Daratumumab Monotherapy Research Articles

Clinical Efficacy of Daratumumab in Monotherapy of Relapsed/Refractory Multiple Myeloma

Background. Daratumumab is IgG1-K humanized anti-CD38 monoclonal antibody. It has a direct impact on tumor and immunomodulatory effect. Aim. To assess the efficacy of daratumumab monotherapy in patients with progressive, and relapsed/refractory multiple myeloma (MM), as well as to find out the degree of toxicity and safety of this drug. Materials & Methods. The trial included 10 MM patients (3 men and 7 women) aged 51-74 years (median 57 years). Stage 3 (according to Durie-Salmon system) was determined in all patients, in 2 of them stage 3B with creatinine clearance < 30 mL/min was reported. According to ISS (International Staging System) criteria, stage 2 and stage 3 were identified in 6 and 4 patients, respectively. All the patients had been previously treated with bortezomib and lenalido-mide with further double refractoriness in 4 out of 10 patients. Bendamustine and carfilzomib were administered to one patient each, both in combined regimens. The number of previous therapy lines was 3-6 (median 5). Results. Overall response was 50 % including 2 (20 %) patients with very good partial remission. In 1 (10 %) patient complete remission was achieved. During the follow-up of 6-32 months (median 15 months) median overall survival was not achieved. Median progression-free survival was 17.8 months. Daratumumab is characterized by favorable safety profile. In 20 % of patients infusion-induced reactions with severity grades 1-2 were observed. Among other adverse events the following should be pointed out: weakness (30 %), nausea (10 %), headache (10 %), anorexia (10 %), thrombocytopenia (20 %), and neutropenia (30 %). No serious complications were reported. Conclusion. Daratumumab treatment is a safe and effective method of anticancer drug therapy in relapsed/refractory MM.

Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial

Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4-43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46-0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2-82·0) in the D-VMP group and 67·9% (62·6-72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34-0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. Janssen Research & Development.

Impact of Daratumumab Monotherapy on Bone Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least 2 Prior Lines of Therapy Including Lenalidomide and a Proteasome Inhibitor; Interim Analysis of a Phase 2 Study (the REBUILD Study)

Impact of Daratumumab Monotherapy on Bone Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least 2 Prior Lines of Therapy Including Lenalidomide and a Proteasome Inhibitor; Interim Analysis of a Phase 2 Study (the REBUILD Study)

Daratumumab Monotherapy for Patients with Relapsed or Refractory (R/R) Natural Killer/T-Cell Lymphoma (NKTCL), Nasal Type: Updated Results from an Open-Label, Single-Arm, Multicenter Phase 2 Study

Hui-qiang Huang and Won-Seog Kim contributed equally to this work. Introduction: NKTCLs are rare, Epstein-Barr virus-associated distinct subtypes of peripheral T-cell lymphoma. These are primarily extranodal and of the nasal type and are more common in Asia and Central/South America (Tse and Kwong. Blood 2013. 121:4997-5005). Outcomes for patients (pts) with R/R NKTCL are very poor, and with no standard therapy, there exists a highly unmet medical need for this pt population. Clinical data from NKTCL pts suggest CD38 as a new prognostic biomarker and novel target for therapy (Wang et al. Ann Hematol 2015. 94:1381-8). Daratumumab (DARA) is a human IgGk monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action that is approved for newly diagnosed and relapsed/refractory multiple myeloma (MM). Interim results from stage 1 of a phase 2 study (NCT02927925) of DARA monotherapy in pts with R/R NKTCL demonstrated high tolerability and pre-specified futility criteria were not met (Kim et al. Blood 2018. 132:1617). Here we present data from stage 2 of the study. Methods: This phase 2 study with Simon's 2-stage design evaluated DARA monotherapy in pts with histologically confirmed extranodal NKTCL nasal type per WHO classification that was refractory to or relapsed after ≥1 line of chemotherapy, and who were not candidates for other treatment modalities. Pts without available tumor samples for biomarker determination were not eligible. DARA 16 mg/kg was administered by IV infusion once weekly for 8 weeks, every other week for 16 weeks, and every 4 weeks thereafter until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) based on blinded independent central review (BICR) per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). Additional endpoints included progression-free survival (PFS) and duration of response based on BICR, overall survival (OS), and safety. Protocol-specified futility criterion for ORR (defined as at most 1 of 15 pts with complete response [CR]/partial response [PR]) was not met at interim analysis of 16 pts; stage 2 enrolled an additional 16 pts. Results: A total of 32 pts were treated with DARA monotherapy. Median age was 56 years, 91% had an ECOG score of 0 or 1, median time from initial NKTCL diagnosis was 24.0 months, median (range) plasma EBV-DNA at baseline was 900 (0-94,800) kIU/L, and 50% of pts had CD38 expression values ≥50%. At the clinical cut-off (June 4, 2019), 91% of pts discontinued treatment (disease progression [66%], pt withdrawal [13%], physician decision [9%], and adverse event [AE; 3%]). At a median follow-up of 16.7 months, ORR based on BICR was 25.0% (Table 1). Response rates were similar for pts who received &amp;lt;3 vs ≥3 prior treatments (26% vs 23%). Among the 8 responders, median duration of response was 55 days (95% CI, 29-339 d). Median PFS was 53 days (95% CI, 32-106 d), with a 4-month PFS rate of 11%. Median OS was 130 days (95% CI, 94-228 d), with a 6-month OS rate of 40%. The most common (&amp;gt;20%) all-grade treatment-emergent adverse events (TEAEs) are listed in Table 2. Eighteen (56%) pts had grade 3/4 TEAEs; thrombocytopenia (22%), and anemia, leukopenia, and neutropenia (16% each) were most common (≥15%). Two pts discontinued treatment due to TEAEs. Infusion-related reactions (IRRs) occurred in 63% of pts and were generally mild: only 2 (6%) pts had grade 3 IRRs (urticaria, hypertension, hypotension), and no grade 4 IRRs were reported. Response to DARA was not associated with CD38 expression: mean (standard deviation) percentage of tumor cells that expressed CD38 was 41.6% (31.92) in non-responders and 56.7% (39.33) in responders. Reductions in NK cells, complement protein C1q, and CD38+ Treg cells were observed in the majority of pts after 1 cycle of DARA. The percentage of pts with an EBV-DNA load reduction from baseline of greater than 25% was 50% in responders and 16.7% in non-responders (Figure 1). Conclusions: DARA 16 mg/kg was well tolerated with no new safety concerns, and only 2 patients discontinuing due to TEAEs. DARA monotherapy demonstrated an encouraging response rate (ORR: 25%) in pts with R/R NKTCL and warrants further study in this poor prognosis pt population. Disclosures Kim: Donga: Research Funding; Kyowa-Kirin: Research Funding; Roche: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; J&amp;J: Research Funding; Mundipharma: Research Funding. Kim:Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Takeda: Consultancy; AstraZeneca: Consultancy, Research Funding. Yoon:J&amp;J: Research Funding. Lim:National Cancer Centre Singapore: Employment. Qing:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. OffLabel Disclosure: Daratumumab is under investigation for NKTCL; daratumumab is approved for use as monotherapy in multiple myeloma.

Daratumumab Monotherapy in Previously Untreated High-Risk Patients with Stage 3B Light Chain (AL) Amyloidosis: A Phase II Multicenter Study By European Myeloma Network (EMN)

