The Addition of IMiDs for Patients with Daratumumab-Refractory Multiple Myeloma Can Overcome Refractoriness to Both Agents
Authors: Fotiou Despina , Gavriatopoulou Maria , Ntanasis-Stathopoulos Ioannis , Migkou Magdalini , Kanellias Nikolaos , Malandrakis Panagiotis , Theodorakakou Foteini , Dialoupi Ioanna , Eleutherakis-Papaiakovou Evangelos , Roussou Maria , Terpos Evangelos , Dimopoulos Meletios A. , Kastritis Efstathios 
Published: November 2020

Introduction: Treatment options for patients with myeloma (MM) expand but development of refractoriness to major drug classes is inevitable in most patients. Management of disease refractory to proteasome inhibitors, IMiDs and antiCD38 monoclonal antibodies is challenging; but there is data to support that some drug combinations provide benefit even when there is resistance to individual drugs. This has been observed with anti-CD38-IMiD combinations and we have previously reported data in patients who have responded to the daratumumab-IMiD combination post refractoriness to both drug classes. These results may be related to the mechanisms of action of daratumumab, it acts both directly and through antibody mediated cytotoxicity, phagocytosis and immune modulation and of IMiDs which also enhance natural killer cell cytotoxicity and modify the immune microenvironment. Other mechanisms may also be involved but we need more clinical and biological data to understand this phenomenon. We present our experience with consecutive patients who were refractory to IMiD combinations and single agent daratumumab, who were retreated with the IMiD and daratumumab, following development of resistance to daratumumab. Methods: A total of 27 consecutive patients who were refractory to an IMiD (lenalidomide or pomalidomide) and progressed on single agent daratumumab, were enrolled. The more recent IMiD to which the patients were refractory prior to daratumumab treatment was added to daratumumab, without any intensification of either schedule (RESET). All patients were treated in the Department of Clinical Therapeutics, in Athens. Results: The median age was 74 years (range 52-86) and 70% were male. The median number of treatment lines prior to RESET was 4 (range 1-16). Eleven patients (41%) had undergone ASCT/HDM. All patients had previously received bortezomib and 60% were refractory, 37% (n=9) were carfilzomib-exposed and 30% refractory, 30% (n=8) were Ixazomib-exposed and 26% refractory; 82% had alkylating agent exposure and 52% were refractory. All patients had prior exposure and 93% of them were refractory to lenalidomide, while 52% (n=14) were pomalidomide-exposed and 48% refractory. The regimen prior to daratumumab monotherapy was IMiD-based in 48% (n=13), PI-based in 26% (n=7), both IMiD & PI containing in 18.5% (n=5), and other in 7% (n=2). At RESET, the IMiD added was lenalidomide in 48% (n=13) and pomalidomide in 52% (n=14). Median time from diagnosis to RESET was 72 months (25.6-135.3). The median time from the last IMiD dose to RESET was 13.2 months (2.13-41.3). The median duration of daratumumab monotherapy prior to RESET was 7.57 months (range 1.61 to 38.2) and the best response achieved was VGPR in 41% , PR in 33.3% a PR and 25.8% had stable disease, prior to progression. Median duration of treatment in RESET was 5.3 months (0.46 to 22.33) and best response distribution was VGPR in 7.4% (n=2), PR in 33.3% (n=9), for an ORR of 41% (n=11). Currently, 9 (33%) patients still receive treatment at RESET and 18 (67%) have progressed. Median PFS in RESET was 8.9 months (95% CI 4-13.7) and the median OS from start of RESET was 20 months (95% CI 6.4-33.6). Both PFS and response to RESET were independent of the type of IMiD added, whether IMiD at most recent line or added at RESET was administered at full or reduced dose, and the dose of dexamethasone at last regimen, Prior response to daratumumab monotherapy or to the most recent IMiD-based regimen and the median number of prior treatment lines also did not affect PFS or response at RESET. Following progression at RESET, 11 patients have received further therapy; the median number of treatment lines post RESET was 2 (1-5). Two patients responded to the subsequent therapy (at least PR). Conclusion: The combination of daratumumab with an IMiD can partly overcome resistance to both agents, even without intensification of either schedule. Importantly, this combination was associated with a 40% ORR and a PFS of 8.9 months, which is quite promising given the advanced refractoriness of these patients to individual treatments. These data also indicate the potential of an anti-CD38 backbone as part of a treatment strategy that extends over multiple lines of therapy, which should be explored in larger prospective trials. Our group is now investigating the impact of individual drugs and their combination to further understand the modulation in the immune environment.

Disclosures
Gavriatopoulou: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria. Terpos:Celgene: Honoraria; Medison: Honoraria; Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding. Dimopoulos:Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria.