 52% single agent58 II 50 RRMM Carfilzomib: 15/20/27 mg/mq (cycle 1/2/3+) on days 1, 2, 8, 9,
15 and 16 every 28 days 25,00%
combination63 Ib/II 84 RRMM Carfilzomib: MTD 20/27 mg/mq on days 1, 2, 8, 9, 15 and 16 every 28 days; lenalidomide: MTD 25 mg orally on days 1 -21; dexamethasone: 40 mg on days 1, 8, 15, 22
single agent102 Ib/II 22 RRMM Carfilzomib MTD 56 mg/mq on days 1,2,8,9,15,16 every 28 days 55% combination103 I 20 RRMM Carfilzomib 20/27 on days 1, 2, 8, 9, 15 and 16 every 28-days;
ARRY-520 MTD: 1,5 mg/mq on days 1, 2, 15 and 16 every 28 days
37% combination61 I 18 RRMM Carfilzomib on days 1, 8, and 15 every 28 days (MTD at 70
mg/mq to be confirmed); dexamethasone 40 mg on days 1, 8, 15, and 22 every 28 days
67% combination104 I/II 72 RRMM Carfilzomib: MTD 20/27 mg/mq on days 1, 2, 8, 9, 15, and 16
every 28 days; pomalidomide on days 1-21; dexamethasone 40 mg on days 1, 8, 15, and 22
64% combination65 I/II 54 NDMM Carfilzomib: MTD 20/36 mg/mq on days 1,2,8,9,15 and 16 every
28 days; cyclophosphamide 300 mg/mq on days 1,8,15; thalidomide 100 mg days 1-28; dexamethasone 40 mg days 1,8,15,22.
91%
combination105 I/II 44 RRMM PAN OS three times weekly during weeks 1 and 3 of each cycle (Days 1, 3, 5, 15, 17, 19). Carfilzomib IV on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle.
64% combination62 I/II 53 NDMM Carfilzomib induction/maintenance: MTD 20/36 mg/mq on days
1,2,8,9,15 and 16 every 28 days; lenalidomide 25 mg on days 1-21, dexamethasone 40 mg on days 1,8,15,22, followed by lenalidomide alone until PD or intolerance.
98%
combination67 I/II 68 RRMM Carilzomib MTD 20/36 mg/mq on days 1,2,8,9,22,23,29,30 every 42 days, melphalan 9mg/mq, prednisone 60mg/mq days 1–4
91% combination64 II 90 NDMM Induction Carfilzomib: 20/27 (cohort 1) or 20/36 (cohort 2) or
20/45 (cohort 3) mg/mq i.v. on days 1, 2, 8, 9, 15 & 16 every 28 days, Thalidomide 200 mg days 1-28, dexamethasone 40 mg on days 1, 8, 15 & 22; Consolidation Carfilzomib 27 mg/mq (cohort 1) or 36 mg/mq (cohort 2) on days 1, 2, 8, 9, 15 and 16 every 28 days, Thalidomide 50 mg days 1-28, dexamethasone 20 mg days 1, 8, 15, 22
93% (cohorts 1 and 2)
combination106 II 24 NDMM Induction: Carfilzomib 20/45 mg/mq on days 1, 2, 8, 9, 15, 16 every 28 days, dexametahsone 40mg on days 1, 8, 15, 22; BiRd: Clarithromycin 500mg twice daily, lenalidomide 25mg on days 1-21 and dexamethasone 40mg D1, 8, 15, 22 every 28 days.
combination66 II 58 NDMM Induction: Carfilzomib : 20/36 mg/mq on days 1,2, 8, 9, 15, 16, cyclophosphamide: 300 mg/mq orally on days 1, 8, 15,
dexamethasone 40 mg orally on days 1, 8, 15, 22 every 28 days. Maintenance: Carfilzomib 36 mg/mq on days 1, 2, 15, 16 every 28 days until PD or intolerance
96%
combination107 II 41 NDMM Carfilzomib 20/36 mg/mq on days 1, 2, 8, 9, 15, 16;
Lenalidomide PO 25 mg days 1-21; dexamethasone 20/10 mg (C1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, 23 every 28 days followed by lenalidomide (10 mg on days 1-21) continuous treatment.
96%
NPI0052 MARIZOMIB
Table 3 Safety of proteasome inhibitors
DRUG PHASE PATIENTS Grade 3-4 Adverse Events
Haematologic Non Haematologic
MLN9708 IXAZOMIB
single agent32 I 60 RRMM Thrombocytopenia: 33% Neutropenia: 17%
Lymphopenia: 8% Dyarrhoea: 33% Fatigue: 8% Rash: 7%
single agent33 I 57 RRMM Thrombocytopenia: 33% Neutropenia: 14% Fatigue: 9% Rash: 7%
combination35 I/II 65 NDMM NR Rash: 5%
combination36 I/II 64 NDMM NR Rash: 16% Pneumonia: 6%
combination II 16 NDMM Thrombocytopenia: 19% Neutropenia: 31% NR
CARFILZOMI B
single agent48 I 29 RRMM Thrombocytopenia: 7% Dyspnea: 7%
single agent51 I 48 RRMM Anemia 19% Thrombocytopenia: 15% Nausea 11% Fatigue 9% single agent52 II 46 RRMM Anemia 37% Thrombocytopenia: 26%
Lymphopenia: 28% Hyponatremia: 13% Renal failure: 13% Pneumonia: 11% Fatigue 9% Dyspnea 9% single agent53 II 266 RRMM Anemia 24% Thrombocytopenia: 29%
Lymphopenia: 20% Neutropenia 11% Fatigue: 7% single agent54 II 129 RRMM Anemia 15% Thrombocytopenia: 13%
Lymphopenia: 16% Neutropenia: 13% Pneumonia: 12% single agent58 II 50 RRMM Anemia 28% Thrombocytopenia: 20%
Lymphopenia: 18% Fatigue: 14% Pneumonia: 12%
combination63 Ib/II 84 RRMM Anemia 37% Thrombocytopenia: 26%
Lymphopenia: 28% hypophosphatemia: 21% Hyponatremia: 11% Hyperglicemia: 13% single agent102 Ib/II 22 RRMM Anemia 27 % Thrombocytopenia: 27 % NR
combination61 I 18 RRMM NR G3 Creatinine increase: 11% Dyspnea: 5%
Pneumonia 5% G4 Hyponatremia xx combination104 I/II 72 RRMM Anemia 34% Thrombocytopenia: 34%
combination62 I/II 53 NDMM Anemia 21% Thrombocytopenia: 17%
Neutropenia: 17% Hypophosphatemia: 25% Rash: 8% Hyperglicemia: 23% Pulmonary embolism: 6% combination65 I/II 54 NDMM Lymphopenia: 23% Neutropenia 17% Hypertension 8% Hyperglicemia: 6% VTE: 6% combination105 I/II 44 RRMM G3 Thrombocytopenia: 30% G3-4
Neutropenia: 22% G3 Fatigue: 11% Nausea/vomiting: 9%
combination106 II 24 NDMM G4 Neutropenia: 5% Infections: 7% Cardiac 55 combination66 II 58 NDMM Anemia 37% Thrombocytopenia: 26%
Lymphopenia: 28%
combination107 II 41 NDMM Anemia 16% Thrombocytopenia: 11%
Lymphopenia: 63% Elletrolites disorders: 18% LFT increase: 13% Rash 11% Fatigue 11% Cardiovascular:8%
NPI0052 MARIZOMIB
single agent88 I 34 RRMM Anemia: 9% Thrombocytopenia: 7%
Table 4 Proteasome inhibitors in phase III trials
Drug Trial Patients Status Carfilzomib
Dose Schedule
Carfilzomib
(PR-171) 2011-003 (ENDEAVOR) (Cd vs Vd)
RRMM Recruiting. 20-56 mg/mq Arm A C: 20 mg/mq on days 1-2 of cycle 1 and 56 mg/mq on days 8,9,15,16 ; 56 mg/mq on days 1,2,8,9,15,16 from Cycle 2; D: 20 mg on days 1,2,8,9,15,16,22,23 every 28 days
Arm B: V: 1.3 mg/mq on days 1,4,8,11; D 20 mg on days 1,2,4,5,8,9,11,12 every 28 days PX-171-009 (ASPIRE) (CRd vs Rd) RRMM Ongoing, enrollment over
20-27 mg/mq Arm A C: 20/27 mg/mq on days 1,2,8,9,15,16 (cycle 1-12) and 1,2,15,16 (cycle 13-18), from cycle 19 and beyond no c); R: 25 mg on days 1-21; D: 40 mg on days 1,8,15,22 every 28 days
Arm B: ); Len: 25 mg on days 1-21; D: 40 mg on days 1,8,15,22 every 28 days PX-171-011 (FOCUS) (C vs BSC) RRMM Ongoing, enrollment over
20-27 mg/mq Arm A C: 20 mg/mq on days 1-2 of cycle 1 and 27 mg/mq on days 8,9,15,16 ; 27 mg/mq on days 1,2,8,9,15,16 from cycle 2 and 27 mg/mq 1,2,15,16 from cycle 10 every 28 days
Arm B BSC (best supportive care): Corticosteroid ± cyclophosphamide 2012-005 (CLARION) (C+ MP vs VMP)
NDMM Recruiting 20-36 mg/mq Arm A C: 20 mg/mq on days 1-2 of cycle 1 and 36 mg/mq on days 8,9,22,23,29,30 and 36 mg/mq on days 1,2, 8,9,22,23,29,30 every 42 days from cycle 2 to cycle 9.
P 60 mg/mq on days 1-4 every 42 days
Arm B V: 1.3 mg/mq on days 1,4,8,11,22,25,29,32(cycles 1-4) and 1,8,22,29(cycles 5-9). P: 60 mg/mq on days 1-4 every 42 days
E1A11
(VRd vs CRd) NDMM Recruiting NR Arm A B on days 1,4,8,11 (cycle 1-8) and 1,8 (cycle 9-12); R on days 1-14, D on days 1,2,4,5,8,9,11,12 (cycle 1-8) and 1,2,8,9(cycle 9-12) every 21 days Arm B C on days 1,2,8,9,15,16; Len on days 1-21; D on days 1,8,15,22 every 21 days
Ixazomib (MLN-9708)
C16010 (MLN-Rd vs Rd)
RRMM Recruiting 4 mg Arm A MLN9708 4.0 mg on days 1,8,15; R 25mg on days 1-21; D 40mg on days 1,8, 15 and 22 every 28 days until disease progression
Arm B Placebo on days 1,8,15 ; R 25mg on days 1-21; D 40mg on days 1,8, 15 and 22 every 28 days until disease progression
C16014 (MLN-Rd vs Rd)
NDMM Recruiting 4 mg Arm A MLN9708 4.0 mg on days 1,8,15; R 25mg on days 1-21; D 40mg on days 1,8, 15 and 22 every 28 days until disease progression
Arm B Placebo on days 1,8,15 ; R 25mg on days 1-21; D 40mg on days 1,8, 15 and 22 every 28 days until disease progression
C: carfilzomib; R: lenalidomide; D: dexamethasone; V: bortezomib; P: prednisone; M: melphalan; MLN: MLN9708; RRMM: relapsed/refractory multiple myeloma; NDMM: newly diagnosed multiple myeloma
