Pomalidomide Plus Dexamethasone (Pd) in the Treatment of Asian Patients with Relapsed/Refractory Myeloma (RRMM) Who Are Previously Treated with Bortezomib and Refractory to Lenalidomide - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Background

Pomalidomide is a 3^rdgeneration immunomodulatory drug that has been approved for the treatment of Patients who progress after prior treatment with bortezomib and lenalidomide. Experience with pomalidomide in Asian patients is very limited till date. In addition, it is unclear if pomalidomide will work in patients who have been exposed to a newer generation of treatments for myeloma including carfilzomib, ixazomib, panobinostat and daratumumab.

Method

We conducted a prospective trial of pomalidomide (4mg daily for 21 days every 4 weeks) plus dexamethasone (40mg once weekly) in myeloma patients who have relapsed after prior bortezomib and are refractory to lenalidomide from Singapore, Korea, Japan, Hong Kong and Taiwan (NCT02158702). Patients were allowed up to 6 prior lines of treatment. If there is less than a minimal response after 3 cycles of pomalidomide and dexamethasone, including progression within 3 cycles, cyclophosphamide 300mg/m²can be added. The trial was started in December 2014 and is still ongoing. To date, 121 patients have been recruited. This interim report presents data available up till the data cut-off date of 30 April 2016.

Results

Eighty-six patients have available base line information and safety data. 55% of patients are male and median age of the cohort is 65 years old. 37% and 27% of patients are International Stage System (ISS) stage 2 and 3 respectively. 35% of patients have abnormal creatinine clearance. Median prior line of treatment is 4. 24% of patients required dose reduction of pomalidomide, 8% require dose reduction of dexamethasone. 70% of patients experience adverse events (AEs) of any grade (31% of episodes grade 3 or higher), with 35% of these episodes related to the study drugs. 47% of patients experienced serious AEs (SAEs) of any grade (91% of episodes grade 3 or higher), with 42% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. Only 1 patient experienced each of these AEs: grade 3 peripheral neuropathy, VTE or grade 3 renal impairment. Five patients withdrew due to toxicity. Fifteen patients died while on the study, 5 from disease progression, 2 from late stage disease, and 8 from sepsis or pneumonia. The median overall length of follow-up is 5 months. The overall median PFS (N=65) was 6.5 months. Those treated with only Pd (n=53) have a median PFS of 6.5 months. Patients with cyclophosphamide added (Pcd) had a median PFS of 5.8 months. Achievement of a partial response (PR) or better was significantly associated with improved PFS. There was no observed difference in PFS by age, number of prior lines of treatment, ISS stage or the presence of high-risk genetics. Overall median OS was 14 months. For those treated with only Pd, the median OS was 14 months whereas it is 10 months for those on Pcd. Forty-four patients have data for response assessment. 22 (50%) achieved a PR or deeper response with 1 achieving CR and 1 stringent CR. The median duration of response was 8.4 months for those who had achieved a PR or more. Eight out of those 44 patients required the addition of cyclophosphamide due to suboptimal response, 2 of whom subsequently achieved a PR. In these patients the median duration of response was 4.7 months. Eleven patients were previously treated with carfilzomib, ixazomib, panobinostat, elotuzumab or daratumumab in clinical trials. Amongst these, 6 (55%) obtained a PR or better and were able to maintain the response for 10 months. In this group, the PFS was 5.5 months and the median OS was 10.3 months.

Conclusion

This is the first prospective report of the efficacy and safety of Pd in Asian patients with RRMM. The combination is highly active in patients who are heavily pre-treated. Our results compare favorably with previously published data from the US and Europe. The regimen appears to be active across age groups, risk categories and prior lines of treatment. In particular, it is very active even in patients who have progressed following treatment with the latest generations of approved drugs including monoclonal antibodies. In patients who have a suboptimal response, the addition of cyclophosphamide can salvage meaningful response. The regimen is well tolerated and toxicity manageable. A randomized study comparing Pcd to Pd will commence soon.