Background: Advances in the anti-plasma cell therapy with the introduction of bortezomib-based therapies have improved the outcomes of patients with systemic light chain (AL) amyloidosis. However, patients with more severe cardiac involvement, (i.e., those with stage 3B disease defined as increased troponin levels with NT-proBNP level &gt; 8500 pg/ml) still have a dismal prognosis with a median survival of 4-9 months. A delay in hematologic response and potential treatment related toxicities, may not allow for improvement in the outcome of these high-risk patients. Unfortunately, patients with stage 3B disease are excluded from clinical trials; their management remains a challenge and new treatment options are urgently needed. Daratumumab is a human IgG1ĸ monoclonal antibody that binds with high affinity to a unique epitope on CD38. It acts on plasma cells that express CD38 via different mechanisms, including direct apoptotic activity and immune system mediated responses. In patients with relapsed or refractory AL amyloidosis, daratumumab monotherapy has shown rapid, deep and high response rates, which are durable. Moreover, daratumumab has shown an excellent toxicity profile and no signal of cardiotoxicity. An ongoing prospective randomized trial evaluates the addition of daratumumab to standard bortezomib-based therapy in previously untreated patients with AL amyloidosis but patients with stage 3B are excluded. In order to offer high risk AL patients a new treatment option we designed this phase 2 trial aiming to enroll exclusively patients with stage 3B disease. Study Design and Methods: This is an open-label, multicenter, Phase 2 study in subjects with newly diagnosed stage 3B AL amyloidosis. Approximately 40 subjects will receive primary therapy with daratumumab. Subject participation will include a Screening Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a Long-term Follow-up Phase. A safety run-in will include 6 subjects treated with daratumumab for at least 1 cycle to establish safety of the study drug in stage 3B AL amyloidosis patients. Dosing of these 6 patients will be staggered so that no subject will receive their first dose sooner than 48 hours after the previously enrolled subject. Safety evaluation will be performed by a Data Safety Monitoring Board after at least 1 cycle is completed for all 6 patients. If no safety signal is observed, the enrollment of the rest of the patients will begin. Subjects will initially receive daratumumab IV at a dose of 16 mg/kg, and by the end of 2019 will switch to daratumumab SC at a fixed dose of 1800 mg. Daratumumab will be administered weekly for Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. Each Cycle will last 28 days. The treatment will continue until disease progression according to Major Organ Deterioration Progression-Free Survival (MOD-PFS) criteria, start of subsequent therapy, or a maximum of 2 years. Patients who after 3 cycles of daratumumab monotherapy, have not achieved at least a hematologic VGPR or a hematologic PR with improved major organ function (i.e., cardiac or renal response per updated response criteria) may receive at the Investigator's discretion, bortezomib (1.3 mg/m2 weekly, for a maximum of 6 cycles) with low dose dexamethasone, in addition to daratumumab (Figure 1). The primary objective is to evaluate the overall survival (OS) rate at 6 months. The secondary objectives include evaluation of overall, VGPR and CR hematologic response rates at 3 and 6 months, MOD-PFS, PFS, organ response rate, treatment effects on patient-reported outcomes, time to and duration of response, safety and tolerability of daratumumab in patients with stage 3B AL amyloidosis. Minimal residual disease (MRD) may be monitored in subjects who achieve hematologic CR using high sensitivity methodologies (such as the Clonoseq NGS assay, or NGF based on the EuroFlow protocol). Safety will be measured by adverse events, laboratory tests, electrocardiograms, echocardiograms, vital sign measurements, physical examination and ECOG performance status. Health-related quality of life will be assessed via patient-reported outcome questionnaires. The study will run in 3 countries (Italy, Greece, and Netherlands), and will open for enrollment in August 2019. The recruitment is expected to last for 18 months, and the maximum time of treatment under the study protocol is 24 months. Disclosures Kastritis: Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria. Minnema:Servier: Honoraria; Jansen Cilag: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Celgene Corporation: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Palladini:Janssen-Cilag: Other: Travel grant; Sebia: Honoraria; Janssen-Cilag: Honoraria; Celgene: Other: Travel grant. OffLabel Disclosure: Daratumumab in AL amyloidosis

Daratumumab in the Clinic, a Real-Word Experience at Yale Cancer Center

Background: Multiple myeloma (MM) is an incurable and heterogeneous neoplasm of clonal plasma cells. Fortunately, the introduction of novel therapeutic agents has altered the landscape of MM with resultant improvements in both overall survival and quality of life for this patient population. The CD38-targeted humanized monoclonal antibody, daratumumab, has played a monumental role in this advancement. It has yielded significantly increased overall response rates and progression-free survival in landmark trials for relapsed/refractory MM (RRMM) (Dimopoulos MA et al, 2018; Spencer A et al, 2018) and has also now been successful in the induction therapy setting for both transplant-ineligible (Mateos MV et al, 2018; Facon T et al, 2019) and transplant-eligible (Moreau P et al, 2019) patients. However, concern has been raised regarding the high incidence of infusion-related reactions, reported to be as high as 71% in original phase I-II trials of daratumumab monotherapy (Lokhorst et al, 2015). We describe the real-world practice pattern of daratumumab utilization at Smilow Cancer Hospital, demonstrating an excellent safety profile and tolerability among our patients. Methods: We retrospectively reviewed the use of daratumumab in the management of RRMM for 57 patients treated at Smilow Cancer Hospital. Data was collected on the choice of treatment regimen, number of cycles administered, and the number and grade of infusion reactions. Per institutional protocol, patients receiving an initial cycle of daratumumab therapy were administered hypersensitivity premedication with acetaminophen, diphenhydramine, dexamethasone, and montelukast. Results: A total of 57 patients receiving treatment with daratumumab were evaluated and received an average of 10.3 cycles with a median of 8 cycles (range, 2-35 cycles). Of these 57 individuals, only 21.1% (12/57) experienced an infusion reaction all of which were grade 1-2 in severity. One hundred percent (12/12) of these patients developed reactions during the first infusion of daratumumab and all individuals completed the dose with no subsequent reactions for the remainder of their treatment course. All patients were able to be switched to rapid daratumumab infusion by their third dose. Of the evaluable patients, 5.4% (3/56) received daratumumab monotherapy while the remaining 94.6% (53/56) were treated with 3 or 4 drug combination regimens. At the time of this report, 49.1% (26/53) of our patients are still receiving daratumumab as a part of their anti-plasma cell therapy. Conclusions: Immunotherapy has served as a large contributor to the dramatic improvement observed in the management of patients with MM. Our review of real-word experience with use of daratumumab demonstrates that this agent is well-tolerated with infusion reaction rates that are significantly lower than those previously reported in the literature (Figure 1). The universal incorporation of the leukotriene receptor antagonist, montelukast, as premedication at our institution may have contributed to these enhanced outcomes. An expanded, multi-center study is being launched to evaluate a real-world experience of adverse event profile and patient-reported quality of life measures with daratumumab utilization, given the paucity of such data currently available. Disclosures Anderson: Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau. Neparidze:Janssen Scientific Affairs, LLC: Research Funding; Eidos Therapeutics: Other: Member of Independent Diagnostic Committee; MMRF/Synteract: Membership on an entity's Board of Directors or advisory committees.

Longitudinal T Cell Immunoprofiling of Patients with Relapsed and/or Refractory Myeloma Who Receive Daratumumab Monotherapy: A Subanalysis of a Phase 2 Study (the REBUILD Study)

Recent evidence suggests immunomodulatory effects of daratumumab in heavily pre-treated Multiple Myeloma (MM) patients (pts); however, the precise effects remain under-characterized, particularly at the molecular level. REBUILD is an ongoing prospective, multicenter, non-comparative, open-label, phase II study that evaluates the effects of daratumumab monotherapy on bone metabolism of pts with relapsed and/or refractory MM (RRMM) who have had ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. Secondary endpoint of the study included the evaluation of T cell dynamics by comprehensive analysis of the T cell receptor (TR) repertoire employing next generation sequencing (NGS) and multi-color flow cytometry. Herein we report the results of this secondary endpoint for the first 14 pts who completed 3 cycles of daratumumab monotherapy. In total, we analyzed 28 paired samples collected at screening (n=14) and on Day 1 of Cycle 4 (C4D1, n=14) of treatment in order to assess potential changes in relation to treatment and clinical response. Patients were grouped based on best responses into responders (i.e. patients with partial response [PR, n=1] and very good PR [VGPR, n=6]), and non-responders (i.e. patients with minimal response [MR, n=2], stable disease [SD, n=4], or progressive disease [PD, n=1]). Starting material was peripheral blood mononuclear cells. TRBV-TRBD-TRBJ gene rearrangements were RT-PCR amplified and subjected to paired-end NGS. Raw NGS reads (n=6,715,406 | median 221,145/sample) were processed through a previously published, purpose-built bioinformatics pipeline. Only productive TRBV-TRBD-TRBJ rearrangements were taken into consideration (n=3,097,565 | median 101,670/sample) for the computation of clonotypes (i.e. TRB rearrangements with identical TRBV gene usage and amino acid complementarity-determining region 3 sequence). Overall, 151,153 distinct clonotypes (median 5,084 clonotypes/sample) were assessed. Both groups (responders/non-responders) displayed clonal T cell expansions both pre- and post-treatment. Clonality was found to be increased after treatment for both responders and non-responders, with statistical significance in the former (median cumulative frequency of the 10 most expanded T cell clonotypes/sample: 31% pre-treatment versus 40% post-treatment, respectively | p=0.04). In both groups, the clonotype repertoire appeared to be renewed with only a small fraction of pre-treatment clonotypes remaining after treatment (1% for non-responders; 0.6% for responders). Interestingly, in the responders' group we noticed a significant shift in the major clonotype repertoire at screening vs C4D1. In particular, in the responders' group the 10 most expanded clonotypes/sample at C4D1 represented expansions of clonotypes present at very low frequency at screening, whereas the most expanded clonotypes at screening decreased or even diminished post-treatment, suggesting that daratumumab treatment led to the emergence of anti-myeloma T cell clones which contributed to clinical response. On the contrary, the 10 most expanded pre-treatment clonotypes in the non-responders' group tended to dominate also the post-treatment repertoire. Of note, 13 shared clonotypes were identified amongst the post-treatment repertoires of different patients (responders/non-responders); shared clonotypes were not found in other entities in public databases, raising the possibility that they may be "disease-specific" and selected by common tumor-associated antigens. With a single exception, shared clonotypes were detected in cases with relevant HLA restrictions, which is noteworthy given the random HLA background of our cohort. Finally, flow cytometry analysis revealed a significant increase post treatment in the percentage of CD3+ T cells (median frequency at screening 60% versus 83% at C4D1 | p=0.003), driven mostly by the expansion of the CD8+ T cell compartment (median frequency at screening 30.8% versus 48.9% at C4D1 | p=0.03) in both groups. In conclusion, TR clonality increases post-treatment through a renewal mechanism; however, pre-treatment clones significantly expanded post-treatment in responders, alluding to the existence of clonotypes with anti-MM properties that may be activated after treatment with daratumumab, arguably contributing to clinical response. Disclosures Kastritis: Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding. Hatjiharissi:Janssen: Honoraria. Katodritou:Genesis: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Amgen: Honoraria. Delimpasi:Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Genesis: Honoraria, Other: Travel grant. Symeonidis:Sanofi: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stamatopoulos:Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. Terpos:Janssen: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding. Chatzidimitriou:Janssen: Honoraria.

Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Efficacy and Safety of Nivolumab Combined with Daratumumab with or without Low-Dose Cyclophosphamide in Relapsed/Refractory Multiple Myeloma; Interim Analysis of the Phase 2 Nivo-Dara Study

Efficacy and Safety of Nivolumab Combined with Daratumumab with or without Low-Dose Cyclophosphamide in Relapsed/Refractory Multiple Myeloma; Interim Analysis of the Phase 2 Nivo-Dara Study

Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Daratumumab (DARA) Maintenance Therapy Improves Depth of Response and Results in Durable Progression-Free Survival (PFS) Following Dara Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) Induction Therapy in Multiple Myeloma (MM): Update of the Lyra Study

Efficacy and Safety of Daratumumab Combined with All-Trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma; Results of the Phase 1/2 Dara/ATRA Study

Efficacy and Safety of Daratumumab Combined with All-Trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma; Results of the Phase 1/2 Dara/ATRA Study

Phase 2 Study of Daratumumab Monotherapy in Previously Untreated Patients With Stage 3B Light Chain (AL) Amyloidosis

Phase 2 Study of Daratumumab Monotherapy in Previously Untreated Patients With Stage 3B Light Chain (AL) Amyloidosis

Daratumumab monotherapy in heavily pretreated Asians patients with relapsed and refractory multiple myeloma

Daratumumab is a first-in-class human immunoglobulin kappa monoclonal antibody targeting CD38. Clinical trials with daratumumab monotherapy in relapsed and refractory multiple myeloma (RRMM) have shown substantial efficacy and favorable safety profiles. However, these trials excluded patients with poor performance status and other significant co-morbidities, thus their.

Results of the Daratumumab Monotherapy Early Access Treatment Protocol (EAP) in Patients from Brazil With Relapsed or Refractory Multiple Myeloma

Results of the Daratumumab Monotherapy Early Access Treatment Protocol (EAP) in Patients from Brazil With Relapsed or Refractory Multiple Myeloma

Daratumumab Monotherapy in Heavily Pretreated Asian Patients With Relapsed and Refractory Multiple Myeloma: A Real-world Experience.

Daratumumab is a promising novel agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its efficacy and toxicity profiles in real-world patients, especially in the Asian population. This was a multicenter, retrospective, longitudinal cohort study set between January 2017 and April 2019. We collected and analyzed clinical and survival data of 21 patients treated with daratumumab monotherapy. All patients were previously exposed to proteasome inhibitors and immunomodulatory drugs. The overall response rate was 42.1%, including one complete remission (4.8%) and three very good partial responses (14.3%). The cycles of daratumumab delivered were three (range=1-10 cycles) and the median progression-free survival was 6 months, while the overall survival was not reached. Infusion reaction was observed in nine patients (42.9%), and one discontinued permanently. Fatigue was the most common adverse event (52.4%), and there were five cases of documented infection during daratumumab treatment, two of them leading to the death of the patient. Daratumumab monotherapy showed fairly promising activity with modest tolerance in heavily treated Asian RRMM patients.

