bortezomib
PS-341, MLN341, LDP-341, NSC 681239, pyrazinoyl-phenylalanine-leucine boronic acid
Bortezomib is a first-in-class proteasome inhibitor licensed for multiple myeloma and mantle cell lymphoma. It is a modified dipeptide in which the terminal carboxylate has been replaced by a boronic acid group, and that boron atom is what does the work. It latches onto the catalytic threonine inside the proteasome's chymotrypsin-like site. It is one of the most thoroughly trialled anticancer agents of the past 25 years and transformed myeloma outcomes.
Mechanism
Bortezomib is a slowly reversible inhibitor of the chymotrypsin-like (β5/PSMB5) catalytic activity of the 26S proteasome, the multi-subunit protease that degrades the great majority of intracellular proteins tagged with polyubiquitin. The boronic acid moiety forms a tetrahedral adduct with the hydroxyl group of the N-terminal threonine (Thr1) in the β5 active site. Dissociation is slow (the reported proteasome-binding half-life is of the order of 110 minutes), which is why weekly or twice-weekly dosing produces sustained pharmacodynamic inhibition despite complex plasma kinetics. Selectivity is good but not absolute: the boronate also engages some serine proteases (HtrA2/Omi, cathepsin A and cathepsin G have been implicated), which is one leading explanation for the neuropathy that does not accompany the epoxyketone inhibitors.
Downstream, proteasome blockade produces a cascade of effects that malignant plasma cells tolerate especially badly. Polyubiquitinated proteins accumulate, generating proteotoxic stress and a terminal unfolded protein response through the IRE1/XBP1 and PERK/ATF4/CHOP arms. IκBα is stabilised, so NF-κB cannot be released to the nucleus, cutting off transcription of survival, adhesion and cytokine genes including IL-6. Pro-apoptotic proteins normally kept at low abundance by proteasomal turnover (p53, p21, p27, NOXA, BIM) accumulate. Myeloma cells are unusually vulnerable because they synthesise immunoglobulin at extraordinary rates and therefore run near the ceiling of their proteasomal capacity already. Bortezomib additionally disrupts myeloma-stroma adhesion in the marrow microenvironment, inhibits angiogenesis, and has a favourable effect on bone, inhibiting osteoclastogenesis via RANKL/NF-κB while promoting osteoblast differentiation through Runx2.
What the research shows
The SUMMIT phase 2 study in 202 patients with heavily pre-treated relapsed and refractory myeloma reported a 35% response rate with 4% complete responses (remarkable in a population with a median of six prior lines) and median overall survival of 16 months, leading directly to accelerated approval. The confirmatory APEX phase 3 trial randomised 669 patients with one to three prior therapies to bortezomib or high-dose dexamethasone; median time to progression was 6.22 versus 3.49 months, response rate 38% versus 18%, and one-year survival 80% versus 66%, with the trial stopped early at interim analysis. VISTA then moved the drug into first-line use in transplant-ineligible patients, adding bortezomib to melphalan and prednisone in 682 patients: median time to progression 24.0 versus 16.6 months, partial response or better 71% versus 35%, complete response 30% versus 4%, and a significant overall survival benefit that persisted on long-term follow-up.
The evidence is not uniformly positive and the negatives are informative. Peripheral neuropathy in the intravenous trials affected roughly 35-40% of patients and was frequently treatment-limiting; a randomised non-inferiority study of subcutaneous versus intravenous administration in 222 patients found equivalent response rates (42% in both arms) with any-grade neuropathy falling from 53% to 38% and grade 3 or worse from 16% to 6%, and subcutaneous dosing is now the default. More strikingly, bortezomib has repeatedly failed outside plasma cell and lymphoid disease. Phase 2 and phase 3 studies in non-small-cell lung cancer, ovarian, renal, pancreatic, head and neck and colorectal cancer, and in melanoma, showed little or no single-agent activity and no benefit when added to chemotherapy, a reminder that proteasome dependence is a property of the secretory plasma cell phenotype rather than a general feature of malignancy. In myelodysplastic syndrome and in amyloid light-chain amyloidosis, results have been more encouraging, and bortezomib-containing regimens are now widely used in AL amyloidosis and in antibody-mediated transplant rejection off licence.
Evidence assessment
High-quality evidence
Approved labelling in the US, EU and UK, supported by multiple randomised phase 3 trials with replicated benefit (APEX in relapsed disease, VISTA in transplant-ineligible newly diagnosed disease, the latter with an overall survival advantage), plus a randomised route-of-administration study that changed practice worldwide. All four cited trials were individually verified against PubMed. Generic products are now widely available and the drug is standard of care.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
A phase 2 study of bortezomib in relapsed, refractory myeloma Preclinical only
Overall response rate 35% including 4% complete responses in a population with a median of six prior lines of therapy; median overall survival 16 months. Formed the basis for FDA accelerated approval.
Bortezomib or high-dose dexamethasone for relapsed multiple myeloma Preclinical only
Median time to progression 6.22 months with bortezomib versus 3.49 months with high-dose dexamethasone (HR 0.55); response rate 38% versus 18%; one-year survival 80% versus 66%. Stopped early at interim analysis for superiority.
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma Preclinical only
Median time to progression 24.0 versus 16.6 months, partial response or better 71% versus 35% and complete response 30% versus 4% when bortezomib was added to melphalan and prednisone; significant overall survival benefit. Established proteasome inhibition in first-line therapy.
Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study Preclinical only
Equivalent overall response rate (42% in both arms) with markedly less toxicity: any-grade peripheral neuropathy 38% versus 53% and grade 3 or worse 6% versus 16%. Changed standard administration route worldwide.
Safety
Peripheral sensory neuropathy is the signature toxicity, often painful, dose-dependent and cumulative; subcutaneous administration and weekly scheduling substantially reduce it, and it is partially reversible on dose reduction or discontinuation. Thrombocytopenia is cyclical, with a nadir around day 11 of each cycle and recovery between cycles, and reflects impaired platelet budding from megakaryocytes rather than marrow destruction. Neutropenia, anaemia, fatigue, nausea, diarrhoea and constipation are common. Herpes zoster reactivation is frequent enough that antiviral prophylaxis is standard practice. Hypotension, including orthostatic and syncopal episodes, occurs in a minority. Less common but serious events include cardiac failure and conduction abnormalities, acute diffuse infiltrative pulmonary disease and ARDS, posterior reversible encephalopathy syndrome, hepatic failure, thrombotic microangiopathy and tumour lysis syndrome. There is a strict warning that bortezomib must never be given intrathecally. Such errors have been fatal. As a CYP3A4 substrate it interacts with strong inducers and inhibitors, and concurrent use with certain drugs requires care.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | EU marketing authorisation granted April 2004; licensed in Great Britain by the MHRA and available as both originator and generic products. Recommended by NICE within specific multiple myeloma treatment lines. The applicable appraisal depends on line of therapy and should be checked against current NICE guidance. Prescription-only medicine, restricted to specialist haemato-oncology use. |
| United States | FDA accelerated approval May 2003 for relapsed/refractory multiple myeloma after at least two prior therapies; converted to regular approval and progressively expanded (2005 for relapsed myeloma after one prior therapy, 2006 for mantle cell lymphoma after one prior therapy, 2008 for previously untreated myeloma, 2014 for previously untreated mantle cell lymphoma). Prescription-only injectable; multiple generics now approved. Contraindicated for intrathecal administration: intrathecal dosing has been fatal. |
| WADA (sport) | Not listed on the WADA Prohibited List. It has no anabolic, hormonal or performance-enhancing profile and is not a masking agent. No therapeutic use exemption is required on prohibited-list grounds, though any athlete receiving it would be under active cancer treatment. |
Questions
Not in the usual sense. It is a peptidomimetic: a modified dipeptide of phenylalanine and a leucine analogue, capped with a pyrazine ring, in which the terminal carboxylic acid has been swapped for a boronic acid. Only two amide bonds link amino-acid-derived units, so it does not have a conventional peptide sequence, and the boron atom that drives its activity is not something you find in natural peptides at all.
Myeloma cells are professional antibody factories, secreting immunoglobulin at rates that already stretch their protein quality-control machinery to its limit. Blocking the proteasome tips them over into terminal proteotoxic stress. Most solid tumour cells have far more spare capacity, and repeated trials in lung, ovarian, renal, pancreatic and colorectal cancer found essentially no benefit.
A randomised non-inferiority trial published in 2011 found that subcutaneous administration achieved the same response rate as intravenous injection (42% in both arms) while cutting grade 3 or worse peripheral neuropathy from 16% to 6%. Since neuropathy was the main reason patients had to stop treatment, the subcutaneous route became the default.
All three hit the same β5 site of the proteasome, but the chemistry differs. Bortezomib and ixazomib are boronic acids and bind reversibly; carfilzomib is an epoxyketone and binds irreversibly. That difference maps onto the side effect profiles: carfilzomib causes much less neuropathy but more cardiovascular toxicity, while ixazomib is orally active with a very long plasma half-life.
No. It has no anabolic, hormonal or masking properties and is not listed in any WADA category. It is a cytotoxic anticancer drug used under specialist supervision.