Bortezomib

Velcade, PS-341, MG-341, LDP-341

Oncology & imaging

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Note on this profile. Bortezomib is an approved chemotherapy drug for multiple myeloma and mantle cell lymphoma, given in hospital or clinic. It is "peptide-based" — a modified dipeptide with a boron atom where the next amino acid would be — rather than a peptide in the usual sense. It has no self-directed or community use and is dangerous outside oncology supervision. This page explains the published science.

Summary

Class: Dipeptidyl boronic acid: pyrazinoic acid–phenylalanine–leucine-boronic acid (a modified dipeptide, molecular weight 384); the first proteasome inhibitor approved for any disease
Mechanism: The boron atom reversibly binds the active site of the 26S proteasome (mainly the β5 "chymotrypsin-like" subunit), stopping cells from disposing of unwanted proteins; myeloma cells, which make huge amounts of antibody protein, cannot cope and die
Routes studied: Intravenous bolus and subcutaneous injection (both approved); oral is not possible (ixazomib is the oral successor)
Half-life: 40–193 h after repeated dosing (long, multi-compartment); proteasome activity recovers within ~72 h of each dose, which sets the schedule
Storage: Unopened 3.5 mg vials at room temperature, protected from light. Reconstituted (1 mg/mL IV or 2.5 mg/mL SC) used within 8 h, of which no more than 3 h in a syringe at room temperature; longer refrigerated per local pharmacy rules
Regulatory status: Approved medicine worldwide (US 2003, EU 2004); generics available

Doses are as reported in studies or by the community — never recommendations.

1What it is

Bortezomib came out of academic work in the 1990s on the proteasome — the cell's protein shredder — by Alfred Goldberg's lab at Harvard and the start-up it spawned (Myogenics, later ProScript). Of hundreds of peptide aldehydes and boronic acids tested, PS-341 was chosen for potency and selectivity. It is a two-amino-acid chain (phenylalanine–leucine) capped at one end with pyrazine-carboxylic acid and at the other with boronic acid instead of a carboxyl group; the boron forms a tight but reversible bond with a threonine in the proteasome's catalytic pocket. Millennium Pharmaceuticals (now Takeda) developed it, and the FDA granted accelerated approval in May 2003 for relapsed myeloma after two prior therapies — the fastest oncology approval of its time — followed by full approval in 2005, mantle cell lymphoma in 2006, first-line myeloma in 2008 and dosing in 2012.

Together with thalidomide-class drugs, it roughly doubled median survival in myeloma. It is included on this site because it is one of the most important peptide-derived drugs ever made, and because the proteasome mechanism comes up in longevity and protein-homeostasis discussions; it is not a research or community compound.

2How it's thought to work

The 26S proteasome degrades proteins tagged with ubiquitin, including regulators of the cell cycle and IκB, the brake on the survival transcription factor NF-κB. Blocking it causes misfolded and regulatory proteins to pile up.

Plasma cells and myeloma cells secrete enormous amounts of immunoglobulin and depend on the proteasome and the "unfolded protein response" to survive; inhibition tips them into endoplasmic-reticulum stress and apoptosis faster than normal cells.

Stabilising IκB keeps NF-κB switched off, reducing survival signals, cytokine production (IL-6) and adhesion in the bone marrow microenvironment; it also sensitises cells to other chemotherapy and steroids.

Bortezomib is reversible and selective for β5 (and β1 at higher concentrations); carfilzomib, the second-generation drug, is irreversible and causes less neuropathy but more cardiovascular toxicity.

The neuropathy is thought to arise from proteasome inhibition in dorsal root ganglion neurons and from off-target effects on mitochondria and HtrA2/Omi; dosing lowers peak levels and halves the rate of severe neuropathy without losing efficacy.

