A Phase I Study of Carfilzomib and Pegylated Liposomal Doxorubicin for Relapsed or Refractory Multiple Myeloma
Authors: Keller Jesse , Fiala Mark A , Sekhar Jeevan , Ceriotti Connie , Allen Melissa , Abboud Camille N. , Stockerl-Goldstein Keith E. , Wildes Tanya M , Tomasson Michael H. , Vij Ravi 
Published: October 2019

Background: Despite improvements in overall survival (OS) and progression free survival (PFS), the prognosis of patients with relapsed/refractory multiple myeloma (RRMM) remains poor. Carfilzomib (CFZ), a second generation proteasome inhibitor, is active as a single-agent or in combination with lenalidomide and/or dexamethasone (DEX) in RRMM. Pegylated liposomal doxorubicin (PLD) combined with bortezomib has been shown to prolong PFS and OS and is FDA approved as combination therapy in MM. We investigated the combination of CFZ with PLD in RRMM in a Phase I study.

Objective: To determine the maximum tolerated dose (MTD) of CFZ combined with PLD.

Patient/Methods: Patients with RRMM after ≥ 1 lines of therapy, with measureable disease, and good performance status, organ function and hematological reserve were eligible. Prior CFZ or PLD/doxorubicin exposure was not exclusionary.

CFZ was given on days 1, 2, 8, 9, 15 and 16 at escalating doses of 27-56mg/m2 and PLD was given on day 8 in 28 day cycles at a dose of 30mg/m2. All dose levels included a lead-in dose of 20mg/m2 of CFZ on days 1 and 2 of cycle 1. Following 6 cycles of combination therapy, PLD was discontinued and patients were treated with maintenance CFZ (once weekly).

Dose escalation was performed using a 3+3 design; MTD was defined as the highest dose level where dose limiting toxicity (DLT) occurred in less than 2 of 6 patients. Disease response was determined using International Myeloma Working Group (IMWG) criteria.

Results: 16 patients were enrolled from May 2012-March 2014. Median age was 66 years (range 53-79) and 11 were female. Seven patients were ISS stage 3, 9 were stage 1. 3 patients had > 50% plasma cells present on bone marrow aspirate, 8 had < 20%. By mSMART criteria, 2 patients were high-risk, 2 were intermediate-risk, and 12 were standard-risk. Most patients were IgG Kappa subtype (12); while 3 patients had Kappa light chain subtype, and 1 had IgG Lambda subtype.

Median number of prior therapies was 3 (range 1-12). Median time from diagnosis to start of protocol was 42 months (range 9-236). 100% had prior exposure to lenalidomide; 87.5% had prior exposure to bortezomib; 75% had undergone autologous transplantation; 6% had prior PLD or doxorubicin exposure; and 6% had prior CFZ exposure.

No DLTs were observed in any cohort. Two patients were unable to complete the first cycle of treatment due to early progressive disease, and were replaced. Grade 3/4 non-hematologic adverse events were rare, but included: UTIs (3), sepsis (2), pneumonitis (2), dyspnea (2), syncope (1), pleural effusion (1).

Grade 3/4 hematologic AEs were limited to: anemia (7), thrombocytopenia (4), neutropenia (5), lymphopenia (4), and hemolysis (2). Most of the neutropenia (60%) and thrombocytopenia (75%) occurred in the 56mg/m2 cohort.

The median number of cycles completed was 3.5 (range <1-13). Disease progression caused discontinuation in 10 patients. Adverse events were the reason for 2; one patient had dyspnea after 2 cycles, one patient had hand-foot syndrome after 3 cycles. Four patients were on treatment at time of submission.

56% of patients had a partial response or better, including 80% treated at the maximum dose level. The median duration of response was 6.9 months. Individual patient responses are summarized in Table 1.

Conclusion: Co-administration of CFZ and PLD is well tolerated and an MTD was not reached despite utilizing the approved single agent doses. Recommended dosage for further studies is: CFZ 56mg/m2 and PLD 30mg/m2. Subsequent phase I dose escalation of a 3 drug regimen CDD (CFZ-PLD-DEX) is ongoing at abstract submission and will be reported at the meeting.

Table 1 ID Dose Level (CFZ;PLD) # of Prior Lines of Therapy Prior ASCT # of Cycles Best Response$ PFS (months) 1 1 (27mg/m2;30mg/m2) 3 Y 7 PR 6.2 2 1 (27mg/m2;30mg/m2) 7 N 7 SD 6.7 3 1 (27mg/m2;30mg/m2) 3 N 3 SD 1.8 4 2 (36mg/m2;30mg/m2) 4 Y 8 PR 6.9 5 2 (36mg/m2;30mg/m2) 12 Y <1 PD 0.8 6 2 (36mg/m2;30mg/m2) 3 Y 3 SD 2.1 7 2 (36mg/m2;30mg/m2) 1 N 2 PR 3.7 8 3 (45mg/m2;30mg/m2) 3 Y 3 SD 1.9 9 3 (45mg/m2;30mg/m2) 5 N <1 PD 0.2 10 3 (45mg/m2;30mg/m2) 1 Y 3 VGPR 3.4 11 3 (45mg/m2;30mg/m2) 1 Y 13* PR 12.8* 12 4 (56mg/m2;30mg/m2) 2 Y 4 PR 3.5 13 4 (56mg/m2;30mg/m2) 8 Y 11* VGPR 10.5* 14 4 (56mg/m2;30mg/m2) 1 Y 8* VGPR 8.4* 15 4 (56mg/m2;30mg/m2) 5 Y 2 PD 1 16 4 (56mg/m2;30mg/m2) 2 Y 5* PR 4.5*

* Ongoing at abstract submission

$ PR: partial response, SD: stable disease; VGPR: very good partial response; PD: progressive disease

Disclosures

Stockerl-Goldstein: Onyx: Speakers Bureau.