Severe Sepsis Caused by Listeria monocytogenes in A Patient Given Monoclonal Antibodies Against CD38 and Proteosome Inhibitor

Severe Sepsis Caused by Listeria monocytogenes in A Patient Given Monoclonal Antibodies Against CD38 and Proteosome Inhibitor

PB2185 DARATUMUMAB MONOTHERAPY IN REAL LIFE COMMUNITY SETTING OF REFRACTORY MYELOMA PATIENTS: A RETROSPECTIVE UNICENTRIC STUDY

Background:Daratumumab (DARA) is a first in class CD38‐directed monoclonal antibody approved for the treatment of relapsed and/or refractory multiple myeloma (RRMM). In phase I/II and III trials, DARA monotherapy can induce an overall response (partial response or better) in about one third of patients, with rapid and durable responses. High occurrence of all grade of Infusion‐Related Reactions–IRRs‐ has been described (up to 50% of cases), including 5% of at least grade 3 IRRs. In some cases IRRs can induce infusion delayed or interruption and need of patient hospitalization. It is known that highest risk of reaction is during the first or second exposure to DARA.Aims:To describe DARA‐related IRR in real life clinical setting, particularly management of first infusion.MethodsStarting from April 2017, 13 RRMM patients received DARA intravenously (i.v.) according to the manufacture schedule. To reduce IRRs, only the first dose was split in 2 administrations within 24 hours. One hour after standard premedication the first 250 ml were given starting at infusion rate of 50 mL/hour as schedule. After 24 hours, premedication was given and the remaining 750 mL were infused as schedule.Results:Our cohort included 13 heavily pre‐treated patients (n = 76 M/F), most of them double refractory (n = 11) with a median of 4 previous lines (range 1‐13). Median age was 61 years (range 46‐74). At least 3 treatment cycles were given to 11 (84%) patients, two cycles to 12 patients.At the first day of infusion, 10/13 patients had a grade 1‐2 IRR treated with suspension of infusion for about 20‐30 minutes followed by infusion of antipyretics or antihistamine. Restarting DARA infusion was safe and comfortable. IRRs were cough in 4 patients, congestion and runny nose in 4 patients, throat tightness and dyspnea in 3 patients and chills in 1 patient. Rarely, a second manifestation of IRRs occurred again. Symptoms were treated in the same way and resolved promptly.None of our patients discontinued treatment for IRR, and up to now 5 patients are completing the third cycle, six patients died for disease progression (2 after the first cycle, 1 after the second cycle, 1 after the third cycle) while for the remaining 6 treatment is ongoing. 6/13 patients had severe adverse events (anemia and neutropenia ≥ grade 3, NCCN) and 2/13 pneumonia grade 3, requiring hospitalization.Clinical benefit was evident for 7/13 patients, with 53% of overall response rate (after 8 infusions): 1 patient achieved a CR, 2 achieved a very good partial remission (VGPR), 4 patients achieved partial response (PR), a patient achieved stable disease (SD).Progression occurred in 2 patients after 1 cycle, 2 patients after 2 cycles and two other after 3 cycles. Overall median PFS was 13 months, median OS was not reached.Summary/Conclusion:In line with published clinical trials in the setting of RRMM, DARA monotherapy is efficacious in RRMM patients with an overall response rate of 53%. According to our schedule, IRRs are weakly and occur only the first day, when the infusion rate is increased from 50 to 100 mL/hour and it can be reduced by splitting the infusion over 24 hours.

PB2132 DARATUMUMAB MONOTHERAPY FOR RELAPSED AND REFRACTORY MULTIPLE MYELOMA REAL CLINICAL PRACTICE. A MULTICENTRIC RETROSPECTIVE STUDY

