A Phase 2 Study of Prolonged Carfilzomib Therapy in Patients with Multiple Myeloma Previously Enrolled in Carfilzomib Clinical Trials.
Authors: Siegel David S. , Wang Michael , Martin Thomas G , Infante Jeffrey R. , Kaufman Jonathan L. , Ranjangam Kanya , Huang Mei , Bilotti Elizabeth , Vij Ravi 
Published: October 2019

Abstract
Abstract 2962

Background:
Carfilzomib (CFZ) is a next-generation selective proteasome inhibitor for the treatment of patients with relapsed and refractory multiple myeloma. PX-171-010 (NCT00884312) is a phase 2 extension study for patients who had previously received CFZ treatment in any phase 1 or 2 study, typically for 12–18 months. Herein we report updated safety and efficacy results for patients enrolled in this ongoing study.

Methods:
The primary endpoint was safety, and patients were also followed for efficacy. All serious adverse events (SAEs), peripheral neuropathy (PN) AEs, and AEs ≥Grade 3 were to be reported, as were any AEs resulting in dose modifications. Patients were evaluated for response every 2 cycles, although more frequent assessments were permitted per local standards of care. Investigator-assessed responses are reported here. Regimen changes consisted of the following: i) changes in CFZ dosing (increases to achieve or maintain disease control or decreases for toxicity); ii) the addition of other approved anti-MM agents at the time of confirmed or suspected progression; and iii) a combination of i) and ii). CFZ dosing could range from 11 mg/m2 to 56 mg/m2with a dose frequency of Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle or alternatively Days 1, 2, 15, and 16.

Results:
A total of 98 patients were enrolled, including 9 patients with solid tumors and 89 patients with MM. At the time of 010 enrollment, the median time since diagnosis for MM patients was 4 years (range, 1–24), and 46.1% had received prior bortezomib therapy. Overall in the safety population (N=98), patients during the 010 study started a median of 10.5 cycles (range, 1–33) of CFZ. When considering treatment during a prior CFZ study as well, total exposure to CFZ was a median of 22 cycles or 89 weeks. The CFZ regimen was changed in 60% of patients during 010; reasons included confirmed or suspected PD (43.9%), AEs (9.2%), and/or other reasons (eg, patient preference, investigator discretion; 20.2%). The median number of regimen changes was 1 (range, 0–7). The CFZ dose was increased in 25.5% of patients, and in 42%, CFZ was used in combination with other anti-MM agents, including dexamethasone (34.7%), lenalidomide (22.4%), and cyclophosphamide (17.3%). Overall, AEs were reported in 82.7% of patients, the most common being upper respiratory tract infection (17.3%), fatigue (17.3%), and anemia (16.3%). Of note, 6.1% reported PN with just 1 patient experiencing a Grade 3 event. SAEs were reported in 50% of patients, most commonly pneumonia (8.2%), influenza (6.1%), dyspnea (6.1%), pyrexia (5.1%), and acute renal failure (5.1%). Discontinuation due to an AE occurred in 11.2%, the most common reason being myocardial infarction (2%). There have been 5 deaths on study with 3 due to AEs (1 related to CFZ), events being myocardial infarction, pneumonia, and 1 pt with both myocardial infarction and pneumonia as cause of death, and 2 due to PD (1 with associated Grade 5 hypercalcemia). The table summarizes response data by CFZ regimen for patients with MM during 010 through the third regimen (at the time of abstract submission, limited response data were available for patients who received ≥4 regimens).

Conclusions:
Extended treatment with CFZ as single agent or in combination with other anti-MM therapy was well tolerated with a safety profile that was consistent with previous CFZ studies. Notably, there was no evidence of unique or late-onset cumulative toxicity. When compared to previous phase 1 and 2 CFZ trials, PN incidence continued to be low and was generally mild to moderate in severity. Similarly, and importantly, patients continued to obtain clinically meaningful responses with multiple regimen and dose changes. Taken together, the safety profile, long-term tolerability, and responses associated with extended treatment with CFZ are promising.

Disclosures:
Siegel: Millennium: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Merck: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Celgene: Advisory Boards, Advisory Boards Other, Honoraria, Speakers Bureau; Onyx Pharmaceuticals: Advisory Boards Other, Honoraria, Speakers Bureau. Off Label Use: Carfilzomib (CFZ) is a next-generation selective proteasome inhibitor that was recently approved for the treatment of patients with relapsed and refractory multiple myeloma. Wang:Onyx Pharmaceuticals: Honoraria, Research Funding. Martin:Onyx Pharmaceuticals: Consultancy; Celgene: Honoraria. Kaufman:Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millenium: Consultancy. Ranjangam:Onyx Pharmaceuticals: Employment. Huang:Onyx Pharmaceuticals: Employment. Bilotti:Celgene: Consultancy, Speakers Bureau; Onyx Therapeutics: Consultancy. Vij:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Research Funding.