Pomalidomide with Low Dose Dexamethasone Is Effective Irrespective of Primary or Secondary Resistance to Lenalidomide but the IMiD-Free Interval Is Important
Authors: Dimopoulos Meletios A , Roussou Maria , Kanellias Nikolaos , Gavriatopoulou Maria , Migkou Magdalini , Panagiotidis Ioannis , Eleutherakis-Papaiakovou Evangelos , Ziogas Dimitrios , Fotiou Despina , Giannouli Stavroula , Tsirigotis Panagiotis , Poziopoulos Christos , Delimpasi Sossana , Mparmparoussi Despoina , Matsouka Charis , Konstantopoulos Kostas , Terpos Evangelos , Kastritis Efstathios 
Published: October 2019

Abstract
Pomalidomide with low dose dexamethasone (Pd) is a standard treatment for patients who have failed both lenalidomide (Len) & bortezomib (Bor). Phase III studies showed that Pd is active irrespective of the number of prior therapies and whether Len or Bor were the last therapies prior to Pd. However, it remains unclear what is the activity of Pd when administered immediately after refractoriness to Len or when is administered following secondary resistance. Furthermore, the importance of the time elapsed from the administration of Len to Pd has not been explored. We analyzed the outcomes of 116 consecutive patients with MM after failure of both Len & Bor that were treated in the Department of Clinical Therapeutics, National and Kapodistrian University of Athens, and who all received pomalidomide 4 mg with weekly dexamethasone.
Median age was 62 years (range 38-86 years); median number of prior treatments was 4 (range 1-9), 58% had received ASCT, 73% were refractory to the last Bor-based regimen and 90% were refractory to the last Len-based regimen. All patients had MM refractory to the last regimen, but 40% had ≥PR to their most recent regimen prior to development of refractoriness. The last regimen prior to Pd included Bor in 62 (53%), Len in 35 (30%) and conventional chemo in 19 (17%). On intent to treat, 34 (29%) patients achieved ≥PR (CR: 3%, VGPR: 7%, PR: 19%). In those which received Len just prior to Pd, ≥PR rate was 26% vs 33% for Bor and 21% for other regimens (p=0.55). Among patients with <PR to any prior Len therapy (primary resistance to Len, N=45) ≥PR was 24% vs 31% for those who had ≥PR to any prior Len during the course of their disease (secondary resistance to Len, N=71) (p=0.42). Among patients who received Len just prior to Pd and who achieved ≥PR before development of resistance, 29% achieved ≥PR vs 18% for those with <PR (p=0.49). Thus, Pd was effective irrespective of primary or secondary refractoriness to Len.
Median follow up was 29 months and 95 (83%) patients have progressed or died. Median PFS was 5.2 months (95% CI 3.8-6.5). Patients who received Len as their last treatment before Pd had PFS similar to that of patients who received either Bor or other regimens (p=0.8). Patients who had ≥PR when treated with Len immediately before Pd (secondary resistant to Len), had PFS similar to that of those with <PR (p=0.61). PFS of patients with primary vs secondary resistance to Len was 4.9 vs 6.5 months (p=0.18). After Pd, 59 (51%) patients received further therapy. PFS2 for all patients is 9.6 months (95% CI 7.6 -10.4). PFS2 was similar for patients who received Len vs Bor or other therapies immediately prior to Pd (9 vs 9.9 vs 7.4 months, p=0.55). For those who had Len just prior to Pd those who achieved ≥PR before development of Len resistance PFS2 was 9.7 vs 7.2 months for those who had <PR (p=0.36) and was similar for patients with primary vs secondary resistance to Len (8.7 vs 9.7 months, p=0.4). Median OS was 13 months (95% CI 9.7-16). OS of patients who received Len immediately before Pd was 11.3 vs 13 months for Bor (p=0.486). Among patients who received Len as their last regimen and who achieved ≥PR before development of resistance, there was a trend for longer OS (16.6 vs 9.9 months for those with <PR, p=0.3) and OS was 12.7 vs 15.7 months for patients with primary vs secondary resistance to Len (p=0.4). We then evaluated the role of time elapsed from the last exposure to Len until start of Pd. Median time from the last Len dose to Pd was 8 months; however, further analysis revealed that ≥PR was 68% for patients (N=29) who had ≥18 months since the last dose of Len. PFS of patients with an interval ≥18 months was 10.5 vs 4 months for those with <18 months (p=0.002) and OS was 20 vs 15 months for those with an interval 12-18 months vs 10 months for those with <12 months interval (p=0.01). These effects remained significant even after adjustment for the number of prior therapies and primary or secondary Len resistance.
In conclusion, Pd is active in MM patients refractory to Len, independently of primary or secondary resistance to Len or if Len was used just prior to Pd. However, patients with ≥18 months of Len-free interval may have longer PFS and OS irrespectively of prior lines of therapy. These data indicate the potential role of "clonal tides" and the emergence of IMiD-sensitive clones after "IMiD-free" periods, but further investigation is needed to identify optimal treatment strategy.

Disclosures
Dimopoulos: Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Delimpasi:Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Terpos:Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; BMS: Consultancy, Honoraria; Novartis: Honoraria; Celgene: Honoraria. Kastritis:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria.