CHICAGO (FRONTLINE MEDICAL NEWS) – It was nice knowing you, bortezomib, but it’s time to move aside and let carfilzomib take over: Progression-free survival of relapsed multiple myeloma was doubled with a combination of double-dose carfilzomib and dexamethasone compared with bortezomib and dexamethasone.

At a median follow-up of 11.2 months, the primary endpoint of median progression-free survival (PFS) among 464 patients assigned to receive carfilzomib (Kyprolis) and dexamethasone (Kd) was 18.7 months, compared with 9.4 months for 465 patients assigned to bortezomib (Velcade) and dexamethasone (Vd), reported Dr. Meletios Dimopoulos of the University of Athens.

“Kd was superior to Vd regardless of age or prior bortezomib exposure, and represents a new standard of care,” Dr. Dimopoulos said at the annual meeting of the American Society of Clinical Oncology.

He reported results from the phase III ENDEAVOR (A Randomized, Open-Label, Phase III Study of Carfilzomib Plus Dexamethasone vs. Bortezomib Plus Dexamethasone in Patients With Relapsed Multiple Myeloma), the first clinical study to pit two proteasome inhibitors head to head in treatment of multiple myeloma.

“It is becoming clearer that carfilzomib is superior to bortezomib, especially at twice the dose,” said Dr. Jeffrey L. Wolf of the University of California, San Francisco. Dr. Wolf was the invited discussant.

Carfilzomib is approved in the United States as single-agent therapy at a dose of 27 mg/m2 infused over 2-10 minutes with dexamethasone for treatment of patients with relapsed or refractory myeloma.

However, in a phase Ib/II study , carfilzomib administered in a 30-minute infusion at a dose of 56 mg/m2 with dexamethasone produced higher response rates with acceptable toxicities, prompting the investigators to explore the higher-dose regimen against the standard of Vd.


A total of 929 patients, stratified by prior proteasome inhibitor therapy, prior lines of treatment, International Staging System (ISS) score, and route of bortezomib administration (IV vs. subcutaneous) were randomized to either Kd or Vd (with bortezomib delivered either by IV bolus or subcutaneous injection), with both regimens to be continued until disease progression or unacceptable toxicity.

The patients had been treated with at least one but not more than three prior lines of therapy, and could have previously received a proteasome inhibitor if they had a partial response or better to prior treatment, had not been treated with a proteasome inhibitor within the last 6 months, and had not discontinued prior therapy because of toxicity.

The patients also had to have adequate cardiac function (left ventricular ejection fraction of 40% or greater) and creatinine clearance (at least 15 mL/min).

As noted before, median PFS at a median follow-up of 11.2 months was 18.7 months with Kd, vs. 9.4 months with Vd (hazard ratio [HR] 0.53, P < .0001).

PFS was superior with Kd across all subgroups of age, performance status, prior peripheral neuropathy, ISS stage, or risk category. The only exception was among patients with compromised renal function (creatinine clearance less than 30 mL/min), who had comparable PFS in each arm.

PFS was also better with Kd among patients with prior bortezomib exposure (median PFS 15.6 vs. 8.1 months) or no bortezomib exposure (median PFS not reached vs. 11.2 months).

The data are not sufficiently mature for an overall survival analysis, and the study will continue until a final OS analysis can be performed, Dr. Dimopoulos said.

For the secondary endpoint of response rates, Kd also showed superiority, with 77% of patients having some degrees of response, compared with 63% of patients assigned to Vd (P <. 0001). Patients treated with Kd had significantly more complete responses (13% vs. 6%, P < .0001) and very good partial responses (54% vs. 29%, P < .0001).

The median duration of response was 21.3 months for Kd, vs. 10.4 months for Vd (P not shown).

There were more grade 3 or greater adverse events among patients on Kd vs. Vd (73% of patients vs 67%, respectively), and more serious adverse events (48% vs. 36%), but more patients in the Vd arm required dose reduction because of side effects (23% vs. 48%), and more patients on Vd discontinued treatment because of disease progression (25% vs. 36%) or adverse events (14% vs. 16%). In all, four patients on Kd and 3 on Vd died from a cause related to an adverse event.

Rates of dyspnea, hypertension, and cardiac failure were slightly more than twice as high with Kd vs. Vd. Peripheral neuropathy was more common among patients on bortezomib, despite three-fourths of patients in this arm receiving it in the subcutaneous injection form, which has been associated with lower rates of neuropathy than with the IV form of bortezomib.

Dr. Wolf noted that the excess in peripheral neuropathy was not surprising, given that bortezomib was delivered twice weekly and that about 25% of patients received it intravenously.

He also noted that among treatment options for patients with relapsed myeloma, Kd was associated with a cost per progression-free month of about $1,222, compared with $1,059 for Vd, $859 for a combination of carfilzomib, lenalidomide (Revlimid) and dexamethasone, and $1,158 for the combination of elotuzumab, lenalidomide, and dexamethasone, used in the ELOQUENT-2 trial , also presented at ASCO 2015.

The study was sponsored by Onyx, a subsidiary of Amgen. Dr. Dimopoulos disclosed receiving honoraria from and consulting for the company. Dr. Wolf disclosed consulting with Onyx and Amgen, serving on the speakers bureau for Milennium, and receiving travel expense from Onyx Consulting and Milennium.


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