Daratumumab Treatment Research Articles

CO174 Real World Data of Daratumumab Treatment in Patient with Multiple Myeloma: A Portuguese Study

CO174 Real World Data of Daratumumab Treatment in Patient with Multiple Myeloma: A Portuguese Study

Analysis of daratumumab reporting in type and screen orders to identify opportunities for information system improvement

Abstract The rapid growth of monoclonal antibody therapies has resulted in a wide variety of targeted treatments towards malignancies. The presence of these antibodies in patient plasma can interfere with blood bank testing, which in turn can create a delay in the process of pretransfusion testing and provision of blood products to patients. Availability of information regarding particular medications can help guide blood bank processes and testing algorithms. Reporting of patient medications that can interfere with blood bank testing, including targeted therapeutic antibodies (e.g. anti-CD38 therapies such as daratumumab), often relies on the ordering provider to provide that information. At our institution, the type and screen (T&S) order contains a prompt that requests the history of daratumumab administration. Available responses are “yes”, “no”, or “unknown”, with the default answer of “unknown”. The goal of this study was to evaluate the reporting practice of daratumumab history in the T&S order and identify potential areas for process improvement. We retrospectively reviewed T&S orders for patients receiving daratumumab therapy during 2022 at a single institution. Of 370 patients who were receiving daratumumab therapy, 214 (57.8%) had T&S orders. Forty of the 214 patients (18.7%) with T&S orders had at least one order with a “yes” answer indicating daratumumab administration. Of the 40 patients with an answer of “yes”, 16 (40%) were associated with the initial T&S after starting therapy. Of the other answer options, 23 of 40 (57.5%) indicated “unknown” and 1 (2.5%) indicated “no”. The remaining T&S orders ordered after the initial order were evaluated for consistency in response. Of 352 total T&S orders placed after the initial T&S orders, 62 (17.6%) were “yes” answers, 4 (1.1%) were “no” answers, and 286 (81.3%) were “unknown”. These results suggest that manual reporting of daratumumab therapy is not optimized at time of initial T&S orders placed after daratumumab treatment is started and is further misaligned with treatment status with subsequent T&S orders. Development of automated methods may help improve the process of reporting medications to the blood bank to guide testing. Future directions include development of an informatics-based approach to link the patient’s medical administration record (MAR) to the laboratory information system (LIS) to provide history of daratumumab therapy to the blood bank. This approach will prioritize: (1) compatibility with the blood bank’s current workflow for testing, (2) clinical needs for ordering laboratory testing, and (3) adaptability for reporting of other relevant interfering therapies to the blood bank as well as to other clinical laboratories.

Identifying clinical response to daratumumab therapy in relapsed/refractory multiple myeloma using a patient-derived in vitro model.

Response to daratumumab in patients with relapsed/refractory multiple myeloma is heterogeneous, and a reliable biomarker of response is lacking. We aimed to develop a method that identifies response to daratumumab therapy. Patient-derived MM cells were collected before start of daratumumab treatment and were cultured in a hydrogel-based culture system. The extent of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro was associated with both clinical response and progression-free survival in corresponding patients. Together, our results demonstrate that in vitro sensitivity to daratumumab therapy in a hydrogel culture with primary MM cells might be used to identify patients most likely to benefit from treatment.

High Prevalence of Iron Deficiency Among Daratumumab-Treated Newly Diagnosed Multiple Myeloma Patients

Background: Iron deficiency (ID), a common cause of anemia, is often overlooked among patients with hematologic malignancies given alternative etiologies. Daratumumab is an anti-CD38 monoclonal antibody used in the management of multiple myeloma (MM). Approximately 45% of patients on daratumumab are anemic. In a study of 22 patients with relapsed refractory AL amyloidosis treated with daratumumab, 40% developed iron deficiency requiring IV iron replacement. It is unclear whether iron deficiency in this setting is specific to AL amyloidosis, or whether it is universally seen with daratumumab treatment. In this study we evaluated iron deficiency parameters, including bone marrow iron stores, in MM patients treated with daratumumab. Methods: We conducted a retrospective study to evaluate the prevalence of ID among newly diagnosed MM patients who were treated uniformly in a phase II study with the combination of daratumumab, ixazomib, lenalidomide and dexamethasone conducted at our center. Laboratory values of ferritin, hemoglobin and MCV were extracted from the medical records at trial enrollment and at 1-year from treatment initiation. ID was defined as ferritin <30 mcg/L. Bone marrow iron stores were assessed at pre-trial and 1-year from therapy initiation by Prussian blue stain of bone marrow clot sections, with grade 0 (absent iron) or grade 1 (trace to low iron) considered as depleted iron storage. Results: Among 54 included patients, 2 (3.7%) had ferritin <30 mcg/L at trial-enrollment, while 27 (50%) developed ID within 1 year and 33 (61%) became iron deficient during their treatment course. All patients (100%) had lower ferritin at 1 year compared to pre-trial value. The median reduction of ferritin at 1-year was 109 (IQR: 41-239 mcg/L), a decrease by 75% (IQR:56- 86%) from baseline value. Fifteen patients (28%) received IV or oral iron replacement, and 4 were already on iron-repletion before the 1-year landmark assessment. The median ferritin improved from 16 to 84 mcg/L (p<.0001) following iron replacement. Forty patients (74%) had improved hemoglobin at 1-year compared to baseline correlated to disease response to therapy. The median increment in hemoglobin was 1.1 (IQR: -0.3 - 2.7 g/dL). Hemoglobin at 1-year was higher in patients having ferritin ≥ 30 mcg/L compared to the ID group: 13.5 (IQR: 12.3-14.1 g/dL) vs 12.8 (IQR: 12.3-13.4 g/dL), p=.05. BM samples from pre-trial (n=37) and 1-year on-trial (n=36) were available for iron staining. Depleted iron storage was more frequent at1-year compared to baseline (63.9% vs 40.5%, p<.05). The median ferritin was lower in patients with iron depleted versus non-iron depleted BM: 58 (IQR: 31-120 mcg/L) vs 243 (IQR: 125-486 mcg/L) at baseline, p=.0002; 27 (IQR: 16-41 mcg/L) vs 59 (IQR: 19-245 mcg/L) at 1-year landmark, p=.07. Comparisons of laboratory markers at initiation and after 1-year on daratumumab trial are listed in Table 1. Conclusions: Our study demonstrated a high prevalence of ID among patients receiving daratumumab-based treatment for newly diagnosed MM. While some decrease in ferritin over treatment course may be caused by myeloma disease control and improved systemic inflammation, this study should increase awareness for ID among MM patients treated with daratumumab. Future studies are needed to better understand the possible role of daratumumab in the pathogenesis of ID in MM and other plasma cell disorders.

Prospective Evaluation of Measurable Residual Disease (MRD) and Sustainability of the Response in Patients with Systemic AL Amyloidosis Treated with Daratumumab

Background: Daratumumab can provide deep hematologic responses for patients with light chain (AL) amyloidosis, both through its direct anti-clonal activity and immunomodulatory effects on other cell populations in the bone marrow (BM) microenvironment. Promising efficacy in the frontline setting when combined with CyBorD (per the ANDROMEDA trial), as well as in the relapsed/refractory setting as monotherapy, has led to daratumumab becoming the first FDA-approved therapy for AL amyloidosis. Though it is administered for up to 24 cycles, the optimal duration of treatment is unclear. Dynamic monitoring of measurable residual disease (MRD) may provide insights into changes in the aberrant plasma cell (PC) clone and sustainability of the hematologic response in relation to daratumumab therapy. Aims: We sought to evaluate the rates of MRD clearance and resurgence both during and after daratumumab therapy for AL amyloidosis. Methods: MRD status was assessed for patients followed at the Boston University Amyloidosis Center, who were treated with a daratumumab-based regimen and achieved a hematologic very good partial response (hemVGPR) or complete response (hemCR) according to consensus criteria (Palladini, 2012). MRD assessments were performed by multiparametric 10-color flow cytometry of BM aspirates (sensitivity level of ≤10 -5) and repeated at 12-month intervals during follow-up. Clonal progression was defined as growth in the aberrant PC clone size of >1-log. Results: Between 2019 and 2023, a total of 66 patients achieved ≥hemVGPR and were tested for MRD; 43 (65%) received daratumumab monotherapy in the relapsed/refractory setting and 23 (35%) in combination with CyBorD as frontline therapy. Collectively, 48 (73%) achieved a hemCR and 18 (27%) a hemVGPR. The median age at diagnosis was 60 years (range 35-78); 19 (29%) patients were female; and 11 (17%) identified as non-white race. MRD assessment was performed once, twice or ≥3 times for 33, 18 and 15 patients, respectively. The first MRD evaluation occurred while still receiving daratumumab for 33 patients (at median 12 cycles, range 6-23); the remaining patients had their first MRD evaluation after therapy completion (median one month after, range 0-25). Of the entire cohort, 28 (42%) patients achieved MRD negativity and 38 (58%) MRD positivity (median estimated aberrant PC clone size 1.5 x 10 -4, range 1.4 x 10 -5 to 1.1 x 10 -2, representing 46.9% ± 32.8% of total PCs) at first evaluation. All but one patient with a hemVGPR had detectable MRD. Of the 23 patients who received frontline daratumumab-CyBorD (18 hemCR and 5 hemVGPR), 8 (35%) achieved MRD negativity at first evaluation; whereas 20 (47%) of the 43 patients who received daratumumab as monotherapy (30 hemCR and 13 hemVGPR) achieved MRD negativity. We surveyed MRD profiles based on the number of daratumumab treatment cycles received (Table 1) and found no apparent patterns with increasing cycles. Serial MRD monitoring was performed for 33 patients (Figure 1). Of 10 patients who continued to receive daratumumab between MRD assessments (group 1), 6 had sustained MRD negativity; 2 had persistent MRD positivity (of whom one had clonal progression); and 2 had MRD clearance (conversion from positive to negative). Of 23 patients who underwent serial MRD assessments after completing daratumumab (group 2), 9 (39%) had sustained MRD negativity; 10 (43%) had persistent MRD positivity; 2 (9%) had MRD clearance; and 2 (9%) had MRD resurgence (conversion from negative to positive), which occurred 17 and 26 months after daratumumab cessation. Clonal progression was observed in 5 of the 10 patients with persistent positivity, of whom 3 experienced a hematologic relapse. Conclusions: Our findings show that patients with AL amyloidosis can attain deep responses with daratumumab-based treatments, even to the depth of undetectable MRD. Clearance of MRD was frequent not only during treatment with daratumumab but also after completion of therapy, suggesting continuing effects on the plasma cell clone. Clonal progression after daratumumab completion was often associated with hematologic relapse. Prospective studies are needed to investigate whether daratumumab may be stopped early for those with undetectable MRD, or whether those with persistent detectable disease may benefit from extending daratumumab treatment beyond 24 cycles.

Myeloid Derived Suppressor Cells and Their Potential Impact on Minimal Residual Disease Status and Disease Response in a Cohort of Patients with Plasma Cell Dyscrasias

Myeloid Derived Suppressor Cells (MDSCs) are known to promote immune-suppressive and tumorigenic effects in plasma cell dyscrasias (PCDs), including multiple myeloma, and may play a role in treatment response and minimal residual disease MRD status in patients undergoing cancer-directed therapies. MDSCs are classified by their granulocyte-like effects (g-MDSCs) or monocyte-like effects (m-MDSCs). To our knowledge, there are no published studies that correlate minimal residual disease (MRD) with the presence of MDSCs and immune effector-cell populations in the blood and bone marrow of patients with PCDs. In 14 patients with PCDs, we defined immune-cell populations in the blood and marrow and correlated them with MRD status, treatment regimens, disease status (stable vs. progressive) and autologous stem cell transplantation status. In the entire cohort, there were a higher proportion of m-MDSCs in blood (blood 5.56%, aspirate 2.47%). There were a higher proportion of g-MDSCs in aspirate (blood 0.04%, aspirate 0.16%). Interestingly, in patients who remained MRD positive (3/13), the proportions were reversed, and we identified more m-MDSC in aspirate than blood, as well as a low proportion of g-MDSCs in both the aspirate and bone marrow. In patients achieving undetectable MRD (10/13) there were higher proportions of CD8 and CD4 T-cells, with no differences in MDSC populations. Not surprisingly, in patients treated with the anti-CD38 antibody daratumumab (5/14), fewer m-MDSCs were isolated in the blood and aspirate, relative to daratumumab-untreated patients (9/14).Daratumumab treatment decreased activated CD4 and CD8 T cells (HLA-DR+/CD38-, HLA-DR-/CD38+ or HLA-DR+/CD38+ CD4 and CD8 T cells) and increased the proportion of inactive HLA-DR-/CD38- CD4 and CD8 T-cells. In patients with progressive disease (3/14), there was a paucity of all immune effector-cells, including MDSCs, T-cells and monocytes with the exception of neutrophils. MDSC populations were no different in pre-transplant patients (3/14) compared to post-transplant (11/14). In this preliminary study, we have enumerated the presence of MDSCs and their potential impact in patients with PCDs undergoing cancer-directed therapy.

Characterization of a New Metabolic Score Correlated with CD38 Cell-Surface Expression and Response to Daratumumab Treatment in Multiple Myeloma

Multiple myeloma (MM) is the second most common hematological malignancy characterized by the uncontrolled accumulation of tumor plasma cells within the bone marrow. During the last 10 years, the development of new therapeutics, including the immune based therapies, significantly improved the life quality and survival of patients. However, the high molecular and clinical heterogeneity of this disease often leads to the development of resistance and relapses. Thus, MM unfortunately remains without definitive treatment in the majority of cases. Although few studies described the mechanisms of resistance to therapies developed by myeloma cells, a better understanding and new strategies to overcome the drug resistance mechanisms linked to Daratumumab remains of major interest for patients care. Among the factors that could be involved in myeloma cell resistance to anti-CD38 immunotherapies, we focused on the mitochondrial metabolism in MM, already described as a significant factor influencing response to treatments in several cancers. First, we defined a metabolic score using RNAseq data from different MM models, calculated with the gene expression of 112 genes involved either in the electron transport chain (Oxphos) or glycolysis. Each gene expression value was standardized and the metabolic score was built using the following equation: score= Σ(Glycolysis gene standardized expression) - Σ(Oxphos gene standardized expression). In our unique panel of 40 Human myeloma cell lines (HMCLs), high metabolic score significantly correlated with the functional metabolic profiles assessed by a Seahorse XFe96 analyzer included high mitochondrial and glycolysis activities on 25 HMCLs (r=0.6, p<0.05). Moreover, we tested the potential prognostic value of this metabolic score using cohorts of newly diagnosed MM patients treated by high dose of chemotherapy and autologous hematopoietic stem cell transplantation. In the MMRF CoMMpass cohort (674 patients), 32% of the patients with high metabolic score, defined using maxstat algorithm, were associated with a poor outcome (score>0.07; p<0.0005). These results were validated in an independent cohort of MM's patient (85 patients, Montpellier cohort), with a significant poor outcome associated with a high score (p<0.0005). Furthermore, we calculated the metabolic score in a cohort of MM's patients at diagnosis, who were then treated with anti-CD38 MoAb Daratumumab after relapse (Montpellier cohort N=42). Interestingly, we observed a significant difference between the mean score of patients with progressive or stable disease (n=13, mean score of 0.3380) and the mean score of patients with very good partial response or complete response (n=22, mean score of -0.0703), p<0.005). To validate these observations, the potential prognostic value was tested in that cohort: patients with high metabolic score were associated with a poor outcome (score>0.08; p<0.0005) suggesting a potential role of metabolism in the response to Dara treatment. We next questioned the possible link between the CD38 expression level at the surface of MM cells and their metabolic profile. For that purpose, we determined the CD38 surface antigen binding capacity (SABC) on 23 HMCLs representatives of MM heterogeneity. We observed a significant anti-correlation between the CD38 expression and the basal oxygen consumption rates (OCR) (r=-0.5, p<0.05) quantified with seahorse. Currently, correlations between CD38 expression measured on primary samples from patients with MM (MFI values) and their respective metabolic score are ongoing. However, these data suggest a link between mitochondrial activity, CD38 cell-surface expression and response to anti-CD38 MoAb. Altogether, our data demonstrated metabolism deregulation is associated with a prognostic value in newly diagnosed MM patients. Furthermore, we also reported a link between MM cell metabolism, CD38 expression and response to anti-CD38 MoAb treatment.

Real-World Analysis of Treatment Patterns and the Effectiveness and Safety Profile of Daratumumab-Based Regimens in Chinese Patients with Newly Diagnosed or Relapsed/Refractory Multiple Myeloma

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Several clinical trials have established DARA-based treatment as a standard of care globally for patients with newly diagnosed or relapsed/refractory multiple myeloma (MM). However, clinical trials do not always reflect routine clinical practice, and real-world (RW) studies thus provide an important complement to conventional clinical trials. Herein, we report results from an observational study that described RW treatment patterns and outcomes in routine clinical practice among patients with MM who were treated with DARA in China. This is possibly the first study to enroll a large population of Chinese patients with MM who were treated with DARA in the RW setting. Methods: This ongoing, multicenter, noninterventional, observational registry study is enrolling Chinese patients who have been diagnosed with symptomatic newly diagnosed or relapsed/refractory MM and either (1) started DARA treatment after August 1, 2019, and were expected to continue ongoing DARA at the time of study initiation (November 3, 2021) or (2) started DARA treatment after study initiation. Patients were excluded from the study if they had received ≥4 prior lines of MM therapy before starting DARA-based treatment or had a diagnosis of other cancers prior to their MM diagnosis. The decision to treat with DARA must have been made prior to and independently of the patient's inclusion in the study, and treatment was administered in accordance with local clinical practice. For patients who started DARA after August 1, 2019, but before study initiation, data were collected both retrospectively through medical chart review and prospectively after enrollment. RW baseline disease characteristics, treatment patterns, response rates, measurable residual disease (MRD), and safety are presented. Outcome and safety analyses were based on the DARA treatment period. Results: As of the cutoff date (April 30, 2023) for this analysis, 210 patients who received ≥1 dose of DARA have been enrolled in the study from 13 participating sites in China. At baseline (last status prior to the first DARA dose), patients had a median age of 64 y (range, 29-89) and a median time since MM diagnosis of 1 y (range, 0-12); the majority of patients had an ECOG performance status of 0 or 1 (82.4%) and a Durie-Salmon MM stage of III (74.4%). Most (83.8%) patients had received ≥1 prior line of therapy before initiating DARA, including 82.4% who had received prior protease inhibitors (PIs) and 58.1% who had received prior immunomodulatory drugs (IMiDs). A summary of prior therapies is provided in Table 1. DARA-based therapy included DARA monotherapy (n = 22) or combination with dexamethasone only (n = 21), PIs ± dexamethasone (n = 57), IMiDs ± dexamethasone (n = 71), PIs and IMiDs ± dexamethasone (n = 29), and other combinations (n = 10). The median DARA exposure time was 5.39 mo (interquartile range [IQR], 2.56-9.69), and the median follow-up time was 10.48 mo (IQR, 7.23-15.31). Of the 179 patients evaluable for response, a best overall response of partial response (PR) or better was achieved by 130 (72.6%) patients and a best response of very good partial response (VGPR) or better was achieved by 93 (52.0%) patients, with responses observed across DARA treatment regimens ( Table 2). MRD results were available for 53/179 (29.6%) patients, with 31/53 (58.5%) patients achieving MRD negativity. Adverse drug reactions were reported for 40 (19.0%) patients overall; events reported in ≥5% of patients included leukopenia (6.2%), thrombocytopenia (5.7%), and neutropenia (5.2%). Serious treatment-emergent adverse events were reported for 29 (13.8%) patients, with pneumonia (n = 10, 4.8%) the only serious event reported in ≥5 patients. Twenty-five patients died as of the cut-off date, regardless of timing (with/without DARA treatment period). Conclusions: This noninterventional, observational study provides RW insights into physician treatment decisions for patients with MM in China and the characteristics of patients who are selected for DARA-based treatment. In addition, the RW effectiveness, duration of therapy, and safety results support the use of DARA-based treatment as a standard of care in Chinese patients with newly diagnosed or relapsed/refractory MM. This study is ongoing, with a total planned enrollment of ~220 patients.

Pathobiology and Targeting of CD38 in Cutaneous T-Cell Lymphoma

Introduction: Cutaneous T-cell lymphoma (CTCL) is a malignancy of mature CD4+ T-cells that primarily affects the skin. Despite a wide variety of topical and systemic therapies for patients, CTCL remains difficult to treat. Because of its high likelihood of relapse and resistance, new therapeutic approaches are needed. We recently showed strong CD38 expression on neoplastic T-cells from patients with mature T-cell neoplasms, including CTCL. In this study, we evaluated i) the role of CD38 in CTCL pathogenesis ii) strategies to enhance CD38 expression in CTCL and iii) tested efficacy of combination therapy in vivo. Methods: Skin and peripheral blood samples from patients and healthy donors were evaluated for CD38 expression by immunohistochemistry (N=7), microarray (N=82), single-cell RNA-sequencing (N=11), and flow cytometry (N=14). To investigate the role of CD38 in CTCL, we generated CD38 knockout cell lines (H9, HH, and HuT-78) using CRISPR/Cas9-mediated genomic deletion. The CD38 wild-type (CD38 WT) and knockout (CD38 KO) cells were purified, cultured, and used for downstream functional analysis. We evaluated the lines for growth, metabolic capacities (XFe24 Seahorse assay), and engraftment potential in vivo. For in vivo therapeutic studies, we transduced firefly-luciferase gene into H9 CD38 WT and CD38 KO cells, and engrafted them intravenously into immunodeficient NOD Rag -/-γc -/- mice. Mice were treated with anti-CD38 antibody daratumumab or IgG control and disease progression was monitored over time using an in vivo imaging system. For combination studies, we evaluated CD38 expression by flow cytometry in H9 cells treated with increasing doses of HDAC inhibitor, panobinostat (5nM, 10nM, 25nM) for 24, 48, and 72 hours. Next, we tested co-treatment with panobinostat and daratumumab in vivo in mice engrafted with H9 CD38 WT cells with four treatment groups (vehicle/IgG, panobinostat/IgG, vehicle/daratumumab, and panobinostat/daratumumab). Results: Patient skin biopsies showed increased CD38 expression at both protein and RNA levels (log fold change 4.8; p<0.0001 by Mann-Whitney test). Across nine days of tracking under standard cell culture conditions, CD38 KO CTCL cells showed minimal growth differences compared to CD38 WT (p=0.22 by linear regression). However, CD38 KO CTCL cells showed significantly increased basal and maximum oxygen consumption rates (OCR) via seahorse assay when compared to CD38 WT cells (basal OCR 2.26 fold increase, p<0.0001; max OCR 1.83 fold increase, p<0.0001 by Mann-Whitney test). Using IVIS luminescent imaging, we found significantly increased in vivo growth of CD38 KO CTCL cells compared to CD38 WT cells (CD38 WT=2.2e8 photons/sec average total flux, N=7; CD38 KO=1e9 photons/sec, N=5; p=0.003 by Mann-Whitney test). These data suggest that the loss of CD38 in CTCL cells can accelerate the development of tumors in mice. In order to study the effectiveness of a targeted drug against CD38 in CTCL, we used anti-CD38 antibody daratumumab in our H9 xenograft model. Daratumumab treatment had a significant therapeutic effect on CD38 WT tumors compared to isotype control, reducing tumor burden by 84% (daratumumab average total flux=1.4e7 photons/sec, N=4; IgG average total flux=9.0e7 photons/sec, N=3; p=0.0002). Additionally, we explored methods to increase CD38 expression on CTCL cells. We found that panobinostat significantly increased CD38 expression on H9 CTCL cells in a dose dependent manner across multiple time points (max 85% increase in CD38 expression with 25nM panobinostat vs. DMSO at 72 hours; p<0.0001 by 2way ANOVA). In vivo testing demonstrated a statistically significant improved survival benefit in mice treated with the combination of panobinostat and daratumumab compared to mice that received daratumumab alone (vehicle median survival 23 days, N=4; daratumumab alone median survival 32 days N=4; panobinostat alone median survival 27.5 days, N=4; combination median survival 39 days, N=4; p=0.01 by log-rank test). The prolonged average survival benefit amounted to approximately one quarter of their entire overall lifespan. Conclusion: Our studies demonstrate strong evidence for further study into how CD38 regulates the growth and survival of CTCL cells. Our data also provide preliminary evidence for the clinical usefulness of combination therapies that increase CD38 expression to enhance tumor cell immunotherapeutic targeting.