A proteasome inhibitor: the barrel that destroys tagged proteins is held shut. Damaged and regulatory proteins accumulate until the cell cannot cope, which myeloma cells — already making vast quantities of antibody — reach sooner than normal cells.Schematic — not to scale

3What the research shows

Relapsed multiple myeloma

SUMMIT (Phase 2, n=202) showed responses in about 35% of heavily pre-treated patients, which earned accelerated approval (Richardson 2003, NEJM). APEX (Phase 3, n=669) found bortezomib superior to high-dose dexamethasone: time to progression 6.2 vs 3.5 months and one-year survival 80% vs 66% (Richardson 2005, NEJM). [2][3]

Newly diagnosed myeloma not eligible for transplant

VISTA (n=682) added bortezomib to melphalan–prednisone (VMP) and improved time to progression (24 vs 16.6 months) and overall survival (median 56 vs 43 months at long-term follow-up) (San Miguel 2008, NEJM; San Miguel 2013, J Clin Oncol). [4]

Induction before transplant and in combination regimens

Multiple Phase 3 trials showed bortezomib-based induction (with thalidomide or lenalidomide and dexamethasone — VTD, VRd) deepens response and prolongs progression-free survival (Cavo 2010, Lancet; Durie 2017, Lancet — SWOG S0777: VRd vs Rd, overall survival benefit). Bortezomib remains the backbone of quadruplets with daratumumab (Moreau 2019, Lancet — CASSIOPEIA; Sonneveld 2024, NEJM — PERSEUS). [8]

Subcutaneous vs intravenous

A Phase 3 non-inferiority trial (n=222) showed equal efficacy with grade ≥3 peripheral neuropathy falling from 16% to 6% and any-grade from 53% to 38% with the route (Moreau 2011, Lancet Oncol). Subcutaneous dosing is now standard. [5]

Mantle cell lymphoma

PINNACLE (Phase 2, n=155) showed a 33% response rate in relapsed disease (Fisher 2006, J Clin Oncol); LYM-3002 (n=487) showed that replacing vincristine with bortezomib in R-CHOP (VR-CAP) improved progression-free survival in untreated patients (Robak 2015, NEJM). [6][7]

Graded B/A

AL amyloidosis, antibody-mediated rejection, Waldenström, lupus

Bortezomib-based regimens are standard in AL amyloidosis (ANDROMEDA trial with daratumumab, Kastritis 2021, NEJM); used off-label with mixed results to deplete plasma cells in transplant rejection and refractory autoimmune disease.

Community / self-directed use

None documented.

4Reported side effects and interactions

Literature-reported

Peripheral neuropathy (sensory, painful; dose-limiting in up to a third with IV twice-weekly dosing, less with or weekly dosing; partially reversible in most); thrombocytopenia that cycles with each treatment course (nadir around day 11, recovery by the next cycle) and neutropenia; nausea, diarrhoea, constipation, loss of appetite; fatigue and fever; orthostatic hypotension; herpes zoster reactivation (around 13% without prophylaxis — antiviral prophylaxis is standard); rare but serious: heart failure and arrhythmias, acute lung injury, posterior reversible encephalopathy syndrome, tumour-lysis syndrome, hepatotoxicity, thrombotic microangiopathy. Intrathecal administration has been fatal and must never occur.

Community-reported

none; no community use.

Theoretical / notable laboratory finding. the green-tea polyphenol EGCG and ascorbic acid (vitamin C) bind the boronic acid group and inactivate bortezomib in cell culture (Golden 2009, Blood; Perrone 2009, Leukemia); whether dietary amounts matter in patients is unproven, but oncology teams generally advise avoiding high-dose green-tea extracts and vitamin C supplements around dosing.

Interactions. metabolised by CYP3A4 and CYP2C19 — strong CYP3A4 inhibitors (ketoconazole, ritonavir) raise exposure and strong inducers (rifampicin, carbamazepine, St John's wort) lower it; additive neuropathy with thalidomide and other neurotoxic drugs; oral hypoglycaemics may need adjustment (both hypo- and hyperglycaemia reported).

Markers researchers commonly monitor

These follow the label and myeloma practice:

Marker	Why it's watched
Full blood count before each dose	platelets fall in a predictable cycle; dosing is held if platelets <25,000/µL or neutrophils <0.75 × 10⁹/L.
Neuropathy grading (symptoms, pin-prick, vibration) at each visit	the dose-limiting toxicity; grade 2 with pain or grade 3 prompts dose reduction or stopping.
Serum and urine paraprotein (M-protein, serum free light chains)	the disease-response markers in myeloma.
Creatinine, uric acid, potassium, phosphate, calcium	tumour-lysis risk at the start of treatment and renal involvement in myeloma.
Blood pressure, including standing	orthostatic hypotension is reported.
Liver enzymes	hepatotoxicity; dose reduced in hepatic impairment.
Fasting glucose in diabetics	glycaemic swings are reported, partly from co-administered dexamethasone.
Varicella-zoster prophylaxis compliance	a process measure rather than a lab, but a key safety point.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Cytotoxic drug handled in a hospital pharmacy with chemotherapy precautions. The 3.5 mg vial is with 3.5 mL of 0.9% saline for IV use (1 mg/mL) or 1.4 mL for use (2.5 mg/mL); the concentrations are different and the route and concentration must be written on the syringe because confusion has caused serious errors. Given as a 3–5 second IV push or subcutaneous injection into the thigh or abdomen, rotating sites, at least 72 h between doses. Use within 8 h of reconstitution. The site calculator is not applicable.

6Commonly studied alongside

Dexamethasone (nearly always), lenalidomide, thalidomide, pomalidomide, cyclophosphamide, melphalan, doxorubicin, daratumumab and isatuximab in myeloma regimens; rituximab-based chemotherapy in lymphoma; carfilzomib and ixazomib as successor proteasome inhibitors. No peptide-community pairings; it has nothing to do with the recovery or metabolic peptides on this site.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	FDA-approved (Velcade, May 2003 accelerated; full 2005) for multiple myeloma and mantle cell lymphoma, IV and subcutaneous; multiple generics since 2022
European Union	EMA-authorised (Velcade, April 2004) for multiple myeloma (relapsed, and untreated in combination) and untreated mantle cell lymphoma (with R-CAP); generics authorised
United Kingdom	MHRA-licensed; NICE-recommended in several myeloma lines
Australia	TGA-registered (Velcade and generics); PBS-listed for myeloma
South Africa	Registered with SAHPRA (Velcade and generics) †
Sport	Not prohibited by WADA

8Open questions

Whether bortezomib's place in frontline myeloma will be taken by carfilzomib or by proteasome-inhibitor-free regimens as CAR-T and bispecific antibodies move earlier.
Mechanism and prevention of neuropathy; no proven neuroprotectant exists.
Clinical relevance of the EGCG/vitamin C interaction seen .

9References

1Adams J et al. (1999). Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. PubMed
2Richardson PG et al. (2003). A phase 2 study of bortezomib in relapsed, refractory myeloma (SUMMIT). NEJM. PubMed · DOI
3Richardson PG et al. (2005). Bortezomib or high-dose dexamethasone for relapsed multiple myeloma (APEX). NEJM. PubMed · DOI
4San Miguel JF et al. (2008). Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma (VISTA). NEJM. PubMed
5Moreau P et al. (2011). Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. PubMed · DOI
6Fisher RI et al. (2006). Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma (PINNACLE). J Clin Oncol. PubMed · DOI
7Robak T et al. (2015). Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma (LYM-3002). NEJM. PubMed · DOI
8Durie BGM et al. (2017). Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777). Lancet. PubMed · DOI
9Golden EB et al. (2009). Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood. PubMed · DOI
10Velcade (bortezomib) US prescribing information and EU Summary of Product Characteristics (current). PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

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11Page history

30 Oct 2026Profile published — awaiting medical review

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