Argentine Multicentric Experience of Carfilzomib Use in Relapsed / Refractory Multiple Myeloma. Report from the GAMM (Grupo Argentino de Mieloma Multiple)

Background:

Carfilzomib is a selective proteasome inhibitor recently approved in Argentina for the treatment of relapsed and refractory multiple myeloma (RRMM) in patients previously treated with bortezomib and immunomodulatory drugs. Carfilzomib has shown to be an effective drug in this difficult to treat population with an acceptable toxicity profile. In this multicentre experience, we decided to report the results of the first patients (not participating in clinical trials) treated with this second class proteasome inhibitor in our country.

Methods:

Retrospective cohort study. We evaluated the efficacy and toxicity of carfilzomib based treatments in RRMM patients from 29 centers in Argentina from April 2013 till April 2017. Patients were follow from first treatment day till death or lost to follow up. The primary endpoint was best response rate and secondary endpoints were progression free survival (PFS) and overall survival (OS). The international uniform response criteria (IMWG 2006) were used to assess response rates. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 4.

OS and PFS were estimated using the Kaplan Meier method using Stata13 program. Hazard ratios were estimated by means of a stratified Cox proportional-hazards model.

The study complies with guiding principles for experimental procedures found in the declaration of Helsinki.

Results:

Data on 106 patients was analyzed. Median of previous treatment lines was 3 (IQR 2-4). The median age of patients were 62 years (IQR 57-68) with a median time from diagnosis to start of treatment of 4 years (IQR 3-7). Thirteen out of 106 (12%) patients were considered as high risk according to cytogenetics abnormalities and 33/106 (31%) patients had ISS score of 3. All patients have been previously treated with bortezomib and immunomodulatory drugs, 52 patients (49%) were refractory to at least one of these drugs and 35 patients (33%) were double refractory.

Fifty patients (47%) received carfilzomib + dexametasone (Kd), 40 patients (38%) carfilzomib + lenalidomide + dexametasone (KRd) and 16 patients (15%) carfilzomib + other agents (Koa) with a median of 6 (IQR 3-7) cycles.

The overall response rate (ORR) (≥ partial response) for the complete cohort was 57% (60 patients), complete response was found in 10% (11 patients) and very good partial response in 13% (14 patients). There was a trend towards better ORR when carfilzomib was associated with Rd or other agents, although not statistically significant (p:0.195).

In the univariate analysis lenalidomide refractory patients (55/106), bortezomib refractory patients (52/106) and double refractory patients (35/106) had a lower chance of achieveing ≥ partial response [hazard ratio (HR): 2.23 (CI 95%: 0.01-4.89), HR: 2.74; 95% (C I95%: 1.29-6.06 and HR: 2.76 (CI 95%: 1.19-6.35) respectively]. In the multivariate analysis only bortezomib refractory patients had lower chance of achieving ≥ partial response [HR: 2.29 (CI 95%: 0.98-5.33).

Median progression free survival (PFS) for the complete cohort was 14 months (CI 95% 10-20) and the median overall survival (OS) was 22 months (CI 95% 14-36). The median PFS was 5 months (CI 95% 4-8) for not responders and 21 months (CI 95% 15-27) for responders (p:0.001). The median OS was 9 months (CI 95% 5-20) for non responders vs 30 months (CI 95% 16-36) for responders (p:0.001).

Double refractory patients had a median PFS of 11 months (CI 95% 6-15) vs 18 months (CI 95% 8-33) for the rest of the patients (p:0.19). Twenty nine patients (27%) discontinued treatment due to adverse events (AE) related to carfilzomib. The more commons AE (any grade) were hematological: anemia 42/106 (40%), thrombocytopenia 31/106 (29%) and neutropenia 30/106 (28%), The most frequent non hematological AE (any grade) were: cardiovascular 23/106 (22%), infections 12/106 (12%) and gastrointestinal 6/106 (6%). Interestingly, 13/29 patients (45%) that discontinued treatment due to AE, were because of cardiovascular events.

Conclusion:

This is the first report of carfilzomib use for the treatment of RRMM in South America as far as our knowledge. Our results were comparable with the reports published in the literature. Carfilzomib alone or in combination with other agents has shown efficacy for the treatment of RRMM patients with an acceptable toxicity. Cardiovascular toxicity should be carefully evaluated in patients treated with carfilzomib.