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Despite significant improvements in myeloma (MM) therapies, patients (pts) refractory to immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (mAbs) have poor prognosis and limited treatment options. Daratumumab (DARA), an anti-CD38 mAb, is active in pts with relapsed/refractory MM through mechanisms that include complement-dependent and antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis and immunomodulation. DARA + IMiDs have substantial efficacy, probably through the combination of their immune and microenvironmental effects. The mechanisms of resistance are not fully elucidated but resistance to DARA may be reversed by addition of IMiDs and vice versa, as previously shown (Gavriatopoulou Blood 2019, Nooka Cancer 2019). We prospectively evaluated the combination of DARA + IMiD following refractoriness to both agents, to assess clinical activity but also to longitudinally assess immune cell populations in the peripheral blood (PB) in order to understand the resulting immunomodulation. Consecutive PB samples from 35 pts refractory to an IMiD (LEN or POM) and progressing on DARA monotherapy were analyzed. The last IMiD on which each patient was refractory was added without modulating DARA backbone (RESET). In consenting pts, PB samples were collected at the time of DARA initiation, at progression to DARA monotherapy and IMiD addition, at response and at progression to DARA-IMiD. Samples were viably frozen and analyzed using specific 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 as viability dye; panel 2: CD14-FITC, CD56-PE, CD66-b-PeCy7, CD80-APC, CD45-APCCy7, CD3/CD19-BV510, CD16-BV421 and 7-AAD as viability dye. Pts' median age was 73 years (range 52-86; 66% male); median prior treatment lines were 3 (range 1-16); all had prior exposure and refractoriness to at least one PI; all were refractory to LEN and 51% to POM, 40% had prior ASCT. The IMiD added was the last used prior to DARA, i.e., LEN in 49% (17/35) and POM in 51% (18/35). Median duration of DARA monotherapy prior to RESET was 7.9 months (range 1-38) and 64% responded (≥PR) before progression. Median duration of RESET therapy was 5.5 months (range 0.46 to 23.86) and 43% had ≥PR (≥MR: 60%) [including VGPR: 8.6% (n=3), PR: 34.3% (n=12), MR: 17.1% (n=6), SD/NR: 28.6% (n=10), PD: 11.4% (n=4)]. Median PFS was 5 months (95% CI 1.5-8.4) and median OS was 19 months (95% CI 13.5-24.5). Based on response at 3-month landmark, PFS was 9 months for pts who achieved ≥ PR vs 4 months for < PR (p=0.031). PFS 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. Multivariate flow cytometry analysis showed significant heterogeneity between pts (n=20). After DARA monotherapy there was an increase in CD8+ T cells compared to baseline which persisted throughout DARA-containing therapy with CD4+ T remaining at similar levels at all time-points. Total Tregs reduced after DARA start; however, within Tregs the relative proportion of Lag3+ Tregs tended to increase during DARA monotherapy. NK cell levels were significantly reduced after DARA and remained low throughout DARA therapy, with no recovery after IMiD addition; within NKs, we noticed an increase of CD16-/CD56+ immunomodulatory/cytokine producing and, to a lesser extent, of CD56-/CD16+ cytotoxic subsets compared to mature CD56+/CD16+ NK cells which tended to decrease, especially during DARA monotherapy. Although the samples at response to DARA/IMiD combination are few (n=10), CD56-CD16+ NK cell percentages at the time of progression to DARA were associated with response to DARA/IMiD. Finally, there was a noticeable increase in M1- and a decrease in M2-type macrophage subsets at response to DARA/IMiD. In conclusion, retaining DARA backbone therapy may be associated with clinically relevant activity (ORR 43%, 5 months median PFS) among pts refractory toDARA and IMiD, when these drugs are combined. Longitudinal evaluation of PB immune cell composition showed DARA-specific immunomodulation, which was not altered after addition of IMiDs, but may be related to restoration of sensitivity to the DARA/IMiD combination. Further investigation is in progress to reveal potential immune signatures of clinical relevance. Disclosures Krevvata: Janssen: Current Employment. Gavriatopoulou: Genesis: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria. Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria.