Background:Daratumumab (DARA) was first approved as monotherapy for patients (P) with relapsed and refractory (RR) multiple myeloma (MM) after treatment with immunomodulatory drugs and proteasome inhibitors, and who have progressed on the last therapy, based on data from the phase 2 SIRIUS trial. Its results show 29% of P with at least partial response, progression‐free survival (Sv) (PFS) of 3.7 months(m) and overall survival (OS) of 17.5 m, and acceptable toxicity.Aims:So far, there are scarce data on treatment with DARA monotherapy in routine clinical practice.MethodsObservational, retrospective and multicenter study of P with RRMM treated with DARA in monotherapy outside clinical trial (CT) in various Spanish regions: Galicia, Asturias, Cantabria y Castilla y León. Statistical descriptive analysis with SPSS®: Sv curves by Kaplan‐Meier and measures of statistical association using Chi2.Results:There were 80 P (61% males) evaluable. Characteristics at diagnosis: age 64.8 years (y) (IQR 57.1‐73.3); previous COPD/asthma: 11.25%; myeloma stage ISS 3: 37.5%, and 2: 31.25%; adverse cytogenetics (del17p, t(4;14), t(14;16)): 21.25%. Characteristics at starting of DARA: age 70.5 y (IQR 60.9‐76.1); adverse cytogenetics: 17/33 P (52.5%); previous lines of treatment: median 3 (1‐10), in 52.5% of P including carfilzomib and/or pomalidomide; previous ASCT: 51.25%.The median of DARA doses administered per patient were 10 (1‐26); it should be pointed out tha t5 P only received 1 dose. The majority (78.7%) received the 1st dose hospitalized, and in 38.7% montelukast was associated to the conventional premedication. The rate of infusion‐ related reactions (IRR) is 23.7% for the 1st dose (grade 1: 78.9%, grade 3: 15.8%), with no difference according to premedication. Only 3 P suffered IRR grade 1 after 2nd dose.Response. Overall R (OR) 66.6% (CR 13.3%, PR + VGPR 33.3%, MR/SD 20%), progression 33.3%. With a median follow‐up of 243 days (IQR 113‐392), 48.7% have died (cause of death 79.4% MM) with no toxic mortality, and 25% continue treatment. PFS and OS are 111 days (87‐252) and 280 days (173‐700), respectively.Adverse events. Any grade adverse events occurred in 38.7%, being the most frequent neutropenia and/or infection (52%), thrombocytopenia (26%), nausea/vomiting (10%) and peripheral neuropathy (4%). All grade 3 (34%), and 4 (18%) adverse events were due to myelotoxicity and infection. In 25% of P a dose of DARA was delayed, for an average of 11 days (2‐30), 55% of them due to infection. None had to discontinue DARA because of toxicity.Summary/Conclusion:Our experience outside clinical trials confirms that DARA monotherapy is a safe and well‐tolerated drug, even in this population of elderly P with advanced disease and multiple previous lines of therapy. There are no serious IRR and the main toxicity, as otherwise should be expected, has been myelosuppression and infections. The OR rate is high, highlighting 46.6% with at least PR, but in spite of this PFS and OS are short, 3.7 m and 9.3 m respectively; in special OS is much lower than previously referred in SIRIUS trial. It should be noted out that 17 P did not complete the 1st cycle of DARA (4 doses) and 5P received only 1 dose, so a better selection of candidates for this Trt will probably improve these results.

S826 IMPROVED EFFICACY AND SAFETY OF A DUAL‐TARGET CAR‐T CELL THERAPY TARGETING BCMA AND CD38 FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA FROM A PHASE I STUDY

Background:Encouraging results are seen from several early phase clinical trials on the cellular immunotherapy for relapsed/refractory (RR) multiple myeloma (MM), including anti‐B cell maturation antigen (BCMA) CAR‐T cell therapy and anti‐CD38 daratumumab (DARA) monotherapy. We conducted an anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in order to avoid negative relapse of single‐target loss. Here we report a promising results on 12 patients about the efficacy and safety in the ongoing phase I study.Aims:1.To evaluate the safety of the anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in RRMM, including cytokine release syndrome (CRS), neurotoxicity and other adverse events. 2.To assess the efficacy of the anti‐BCMA and anti‐CD38 dual‐target CAR‐T cell in RRMM, including the overall response rate(ORR),duration of remission and Progression‐free survival(PFS). 3.To estimate the proliferation and persistence of the dual‐target CAR‐T cell in the blood of RRMM patients.Methods:A phase I clinical trial (ChiCTR1800018143) has been launched to evaluate the efficacy and safety of the dual‐target CAR‐T cell product for RRMM. The enrolled RRMM patients had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double‐relapsed or relapse after autologous hematopoietic stem cell transplantation(ASCT). Patients were subjected to a lymphodepleting regimen with Cy(250 mg/m2,d‐5 to d‐3) and Flu(25 mg/m2,d‐5 to d‐3) daily prior to the CAR‐T infusion (d0).The median number of infused cells was 2.17(0.5∼4.0) × 106 CAR+ cells/kg. The median follow‐up times is 21.5(6∼33)weeks and 66.7%(8/12) are more than 5 months. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma(2016), and the toxicity was graded by CTCAE 5.0.Results:As of January 31, 2019, 12 patients consisting of 66.67%(8/12) with genetic abnormalities,16.7%(2/12) with ASCT and 16.7%(2/12) with extrandal disease, have been infused with thedual‐target CAR‐T cell product. The overall response rate(ORR) is 83.3%(10/12), including 5 sCR, 2 VGPR and 3 PR. the shortest duration of sCR is 8 weeks and the longest one is over 26 weeks and 60%(3/5) have still maintained sCR more than 2 month. More encouragingly, 60%(6/10) have still kept sustained remission and allextramedullary lesions have been eliminated.The 8‐week Progression‐free survival(PFS) is 0.90 and 12‐week PFS is 0.77. Up to now, the CAR‐T cells still exists in the patients’ peripheral blood by flow cytometry and q‐PCR. The peak time of CAR‐T cells proliferation of sCR patients is about the 2nd week after infusion, which is earlier than other patients. 83.3%(10/12) were observed with cytokine release syndrome (CRS) and severe CRS(≥ Grade 3) accounted for 33.33%(4/12). No neurotoxicity was observed. Almost all the patients were observed with hematological toxicities. 16.7%(2/12) of patients was observed with hepatotoxicity and one patient with nephrotoxicity, which were relieved after symptomatic treatment.Summary/Conclusion:Our study demonstrates an improved efficacy with dual‐target CAR‐T therapy targeting BCMA and CD38 for RRMM with a high ORR, especially a higher rate and a longer duration of sCR. CRS and hematological toxicities are observed but manageable. Other toxicity is rare. These initial data provide strong evidence to support the further development of the dual‐target CAR‐T therapy for RRMM.ChiCTR1800018143 image

