Velcade (Bortezomib)

Velcade (bortezomib) is the first-line treatment for multiple myeloma and mantle cell lymphoma. It is an intravenous injection that belongs to a class of treatments called proteasome inhibitors. The therapy was co-developed by Millenium Pharmaceuticals, now a subsidiary of Takeda, and Janssen.

How does Velcade work?

Bortezomib is a small molecule that inhibits the activity of the 26S proteasomes, which are large protein complexes that degrade or break down proteins that are marked by the body’s cellular machinery for destruction. This includes abnormal or misfolded proteins as well as aged or damaged cellular compartments. This process is required for recycling components in the cells and for maintaining the functional integrity of the cells. Thus, inhibiting the function of the 26S proteasomes is toxic for cells and leads to their death.

Malignant myeloma cells are more dependent on the 26S proteasomes than normal cells. Therefore, blocking the 26S proteasome will have a bigger effect on myeloma cells compared with healthy cells.

Velcade in clinical trials

A multicenter, open-label, non-randomized, Phase 2 study called SUMMIT analyzed the safety and efficacy of Velcade in 202 patients with relapsed or refractory myeloma. The participants received eight cycles of 1.3 mg of Velcade per square meter of body surface area, twice weekly for two weeks, followed by one week without treatment. Patients with progressive disease after two cycles, or stable disease after four cycles, received 20 mg per day of oral dexamethasone — a synthetic adrenocortical steroid — on the day of and the day after Velcade administration in the subsequent cycles.

The results of that study were published in the New England Journal of Medicine. The overall response rate (ORR), as evaluated according to the European group for blood and marrow transplantation (EBMT) criteria, was 35% for Velcade and 50% for Velcade plus dexamethasone. The regimen was well-tolerated by the participants. The main adverse events included thrombocytopenia (low platelet counts), fatigue, neutropenia (low neutrophil counts), and peripheral neuropathy, or weakness and numbness in the hands and feet.

This was followed by another Phase 2 open-label study called CREST, conducted in 54 patients with relapsed or refractory myeloma. These participants received 1 or 1.3 mg per square meter of body surface area of Velcade twice weekly for two weeks for a maximum of eight cycles. Those with progressive disease received 20 mg of oral dexamethasone after two cycles, while those with stable disease were given 20 mg of the steroid after four cycles. The complete response (CR) plus partial response (PR) rate was evaluated according to the EGMT criteria.

Published in the British Journal of Hematology, those results  showed that the CR+PR rates were 30% and 38% for the 1 and 1.3 mg per square meter doses of Velcade alone. The CR+PR rates for patients treated with Velcade plus dexamethasone were 37% and 50% for the 1 and 1.3 mg per square meter doses of Velcade.

An international, multi-center, randomized, open-label, Phase 3 study (NCT00048230) called APEX compared the safety and efficacy of Velcade with high-dose dexamethasone (40 mg) in 669 patients with multiple myeloma who relapsed after one or more therapies. Participants received 1.3 mg per square meter of body surface area of Velcade on days 1, 4, 8, and 11 for eight cycles. This was followed by treatment on days 1, 8, 15, and 22 for three cycles, or high-dose oral dexamethasone on days 1-4, 9-12, and 17-20 for four cycles, with subsequent treatment on days 1 through 4 for five cycles. Those participants who were assigned to receive dexamethasone were permitted to cross over to receive Velcade in a companion study after disease progression.

The results of this study were published in the New England Journal of Medicine. Patients treated with Velcade showed a combined complete and partial response rate of 38% compared with 18% with dexamethasone. The median time for cancer progression was 189 days after treatment with Velcade compared with 106 days with dexamethasone. The one-year survival rate was 80% for those treated with Velcade compared with 66% for those treated with dexamethasone.

Therefore, this study clearly established the superior efficacy of Velcade over dexamethasone for the treatment of relapsed and refractory multiple myeloma.

Based on these data, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Velcade in 2003 as a single agent for the treatment of patients with multiple myeloma after two prior therapies and progressing on their most recent therapy.

Velcade now is part of several combination therapies for patients with myeloma. These include:

  • Velcade plus dexamethasone as an initial therapy regimen both for myeloma patients who are eligible for high-dose chemotherapy and stem cell transplant and those who are not
  • Velcade plus Revlimid (lenalidomide) plus dexamethasone — known as VRD — as a frontline therapy for newly diagnosed, relapsed, and refractory myeloma patients, including those at high-risk
  • Velcade plus Cytoxan (cyclophosphamide) plus dexamethasone — called CyBorD or VCD — as a frontline therapy in myeloma patients eligible for transplant
  • Velcade plus Adriamycin (doxorubicin) as a treatment for relapsed and refractory myeloma patients who have not previously received Velcade and who have received at least one prior therapy
  • Velcade as a monotherapy for maintenance following stem cell transplants to reduce the risk of relapse and extend survival
  • Velcade plus Farydak (panobinostat) plus dexamethasone as a therapy to treat patients with myeloma who have received at least two other treatments, including Velcade plus immunomodulatory agents such as Revlimid, Thalomid (thalidomide) or Pomalyst (pomalidomide)
  • Velcade re-treatment for previously treated myeloma patients whose disease has relapsed or become refractory

Several other Velcade combination therapies are being evaluated in ongoing clinical trials for the treatment of myeloma. Some Phase 3 trials being tested for newly diagnosed myeloma patients include:

  • a trial (NCT03652064) comparing the efficacy of Darzalex (daratumumab), Velcade, Revlimid, and dexamethasone (D-VRd) with that of Velcade, Revlimid, and dexamethasone (VRd)
  • the IMROZ trial (NCT03319667), studying the efficacy of a combination therapy regimen that includes Velcade, Revlimid, the investigational isatuximab, and dexamethasone
  • a trial (NCT01863550) comparing the effect of Velcade plus Revlimid plus dexamethasone with that of Kyprolis (carfilzomib) plus Revlimid plus dexamethasone

Some of the Phase 3 trials testing the efficacy of Velcade combination therapies for relapsed and/or refractory myeloma include:

  • the BOSTON trial (NCT03110562) testing the effect of Velcade plus low-dose dexamethasone plus Xpovio (selinexor)
  • the OPTIMISMM trial (NCT01734928) testing the effect of Velcade plus low-dose dexamethasone plus Pomalyst

Other details

The most common side effects of Velcade include fatigue and weakness, gastrointestinal disturbances including nausea, vomiting, diarrhea, and constipation, peripheral neuropathy, thrombocytopenia, and neutropenia.


Last updated: Nov. 13, 2019


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