A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma

Abstract

Purpose: Pegylated liposomal doxorubicin (PLD) combined with bortezomib is an effective salvage regimen for relapsed refractory multiple myeloma (RRMM). Carfilzomib, a second-generation proteasome inhibitor, has clinical efficacy even among bortezomib-refractory patients.

Patients and methods: We performed a phase I/II trial of carfilzomib, PLD, and dexamethasone (KDD) with the primary endpoints being safety and efficacy (NCT01246063). Twenty-three patients were enrolled in the phase I portion and the MTD of carfilzomib was determined to be 56 mg/m2 (days 1, 2, 8, 9, 15, and 16) when combined with PLD (30 mg/m2 on day 8) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, and 16). Seventeen additional patients were enrolled in the phase II portion.

Results: KDD was determined to be well tolerated with the only common grade 3/4 nonhematologic adverse events of infection. Grade 3/4 hematologic toxicity included lymphopenia (63%), thrombocytopenia (40%), anemia (40%), and neutropenia (28%). In the cohort of patients treated at the MTD, where median prior therapies were 2% and 42% were refractory to bortezomib, the overall response rate was 83% (20/24) with 54% (13/24) having a very good partial response or better. The median progression-free survival was 13.7 months (95% CI, 5.0-21.7).

Conclusions: This trial is the first to report outcomes using a triplet regimen of high-dose carfilzomib. KDD was well tolerated and appears efficacious in RRMM. Additional study is needed to more precisely determine patient outcomes with this regimen and its utility compared with other carfilzomib containing salvage regimens.

Conflict of interest statement

Conflicts of Interest:

Schroeder: Consultancy/Honorarium (Incyte, Amgen, Sanofi); Fiala: None; Huselton: None; Cardone: Ownership (Eutropics); Jaeger: None; Jean: Ownership (Eutropics); Shea: Ownership (Eutropics); Ghobadi: None; Wildes: Research Founding (Janssen) Honorarium (Carevive); Stockerl-Goldstein: None; Vij: Research Funding (Amgen, Takeda, BMS, Celgene) Ad Boards (Amgen, Takeda, BMS, Celgene, Janssen, Jazz).

©2019 American Association for Cancer Research.

Figures

Figure 1:. Dose Escalation Table and Dosing Schema

[A] Dose escalation [B] Dosing schedule as administered in Phase II

Figure 2:. Common Toxicities

The percentage of patients reporting [A] hematologic toxicity, [B] GI upset and constitutional symptoms, [C] infectious complications, and [D] cardiopulmonary toxicities.

Figure 3:. Progression-Free and Overall Survival Curves

The estimated median progression-free survival of patients treated at the MTD was 13.4 months (95% CI 5.0–21.7). Median estimated overall survival has not been reached after a median follow-up of 23.3 months.

Figure 4:. Correlative Studies

[A] HRK priming of responders versus non-responders. [B] Progression-free survival of the highest quintile of HRK expression versus the rest of the cohort. [C] HRK priming pre and post-KDD treatment. [D] HRK Priming in bortezomib-refractory versus bortezomib-sensitive/naïve patients.

Figure 5:. Mitochondrial Priming

DNA damaging (orange) or proteasome inhibiting (blue) drugs illicit apoptosis signaling through select member(s) of BH3-only pro-apoptotic protein family (BIM, NOXA (blue), PUMA, BAD, HRK (orange), BID, and MS-1). These proteins then carry the apoptosis signal to mitochondria, where they impact the free pool of effector pro-apoptotic proteins. When dissociated from anti-apoptotic proteins, the effector proteins cause mitochondrial outer membrane permeabilization (MOMP) triggering the mitochondrial apoptosis signal. In this assay, BH3-only mimetic peptides artificially reproduce this signaling pathway and the MOMP signal from the drug associated BH3 only protein is subsequently analyzed. The extent of MOMP is measured by flow cytometry using a mitochondrial potentiometric dye, JC-1. Thus, BH3 profiling surveys how likely the drugs are to complete the apoptotic signal. This was performed in ex vivo experiments at pretreatment as described previously.