A deep and profound hematologic response is associated with substantial improvement in the probability of improvement in organ function and survival in patients with AL amyloidosis or LCDD. Bortezomib-based therapy is the mainstay of anti-clonal therapy for AL amyloidosis and LCDD, however, hemCR is achieved in only 20% of patients. Daratumumab has shown to be active and able to induce rapid responses in patients with AL amyloidosis. Plasma cell clones in AL are small and indolent and further improvement of hematologic response could be achieved by consolidation strategies. Given the activity of daratumumab and the rapid induction of deep responses in AL amyloidosis, we treated patients with AL amyloidosis or LCDD , who had not achieved a hemCR after standard therapy, with a short course of daratumumab. In consenting patients, we evaluated MRD in the bone marrow (BM), before and after consolidation, by means of next generation multiparametric flow cytometry (NGF-MFC), using the Euroflow protocol. Thus, beyond the presence of MRD , we were able to evaluate also other components of the BM microenvironment and their changes before and after daratumumab. All patients were treated in the Department of Clinical Therapeutics, Athens, Greece. The study included patients who had achieved either PR or VGPR after completing standard bortezomib-based primary therapy. Consolidation included 4 weekly infusions of daratumumab 16 mg/kg. Pre-emptive therapy for IRR was given starting two days before the first infusion of daratumumab that included low dose steroids (equivalent of 16 mg of methylprednisolone), H1 & H2 inhibitors and montelukast. Twenty-five patients (20 with AL and 5 with LCDD) received daratumumab consolidation. Among patients with AL amyloidosis, median age is 65, kidneys and heart were involved in 70% and 75% respectively, baseline Mayo stage was 20%, 70% and 10% for stage 1,2 & 3 respectively. Baseline immunofixation in serum or urine was positive in all patients, median baseline dFLC at diagnosis was 125 mg/L (range 60-7228). Median time from start of first line therapy to daratumumab consolidation was 7 months and all patients had completed their planned therapy. At the time of initiation of daratumumab, 24 patients were in VGPR and one in PR and the median dFLC level was 12 mg/L; all had positive serum or urine immunofixation and in all patients MRD was detectable by NGF-MFC. Except for one patient, all the others received the planned 4 daratumumab infusion. Mild IRRs occurred in 3 patients (grade 1 in 2 and grade 2 in one patient); no IRRs occurred after the first infusion. One month after completion of consolidation with daratumumab, median dFLC dropped to 5 mg/L and 10 (40%) of the patients improved their response: 36% from VGPR to hemCR and one patient with PR to VGPR. Among those that achieved a hemCR, 5 (50%) became MRD negative by NGF-MFC. However, even among those that remained MRD-positive there was a decrease in the number of aberrant plasma cells (APCs) by a median of one log. In MRD-positive patients a change in the composition of the remaining phenotypic subclones of APCs was also observed. Regarding the other BM cell populations, we observed statistically significant changes in B-cell precursors (increased from 14.32%+/-11.75% to 34.76% +/-24.11%, p=0.0004), naïve B-cells (decreased from 65.58%+/-17.56% to 47.37%+/-22.66%, p=0.0003), T cells (increased from 6.44% +/- 2.78% to 10.86%+/- 6.407%, p=0.0007), CD27+ NK & NKT cells (increased from 15.65% +/-13.5% to 36.34%+/- 24.43%, p=0.0002), mast cells (increased from 0.0092%+/-0.0123% to 0.011%+/-0.012%, p=0.002) and erythroblasts (increased from 1.82%+/-0.97% to 2.41%+/- 1.03%, p=0.076). Due to the small numbers it was not possible to make meaningful comparison between MRD positive and negative patients. However, the above results indicate that even a short course of daratumumab was able to cause significant changes in the BM microenvironment of these patients. From this small prospective study we conclude that consolidation with a short course of daratumumab can improve the depth of response in patients with AL or LCDD that have not achieved a hemCR after primary therapy, even to the depth of undetected MRD. In addition, daratumumab causes significant changes in the BM environment, which need further investigation in order to understand their implications. Disclosures Kastritis: Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gavriatopoulou:Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Sanofi: Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. OffLabel Disclosure: daratumumab for AL amyloidosis