Carfilzomib for multiple myeloma

Approved indication: multiple myeloma
Kyprolis (Amgen)
vials containing 30 mg and 60 mg powder
Australian Medicines Handbook section 14.1.8

Carfilzomib is a new intravenous drug for multiple myeloma. It is indicated for people with relapsed or refractory disease after at least one previous therapy. It should be given in combination with dexamethasone or with lenalidomide and dexamethasone.

Like bortezomib, carfilzomib is a proteasome inhibitor. It works by interfering with the system for breaking down proteins within cells. As cancer cells are rapidly multiplying, inhibiting proteasomes causes proteins to accumulate. In in vitro and animal studies, this slows cell growth and eventually causes cell death.

The approval of carfilzomib is based on two randomised open-label trials – ASPIRE¹ and ENDEAVOR.² The trials enrolled people who had been treated with 1–3 previous therapies.

In the ASPIRE study, carfilzomib with lenalidomide and dexamethasone was compared to lenalidomide and dexamethasone alone for 18 treatment cycles. Patients who had previously progressed on bortezomib or lenalidomide with dexamethasone, or had previously discontinued lenalidomide and dexamethasone because of an adverse effect, were not allowed in the trial.¹

The progression-free survival of patients was longer when carfilzomib was added to lenalidomide and dexamethasone compared with those given lenalidomide and dexamethasone alone (26.3 vs 17.6 months, p=0.0001). Also more patients in the carfilzomib arm had at least a partial response to treatment (87.1 vs 66.7%, p<0.001) (see Table). 

Diarrhoea (42.3% vs 33.7%), thrombocytopenia (29.3% vs 22.9%), cough (28.8% vs 17.7%), fever (28.6% vs 20.8%), upper respiratory tract infection (28.6% vs 19.5%), hypokalaemia (27.6% vs 13.4%), hypertension (14.5% vs 7.5%), and headache (13.5% vs 8%) were more common with carfilzomib than with the comparator.¹

In the ENDEAVOR study, carfilzomib plus dexamethasone was compared to bortezomib plus dexamethasone. Although patients who had previously been treated with carfilzomib or bortezomib were allowed in the trial, they must have had at least a partial response to the treatment before relapse and not discontinued because of an adverse effect.²

As in the ASPIRE trial, progression-free survival was significantly longer in the carfilzomib arm compared with the comparator (18.7 vs 9.4 months, p<0.0001). Overall response rates were also higher (76.9 vs 62.6%, p<0.0001) (see Table).²

Anaemia (40.8% vs 27.6% of patients), fever (31.3% vs 14.7%), dyspnoea (30.5% vs 13.2%), hypertension (29.8% vs 9.6%), cough (26.1% vs 14.9%), muscle spasms (19.7% vs 6.1%), and bronchitis (21.4% vs 10.1%) were more frequent with carfilzomib than with bortezomib.²

Cardiac failure (7%) was reported with carfilzomib in the trials, as was myocardial infarction (2%) and myocardial ischaemia (1%). Some of these cases were fatal. Other serious and potentially life-threatening adverse events with carfilzomib include pulmonary and hepatic toxicities, pulmonary hypertension, dyspnoea, hypertension, acute renal failure, tumour lysis syndrome, infusion reactions, thrombocytopenia, posterior reversible encephalopathy syndrome and thrombotic microangiopathy. Patients need to be closely monitored during treatment and the dose of carfilzomib may need to be reduced or stopped until symptoms have resolved. Checking hydration, fluid requirements and electrolytes is important.

This drug is not recommended during pregnancy and contraception should be used during treatment. There are no data in humans but carfilzomib caused embryo-fetal toxicity in pregnant rabbits. It is not known if the drug is excreted in breast milk.

Carfilzomib is administered in 28-day cycles. An intravenous infusion is given on two consecutive days each week for three weeks followed by a 12-day rest period. After administration, carfilzomib is rapidly metabolised by peptidase cleavage and epoxide hydrolysis and the inactive metabolites are excreted in the urine. On the basis of preliminary data, interactions with other medicines are not expected.

Consider giving patients antiviral prophylaxis to prevent herpes zoster infection. Thromboprophylaxis is recommended in patients also receiving lenalidomide and dexamethasone depending on their risk.

More than 75% of pre-treated patients appeared to respond to carfilzomib when given as combination therapy. However, it is not yet known if it will extend survival. Toxicity may limit treatment and fatal reactions can occasionally occur so monitoring is paramount. 

🅃 🅃 manufacturer provided additional useful information

The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the website of the Food and Drug Administration in the USA and the European Medicines Agency.

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