ORLANDO, Fla.—Treatment with single-agent carfilzomib achieved durable responses in patients with relapsed/refractory multiple myeloma whose disease had relapsed after they received all available therapies (including bortezomib and immunomodulatory agents), suggesting that this agent has the potential to offer substantial clinical benefit.
Results of the open-label, single-arm phase 2b trial also found carfilzomib to be well tolerated. Adverse events (AEs) were manageable, no new or unexpected toxicities were observed, and, importantly, exacerbation of preexisting peripheral neuropathy was uncommon. Lack of cumulative AEs allow prolonged single-agent dosing for chronic-disease control, said David Samuel diCapua Siegel, MD, PhD, of John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, N.J.
Carfilzomib, a novel and highly selective epoxyketone proteasome inhibitor, is currently in clinical development for treatment of multiple myeloma. Phase 1 and 2 studies have demonstrated durable single-agent antitumor activity in those with relapsed or refractory disease.
The study enrolled 266 patients with multiply relapsed multiple myeloma whose disease was refractory to the most recent prior treatment regimen. Refractory was defined as having <25% response on therapy or progression during or <60 days after completion of therapy. Eligibility included receipt of ≥2 prior therapies, including 1) bortezomib and either thalidomide or lenalidomide; and 2) an alkylating agent, Dr. diCapua Siegel said in an oral presentation during the 52nd American Society of Hematology Annual Meeting and Exposition.
Patients received carfilzomib 20 mg/m2 on a QDx2 schedule (days 1, 2, 8, 9, 15, 16) for 28 days in cycle 1 and were dose escalated to carfilzomib 27 mg/m2 on the same schedule thereafter for up to 12 cycles; those completing 12 cycles were eligible to enter an extension study. Primary end point was overall response rate (ORR) (≥ partial response [PR]). Secondary end points included clinical benefit response (CBR) (ORR + minimal response [MR]), duration of response for ≥PR and ≥MR (DOR), overall survival, time to progression, progression free survival, and safety. Responses and progression were determined according to International Myeloma Working Group criteria and were assessed and confirmed by an Independent Response Committee.
Median duration of multiple myeloma was 5.4 years, including 83% of patients whose disease had progressed on or within 60 days of their last therapy and 17% whose disease had achieved <25% response to the regimen immediately preceding study entry. Of 266 patients enrolled, 257 were evaluable for response; 9 patients were considered not evaluable based on missing baseline or lacking at least one post-baseline M-protein. Patients were heavily pretreated, receiving a median of 5 prior lines of therapy (range, 1-20; median of 13 antimyeloma agents); 82% had received ≥4 lines of prior therapy. Prior antimyeloma agents included 99.6% (265/266 patients) bortezomib (median 2 prior regimens containing bortezomib), 100% either thalidomide (75%) or lenalidomide (94%), 98% corticosteroids, 93% alkylating agents, 74% stem cell transplant, and 64% anthracyclines; 73% were refractory to bortezomib and 15% were not refractory but intolerant to bortezomib.
An ORR (≥PR) of 24.1% was determined, the CBR (ORR + MR) was 34.2%. Responses are detailed in Table 1.Please click here for more study data. Median DOR of patients was 8.3 months. An additional 32% (83 patients) achieved stable disease (SD) for at least 6 weeks. To date, 16% have completed all 12 cycles of protocol-specified therapy, and most have entered the extension protocol.
The most common (≥5%) treatment-emergent AEs grade 3/4 regardless of relationship to study drug were predominantly hematologic and included thrombocytopenia (27%), anemia (22%), lymphopenia (18%), neutropenia (10%), fatigue (7.1%). Peripheral neuropathy occurred in 0.8% (2/257) patients.
Although 206 patients (77%) had grade 1/2 peripheral neuropathy at baseline, new-onset peripheral neuropathy was infrequent, with grade ≥3 occurring in 0.97%. A subset analysis demonstrated that peripheral neuropathy had no impact on depth or durability of responses or on tolerability of carfilzomib in this patient population, Thomas Martin, MD, of the University of San Francisco, San Francisco, Calif., and colleagues reported in a poster presentation. Reports of new or worsening peripheral neuropathy were very uncommon, and paresthesias and dysesthesia were generally infrequent and mild.
During the study, peripheral neuropathy data were collected for all patients, including neuropathy history, neurological physical exam, and peripheral neuropathy-related quality of life data (FACT-GOG/NTx v 4.0 scores) at screening. Prospective neurological exams and subjective reporting of peripheral neuropathy occurred every 2 cycles until study discontinuation. AEs reported as “neuropathy peripheral,” “neuropathic pain,” “neuropathy,” and “peripheral sensory neuropathy” were included as peripheral neuropathy; AE reports of “paraesthesias” and “dysesthesias” were counted separately.
Of 266 patients enrolled, 206 (89%) had a history of peripheral neuropathy attributable to prior antimyeloma therapy, including thalidomide in 108 patients (41%), bortezomib in 134 (50%), or both bortezomib and thalidomide in 17 (6.4%). Median disease duration was 5.9 years. Those with active peripheral neuropathy at baseline had received a median of 5 prior lines of therapy (range, 1-20), with a median of 13 antimyeloma agents, including a median of 2 prior bortezomib- and 1 prior thalidomide-containing regimens. Prior therapies included 100% bortezomib, and 100% either thalidomide (77%) or lenalidomide (95%).
Responses in the subset of evaluable patients (n=202) with baseline peripheral neuropathy were nearly identical to those seen in the full study population, with an ORR (≥PR) of 23.7% and a CBR (≥MR) of 33.7%. Please click here for more study data.
The investigators concluded that carfilzomib can be given to patients with baseline peripheral neuropathy with little risk of exacerbation.