Pomalidomide Plus Low-Dose Dexamethasone In Relapsed Or Refractory Multiple Myeloma (RRMM) With Deletion (del)17p and/Or Translocation t(4;14)
Authors: Leleu Xavier , Karlin Lionel , Macro Margaret , Hulin Cyrille , Garderet Laurent , Roussel Murielle , Arnulf Bertrand , Pegourie Brigitte , Kolb Brigitte , Stoppa Anne-Marie , Brechiniac Sabine , Michallet Mauricette , Marit Gerald , Mathiot Claire , Banos Anne , Lacotte Laurence , Tiab Mourad , Dib Mamoun , Fuzibet Jean-Gabriel , Petillon Marie-Odile , Rodon Philippe , Wetterwald Marc , Royer Bruno , Legros Laurence , Benboubker Lotfi , Decaux Olivier , Caillot Denis , Escoffre-Barbe Martine , Fermand Jean Paul , Moreau Philippe , Attal Michel , Avet-Loiseau Hervé , Facon Thierry 
Published: October 2019

Abstract

Background
Multiple myeloma with del(17p) and/or t(4;14) are characterized with short survival related to early relapse rate (median TTP <4 months) and rapid development of mechanisms of resistance to multiple agents. Furthermore, RRMM to IMiDs® imunomodulatory agent and proteasome inhibitors (bortezomib) also display a shortened median survival of approximately 9 months. We and others have previously showed that pomalidomide plus low-dose dexamethasone has produced 30% to 40% response rate (ORR, PR and greater) with prolonged duration of response (DOR) and median time to progression (TTP) in RRMM who have progressed after multiple treatment options. However, the median TTP was much shorter <4 months for patients with del17p and/or t(4;14) who have been previously exposed to a median of 5- 6 lines of therapies in those studies.
We have designed a phase 2 multicenter, open-label study aimed to determine the efficacy and safety profile of pomalidomide in RRMM patients with del(17p) and/or t(4;14).

Method
This study enrolled patients with progressive RRMM that were relapsing but not necessarily refractory to lenalidomide (minimum two cycles). Del(17p) and/or t(4;14) was identified centrally by Pr. Avet-Loiseau using FISH on bone marrow plasma cells. The response was evaluated centrally in Lille according to IMWG criteria. The primary objective was to evaluate TTP using pomalidomide plus low-dose dexamethasone in RRMM with del(17p) and/or t(4;14). Pomalidomide was given orally at 4 mg daily on days 1–21 of each 28-days and dexamethasone orally at 40 mg daily on days 1, 8, 15 and 22 of each cycle. Venous thrombotic events (VTE) prophylaxis was mandatory. The primary analysis was conducted on the ITT population. An interim analysis is reported.

Results
50 patients (gender ratio 1.5) were enrolled, the median age was 59 yrs (range, 30-80). The median time from diagnosis to enrolment was 3 years (IQ 2-4), 40% had ISS 3, and 60% high beta2m. All patients had loss of 17p (46%) and/or t(4;14) (64%). At entry into the trial, 30% had Hb <10 g/dL, 12% platelet count <100 G/L and 4% neutrophils <1 G/L, 6% had circulating plasma cells and 10% presence of clinically plasmacytomas. The median number of prior lines of therapy was 3 (1-10). All patients had prior exposure to lenalidomide with 84% refractory, 96% had received a proteasome inhibitor with 54% that became refractory; 90% had got an alkylating agent, with 36% became refractory; 76% had an autotransplant and 2% an allotransplant. Overall, 76% were refractory to the last line of therapy prior to study entry. The overall response rate (ORR) was 20% (27% in del17p and 16% in t(4;14)), including 6% >VGPR, and 54% had stable disease. The median duration of response was not reached, but the 6-months event-free survival (EFS) was 54%.
With a median follow-up of 5 months (IQ 3-11), 66% have stopped treatment including 76% due to progression of MM, and 38% had died. The median OS for the cohort as a whole is 12 months (CI95% 5;nr), with a 8-months event-free survival rate of 59%. Interestingly, del(17p) patients benefited more from pomalidomide plus low-dose dexamethasone as median OS was not reached, with 63% 8-months OS, while 9 months (4.5;16) for t(4;14). The median TTP for the cohort as a whole is approaching 3 months (2-5), nonetheless longer for del17p, 8 months (3;nr) versus 3 months (2;4) for t(4;14). We then concentrated on RRMM with more than 2 cycles, and found a similar profile with a clear cut benefit for del17p as compared to t(4;14) treated with pomalidomide plus low-dose dexamethasone. Toxicity was manageable in these fragile RRMM patients with 40% of serious adverse events (SAEs) reported related to the studied treatment, 13% of which led to death and 21% to permanent drug discontinuation. An other 48% led to drug dose reduction. No occurrence or worsening of neuropathy was reported, and only 1 pulmonary embolism was noted.

Conclusion
Pomalidomide plus low dose dexamethasone is active and well tolerated in this RRMM population characterized with high and rapid development of a refractoriness state, particularly with del(17p). This study provides further evidence that IMiD® compound, including pomalidomide is active in patients with adverse FISH cytogenetic and that ongoing triplet-based combination should demonstrate improved response rates and survival in future studies. Updated results will be presented at ASH2013.

Disclosures:
Leleu: JANSSEN: Honoraria; CELGENE: Honoraria. Off Label Use: Pomalidomide. Karlin:Janssen: Honoraria; Celgene: Export board committee Other, Honoraria. Roussel:JANSSEN: Honoraria; CELGENE: Honoraria. Moreau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Attal:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Avet-Loiseau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Facon:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau.