Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma Overcomes Negative Prognostic Impact of Adverse Cytogenetics and Prior Resistance to Lenalidomide and Bortezomib
Authors: Mark Tomer M , Boyer Angelique , Yadlapati Sujitha , Rossi Adriana C , Pearse Roger N , Pekle Karen , Perry Arthur , Pogonowski Kathleen , Aneja Ekta , Tegnestam Linda , Jayabalan David , Ely Scott , Coleman Morton , Huang Xiangao , Di Liberto Maurizio , Chen-Kiang Selina , Niesvizky Ruben 
Published: October 2019

Abstract
Background: Pomalidomide is a distinct IMiD¨ immunomodulatory agent with activity in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide (LEN) treatment. We have previously reported that the addition of clarithromycin enhances the anti-myeloma activity of pomalidomide+dexamethasone (Pom/Dex) in the treatment of RRMM (Mark et al, ASH 2012). We now report on the clinical benefit of ClaPd with regard to the presence of the negative prognostic features of adverse cytogenetics and prior resistance to novel agents.
Methods: One hundred twenty patients (pts) with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPd. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included LEN. ClaPd is clarithromycin 500 mg twice daily, pomalidomide 4mg for days 1-21, and dexamethasone 40 mg on days 1,8,15,22 of a 28-day cycle. All subjects had thromboprophylaxis with 81 mg aspirin daily. Disease response evaluation was performed monthly with serum and urine protein electrophoresis, immunofixation, and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Cytogenetic testing was performed on CD138-selected cells. Treatment was continued as tolerated by the patient until disease progression.
Results: One hundred seventeen pts had completed at least 1 cycle of ClaPd and were eligible for disease response analysis at data cut-off. All pts were included in the survival analysis. Median time on study was 7.2 months (range 0.3-55.8). Patients had undergone a median of 5 (range 3-15) prior lines of therapy. High risk cytogenetics were present in 72 patients (64%, n =113) as per IMWG definition. The proportion of patients who were refractory to LEN, refractory to bortezomib (BORT), and double (LEN+BORT) refractory were 84%, 78%, and 68%, respectively. The median number of ClaPd cycles was 8 (range 1-56). Median progression-free survival (PFS) and duration of response for the entire cohort was 7.7 and 9.3 months. Overall response rate for the overall, LEN-refractory, BORT-refractory, and double-refractory cohorts did not differ significantly, Table 1. Median PFS for high vs low-risk cytogenetic groups did not differ significantly: 7.7 vs 8.3 months (P = 0.5038); however, subjects with del17p (n=27) had significantly shorter PFS at 3.73 vs 8.67 months (P = 0.0036). The presence of t(4;14) (n= 11), t(14;16) (n = 7), gain 1q (n = 46) in the absence of concurrent del 17p had no significant impact on PFS. Median PFS was not affected by LEN-refractory, BORT-refractory, or double-refractory MM status at 7.7 (P = .5193), 6.5 (P = 0.2618), and 5.8 months (P = 0.2163) respectively. Median overall survival (OS) for the group was 19.3 months (CI 14.2, 26.7). Loss of 17p was associated with significantly shorter survival at 13.2 vs 25 months (P = .0008). Other adverse cytogenetic factors did not affect OS. Median OS was not affected by LEN-refractory, BORT-refractory, or double-refractory MM status at 19.2 (P = .9355), 16.8 (P = 0.5983), and 16.8 months (P = 0.3893) respectively.
Conclusions: ClaPd is a highly effective and tolerable regimen for heavily treated RRMM that has progressed after prior treatments. Response rates are higher and survival outcomes are longer than expected from prior reports of Pom/Dex activity in similar populations. The presence of double refractory disease did not significantly impact clinical outcomes. Known adverse cytogenetic factors did not affect observed PFS and OS with the exception of del 17p leading to approximately 50% decrease in PFS and OS. This 17p OS result is consistent with previously reported data by Leleu (2015, OS = 12 months); however for ClaPD, t(4;14) had no impact while Leleu 2015 reported decrease in OS to 9.2 months with Pom/Dex. This finding may be due to sampling error due to the relatively low % of pts with t(4;14) (10%) in our study as opposed to the 64% in the Leleu report.
Table 1. Best Response (IMWG Criteria) n (%) Overall (N = 117) Lenalidomide-refractory (n = 101) Bortezomib-refractory (n = 94) Double-Refractory (N = 81) ORR (>= PR) 70 (60) 59 (58) 52 (55) 44 (54) CBR (>= MR) 78 (67) 66 (65) 83 (88) 51 (61) sCR 6 (5) 6 (6) 5 (5) 5 (6) CR 1 (1) 1 (1) 1 (1) 1 (1) VGPR 20 (17) 15 (15) 14 (15) 9 (11) PR 43 (37) 37 (37) 32 (34) 29 (36) MR 8 (7) 7 (7) 7 (9) 7 (9) SD 29 (25) 23 (23) 24 (26) 20 (25) PD 10 (9) 10 (10) 8 (9) 8 (10)

Disclosures
Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Off label use of clarithromycin in combination with pomalidomide for treatment of relapsed myeloma. . Rossi:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Pearse:Celegen: Consultancy. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Perry:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Huang:Celgene: Research Funding. Chen-Kiang:Celgene: Consultancy. Niesvizky:Celgene: Consultancy, Speakers Bureau.