PB2146 SINGLE AGENT DARATUMUMAB IN VERY ADVANCED RELAPSED/REFRACTORY MULTIPLE MYELOMA PATIENTS: A REAL‐LIFE SINGLE CENTER RETROSPECTIVE STUDY

Background:Daratumumab is approved as a single agent for the treatment of patients (pts) with relapsed and refractory multiple myeloma (RRMM) who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMID), or who are double refractory to a PI and an IMID. In this setting, the pooled analysis of the GEN501 and SIRIUS trials showed an overall response rate (ORR) of 31%, a median progression‐free survival (PFS) and overall survival (OS) of 4.0 and 20.1 months, respectively. To date, few real‐life data have reported the efficacy of single agent daratumumab in unselected advanced myeloma patients.Aims:To evaluate efficacy and tolerance of single‐agent daratumumab in advanced RRMM patients outside clinical trials.MethodsAll consecutive patients treated in our institution between April 2016 and April 2018 were included in this retrospective study if they fulfilled all the following criteria: (i) diagnosis of RRMM who have received at least three prior lines of therapy including a PI and an IMID, or who were double refractory to PI and IMID, (ii) treatment with single agent daratumumab (iii) outside clinical trials. The response categories were defined according to the International Myeloma Working Group consensus criteria. OS and PFS were estimated using the Kaplan‐Meier method. Safety was evaluated through the rate of infusion related reactions (IRR) and adverse events (AE).Results:41 consecutive pts were analyzed. The median age was 68 years, including 7 pts (17%) older than 75 years. Eight pts (20%) had ECOG performans status &gt;2. Ten (24%) had high‐risk cytogenetic, and 13 (32%) had extra‐medullary disease. The median number of prior therapies was 4 (range 2‐9). All pts were previously exposed to PI and IMID, 59% were refractory to both PI and IMID and 95% refractory to IMID. All pts were refractory to the last line of therapy. The ORR was 24.4% (10/41), including 4.9% VGPR (2/41). At a median follow‐up time of 6.5 months, all pts had discontinued daratumumab because of disease progression. The median PFS was 1.9 months (CI 1.4‐2.5). For pts achieving partial response or better, the median PFS was 10.1 months (CI 8.3‐11.6). Median time to response for those patients was 1.2 months (CI 1.0‐1.8), and median response duration was 9.0 months (CI 4.6‐10.6). Median OS was 6.5 months (CI 3.1‐10.0). Twelve IRR occurred (29.3%) and mostly (11/12) consisted of grade 1‐2 reaction. Only one grade 4 IRR occurred needing permanent discontinuation of the drug. Others AE mostly (&gt;20%) consisted of infections, anemia and thrombocytopenia, with no new safety signal identified.Summary/Conclusion:This real‐life study demonstrated favorable safety profile but modest clinical efficacy of daratumumab monotherapy in very advanced unselected RRMM patients.