Carfilzomib ^[1], a new drug similar to Velcade ^[2] (bor­tez­o­mib), has been shown to be 18 per­cent to 54 per­cent effective against multiple myeloma in re­lapsed and refractory patients, depending on the level of prior treat­ment.

Carfilzomib ther­apy has pre­vi­ously been shown to result in greater than 80 per­cent proteasome inhibition. Furthermore, car­filz­o­mib in comparison to current treat­ments presents a reduction in the occurrence of periph­eral neu­rop­athy, a painful side effect that causes pain and numbness in the hands and feet. A pre­vi­ous article ^[3] discusses how car­filz­o­mib uses proteasome inhibition to stop tumor growth.

Two ongoing Phase 2 clinical trials, as well as a few pre-clinical studies, were presented at the recent ASH conference. Phase 2 trials create standards for dosing and efficacy, and are followed by Phase 3 comparative trials before the drug enters the market. Both trials used the same 28-day treat­ment cycle, with most patients undergoing at least four cycles. In the first cycle only, each dose was preceded by dexa­meth­a­sone. Patients responded quickly to the drug, typically in the first cycle.

In the first study, Dr. Sundar Jagannath and his team enrolled 46 patients with re­lapsed and refractory multiple myeloma. All participants had pre­vi­ously failed treat­ment on Velcade and an average of five other treat­ments. Other prior treat­ments included thalidomide ^[4] (Thalomid), Revlimid ^[5] (lena­lido­mide), and stem cell trans­plan­ta­tion. Twenty-two patients started at least four cycles of car­filz­o­mib.

Of the 39 patients with measurable M-protein, 10 patients (26 per­cent) have achieved a complete response or a partial/very good response to date. An addi­tional 16 patients (41 per­cent) have achieved a stable con­di­tion.

The second study, presented by Dr. Ravi Vij, involves less heavily pre-treated patients than the Jagannath study. The 29 patients with measurable M-protein either have no prior Velcade treat­ment (45 per­cent), were responsive to Velcade for longer than six months (45 per­cent), or re­lapsed less than six months after Velcade treat­ment (10 per­cent).

The 13 patients with no pre­vi­ous exposure to Velcade had an over­all 54 per­cent response rate, with one complete response, two very good partial responses, and four partial responses; four addi­tional patients achieved stable disease. After a median follow-up of 109 days, all subjects have remained in remission.

Of 16 patients who pre­vi­ously received Velcade treat­ment, three (18 per­cent) achieved a partial response, one achieved a minimal response, and nine reached stable disease, with a median 169-day follow-up period.

Side effects were largely man­ageable. Although periph­eral neu­rop­athy is reduced in severity compared to Velcade, it remains the most common side effect of this family of drugs. In the Jagannath study, 78 per­cent of patients reported Grade 1 or 2 periph­eral neu­rop­athy at base­line. However, the symp­tom did not cause any participants to lower their dosage or dis­con­tinue the study. Strikingly, in the Vij study, most patients did not report periph­eral neu­rop­athy.

Other common side effects in both studies are fatigue and nausea. Blood-related changes include anemia (low hemoglobin levels), thrombo­cytopenia (low levels of blood platelets that help regulate blood clot formation), and neu­tro­penia (lower count of neutrophils, a type of white blood cell). Side effects unique to, but common in, the Jagannath trial have been upper res­pira­tory in­fec­tion and diarrhea. Renal health was impaired in fifteen patients (33 per­cent) to varying degrees, and seven patients (15 per­cent) dis­con­tinued treat­ment as a result of a renal adverse event or acute renal failure. Several patients in the Vij trial experienced vomiting and insomnia. Five patients showed increased creatinine over the course of the study, but only one patient stopped treat­ment due to an adverse renal event. In each study, a handful of patients (max. 2) is thought to have undergone tumor lysis, a critical event that necessitated ending treat­ment.

In comparison to Velcade, car­filz­o­mib presents a significant improvement for sufferers prone to periph­eral neu­rop­athy. Future research will combine car­filz­o­mib with other chemotherapy agents in multiple myeloma patients.

Sources: Abstracts 864 ^[6] and 865 ^[6].