IMiD Retreatment in Patients Refractory to Both an IMiD and an Anti-CD38 Antibody Induces Significant Response Rates Post Anti-CD38 Exposure
Authors: Gavriatopoulou Maria , Ntanasis-Stathopoulos Ioannis , Malandrakis Panagiotis , Fotiou Despina , Migkou Magdalini , Kanellias Nikolaos , Eleutherakis-Papaiakovou Evangelos , Dialoupi Ioanna , Theodorakakou Foteini , Roussou Maria , Terpos Evangelos , Kastritis Efstathios , Dimopoulos Meletios A. 
Published: February 2021

INTRODUCTION
The survival of myeloma patients has doubled the past decade, however, patients refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) still have poor prognosis. Immunotherapy with monoclonal antibodies targeting cell-surface antigens is a promising treatment strategy with different mechanisms of action and has been integrated both in the newly diagnosed and relapsed/refractory setting. The combination of daratumumab, pomalidomide and dexamethasone (DaraPomDex) has demonstrated significant activity even in patients refractory to both drugs and a potential mechanism may be re-sensitization to pomalidomide. Another report showed that daratumumab-refractory patients who previously failed IMiD, responded when the IMiD was added to daratumumab. This provided a proof of principle that anti-CD38 antibodies can alter the underlying pathophysiology, and can potentially overcome refractoriness to IMIDs. Increased CD38 expression after IMiD exposure could be a mechanism of IMiD resistance, and anti-CD38 agents may act by eliminating this effect. Daratumumab induces clonal CD8+ T-cell expansion that may contribute to clinical responses, which is augmented by IMiDs, resulting in synergy.Potential loss of this response in progressing patients may be recaptured after the reintroduction of IMiDs. Another potential mechanism could involve the reemergence of IMiD-sensitive clones after an IMiD-free period. There is data that daratumumab alters the tumor immune microenvironment, and this effect may be long lasting , even after daratumumab discontinuation . The aim of the study was to evaluate the efficacy of re-treatment with IMiD-based therapy in patients refractory both to IMiDs and anti-CD38 antibodies.
PATIENTS AND METHODS
The study included 38 patients who were refractory to antiCD-38-based therapy and to at least one IMiD. Overall, 26 (68%) patients had received lenalidomide, 11 (29%) pomalidomide and 1 (3%) thalidomide before anti-CD38 treatment.
RESULTS
Median number of prior lines before IMiD retreatment was 4 (range 2 to 13). The patient distribution per R-ISS was: R-ISS 1: 8, R-ISS 2: 9, R-ISS 3: 4. Overall, 4 (11%) patients received lenalidomide-, 33 (86.5%) pomalidomide-, and 1 (2.5%) thalidomide-based regimens post anti-CD38. The majority of patients were treated with pomalidomide-cyclophosphamide-dexamethasone (PCD) (n=13) and pomalidomide-dexamethasone (PomD) (n=11). The remaining 14 patients were treated with other IMiD-based triplets. Importantly, 10 (26%) patients received the same IMiD as prior to anti-CD38 exposure (lenalidomide n=2, pomalidomide n=8).
Median time from diagnosis to IMiD re-treatment was 61.5 months. Overall, 20 patients (53%) achieved a response during IMiD retreatment, including CR=1, VGPR=5, PR=10 and MR=4; 11 patients achieved SD, whereas 7 patients progressed. The disease control rate (DCR=SD+PR+VGPR+CR) was 82%. Among the patients re-exposed to the same IMiD, 5 responded, 3 progressed and 2 remained stable. Among the responders, 1 achieved VGPR with PCD, 2 PR with PCD and DaraPomDex, whereas 2 showed MR with PCD and PCD with Bortezomib. 79% (22/28) of the patients received pomalidomide following previous exposure to lenalidomide; among them, 15/22 (68%) patients responded (1 CR, 4 VGPR, 8 PR, 2 MR), 3 remained stable and 4 progressed. Interestingly, 10 out of 13 (77%) patients who received PCD responded.
Median PFS for all patients was 4 months (range 2.9-4.8). Median time to next treatment (TtNT) for the whole study cohort as well as for those who received the same IMiD pre- and post-exposure to anti-CD38 was 4.2 months as well. Median duration of response (DoR) for the responders was 7 months. Median TtNT for those who received pomalidomide after previous exposure to lenalidomide (n=22) was 3.9 months; median DoR among the responders was 6.6 months. Median OS 5.3 range 0.5-35.5.
CONCLUSION
IMiD retreatment in patients refractory to both an IMiD and an anti-CD38 antibody can induce significant response rates, even among patients re-exposed to the same IMiD. This indicates that after anti-CD38 therapy a long lasting, probably immunomodulatory effect may be associated with some degree of re-sensitization to IMiDs. The subgroup of patients receiving PCD derived the most benefit. In this context, a prospective study evaluating the role of PCD in this population is currently ongoing.

Disclosures
Gavriatopoulou: Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Terpos:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Kastritis:Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Pfizer: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria.