Abstract
3 min readTopic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Multiple myeloma remains incurable for most patients (pts) who will eventually develop multiple drug resistance. Pts refractory to immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (mAbs) have poor prognosis and limited treatment options. Combinations of different drug classes may overcome to some degree resistance to each drug individually; preliminary data on small pts cohorts show that resistance to Daratumumab (DARA) may be reversed by addition of IMiDs and vice versa, via synergistic immune and microenvironmental effects that remain poorly understood. Aims: To evaluate the combination of Daratumumab plus IMiD as a salvage therapy in pts previously refractory to both agents in parallel with the investigation of the immune profile at distinct timepoints to monitor for the dynamics of resulting immunomodulation during the course of the disease. Methods: All pts in the study (N=37) were refractory to at least one PI and one IMiD and had progressed to Dara monotherapy. Following progression to Dara, the last IMiD on which each patient was refractory (pomalidomide, Pom, in 18 pts; lenalidomide, Len, in 17pts), was added without modulating Dara backbone (RESET). Consecutive peripheral blood (PB) samples were collected at four time points; i) at Dara initiation, ii) at progression to Dara monotherapy, iii) at response and/or iv) progression to Dara/IMiD combination. PB samples were analyzed with flow cytometry with two 8-color panels. Panel 1: CD38-FITC, Granzyme B-PE, CD127-PeCy7, CD25-APC, CD4-APCCy7, CD3-BV510, Lag-3-BV421 and 7-AAD; panel 2: CD14-FITC, CD56-PE, CD66-b-PeCy7, CD80-APC, CD45-APCCy7, CD3/CD19-BV510, CD16-BV421 and 7-AAD. Results: Median age of the participants was 73 years (range 52-86; 66% male), all were refractory to Len, 51% were refractory to Pom and had a median of 3 prior treatment lines (range 1-16). The median duration of Dara monotherapy was 7.9 months, ORR was 57% and median PFS was 7.5 months. Median duration of RESET therapy (DARA plus IMiD) was 5.5 months (range 0.5-24), with ≥PR in 40% (54% had ≥MR), a median PFS of 5 months and median OS of 19 months. Pts achieving ≥PR at 3-month landmark, had PFS of 9 months vs. 4 months for those with <PR (p=0.01), with a respective median OS of 23 vs. 11 months. Multivariate flow cytometry analysis showed significant heterogeneity in the immune profile between pts. After DARA monotherapy there was a significant decrease in total NK cells and a significantly skewed CD4/CD8 ratio due to increase in the circulating cytotoxic CD8+ T cells. To the subset level, there was an apparent relative increase of the immunomodulary CD56highCD16- subset among total NK cells, at the expense of the mature CD56+CD16+ NK cells. These changes persisted throughout the DARA-containing therapy and were not affected by the addition of IMiD. PFS, OS and response to RESET were independent of type or dose of IMiD, prior response to DARA monotherapy or IMiD, number of prior treatments, ISS at diagnosis or at time of RESET, however, the increased M1/M2 ratio (value >1) prior to RESET initiation proved the strongest predictor of response to RESET therapy and conferred a 2.2-fold improved PFS when compared with pts with increased M2 macrophages (p<0.001). Summary/Conclusion: Retaining DARA backbone therapy may be associated with clinically relevant activity among pts refractory to DARA and IMiDs, when these drugs are combined. DARA-specific immunomodulation, was not altered after the addition of IMiD while the baseline macrophage M1/M2 ratio was strongly associated with clinical response to Dara-IMiD combination. Further efforts are needed to reveal immune signatures with strong predictive/prognostic value. Keywords: relapsed/refractory, Multiple myeloma, Synergy, Immunomodulation
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