Daratumumab Maintenance after Autologous Hematopoietic Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma

Background: Maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT) is a standard of care in newly diagnosed multiple myeloma (NDMM). Lenalidomide maintenance after transplantation is the most frequently recommended regimen. Daratumumab has been increasingly used as a maintenance drug in NDMM. However, there is no enough clinical information about daratumumab as maintenance strategy after ASCT. This study is aim to evaluate the efficacy and safety of daratumumab as maintenance after ASCT for NDMM. Patients and Methods: Clinical data, hematological and renal response, and safety of 15 post-transplant patients with NDMM who had received daratumumab maintenance between 1 May 2022 and 30 June 2023 were retrospectively analyzed. Daratumumab-naive patients received weekly dosing (16mg/kg) for the first 8 weeks. Results: Fifteen patients (11 males and 4 females) with median age of 58 years (41～72 years) , were included. Thirteen patients were daratumumab native, 6 patients had renal impairment, and 2 patients with high-risk cytogenetics. The median infusion times of daratumumab were 12 (6～17) times. Efficacy was evaluable in all 15 patients，and daratumumab maintenance therapy increase the rate of stringent complete response (from 6 [40%] to 9 [60%] ) by 20%，improved the renal response rate and median eGFR in patients with renal injury. During maintenance therapy with daratumumab, the most common hematological grade 3 adverse events(AE) were lymphopenia (4 [26.67%] of 15 patients), non-hematologic adverse events were infusion-related reactions (7 [46.67%] of 15 patients) and grade 3 pneumonia (5 [33.33%] of 15 patients). These 5 pneumonia patients were daratumumab naive ( 5 [38.46%] of 13 patients) , with median 8 (6～10)infusions. Among them, 3 patients chest CT showed interstitial infiltrates, and combination of methylprednisolone was effective. With a median follow-up of 12 months, one patient had died (not related to daratumumab treatment), 1-year OS rate was 93.33%. Conclusions: Daratumumab was safe and effective as a maintenance agent for post-ASCT patients with NDMM, and adverse events were controllable. The most common AE is grade 3 pneumonia, maybe a less dose-intense maintenance regimen for the first 8 weeks can reduce the incidence of pneumonia.

Real-world Duration of Use and Dosing Frequency of Daratumumab in Patients With Multiple Myeloma in the United States

Daratumumab (DARA) is an anti-CD38 monoclonal antibody approved as a combination therapy for newly diagnosed multiple myeloma (MM) and as monotherapy and combination therapy for relapsed or refractory MM cases. We assessed the length of DARA use across lines of therapy and the probabilities of treatment discontinuation in patients with MM in the real-world. We used the deidentified Clinformatics Data Mart database from Optum to identify patients with MM (n=2124) who received DARA-containing treatment between November 1, 2015 and March 31, 2021 in the United States. Patients were excluded if they had received a stem cell transplant. The duration of DARA use was defined as the time interval between the first initiation and discontinuation of DARA as a time-to-event outcome using the Kaplan-Meier method. A gap of more than 60 days between 2 consequent DARA claim dates was defined as DARA discontinuation. The median duration of continuous DARA use was 16.6 months. By 24 months, 33.1% of patients remained on DARA treatment. In a subgroup analysis of patients with 12 months or more continuous insurance coverage (n=1246), the median length of DARA use was 24.7 months; by 24 months, 51.8% remained on DARA treatment. The dose adherence ratios (observed DARA doses relative to the label) were close to 1.0, particularly among patients with longer follow-up, indicating that real-world DARA dosing frequency was similar to that on the approved label. In summary, this real-world analysis reported that the median duration of continuous DARA use is 16.6 months, with high dosing adherence in patients who have MM.

P-164 Reduction in disease symptoms/impacts after daratumumab, lenalidomide, bortezomib, and dexamethasone treatment for transplant-eligible patients with newly diagnosed multiple myeloma (GRIFFIN study)

P-164 Reduction in disease symptoms/impacts after daratumumab, lenalidomide, bortezomib, and dexamethasone treatment for transplant-eligible patients with newly diagnosed multiple myeloma (GRIFFIN study)

Identifying therapeutic monoclonal antibodies using target protein collision electrophoresis reflex assay to separate the wheat from the chaff

Monoclonal gammopathies are characterized by the presence of monoclonal immunoglobulins, also known as M-proteins. Therapeutic monoclonal antibodies (t-mAbs) can interfere in laboratory assays used to monitor the state of disease, such as serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE). To establish a correct interpretation of IFE, Target protein-Collision Immunofixation Electrophoresis Reflex Assay (T-CIERA) was developed to identify t-mAbs in IFE. Here we demonstrate that T-CIERA is applicable to a wide variety of t-mAbs for which the target protein is commercially available. Moreover, the shift observed was characteristic for each t-mAb, and T-CIERA enabled the identification of multiple t-mAbs sharing a common target protein. Additionally, the lower limit of detection (LLOD) was determined objectively, and T-CIERA demonstrated an adequate LLOD for all tested t-mAbs. Furthermore, T-CIERA was also successfully applied to serum samples obtained from patients receiving daratumumab, isatuximab, elotuzumab, and durvalumab treatment. In conclusion, T-CIERA is a suitable reflex assay for identifying a wide variety of t-mAbs, including those for which no commercial assay is available to deal with their interference. Moreover, CD38-CIERA could serve as an alternative or complementary test to the commercially available Hydrashift assay kits. T-CIERA would enable laboratories without mass spectrometry equipment and expertise in this area to distinguish between drug and disease to improve clinical response monitoring and diagnosis of monoclonal gammopathies.

Outcome of carfilzomib/pomalidomide-based regimens after daratumumab-based treatment in relapsed multiple myeloma: A Canadian Myeloma Research Group Database analysis.

Although daratumumab-containing regimens improve multiple myeloma (MM) outcomes, recurrence is inevitable. We performed a retrospective study using the Canadian Myeloma Research Group Database to benchmark the efficacy of carfilzomib- or pomalidomide-based therapies immediately following progression on daratumumab treatment. We identified 178 such patients; median number of prior lines of therapy was 3, 97% triple-class exposed, and 60% triple-class refractory. In our cohort, 75 received a subsequent carfilzomib-based therapy, 79 received a pomalidomide-based therapy, and 24 received a treatment with both immunomodulatory drug (IMiD) and proteasome inhibitor (PI) using carfilzomib and/or pomalidomide. The median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 4.5 and 14.2 months, respectively. Carfilzomib-based therapy yielded a median PFS and OS of 4.5 and 10.2 months, respectively, compared to 5.2 and 21.7 months for pomalidomide-based therapy. Patients who received both IMiD and PI with carfilzomib and/or pomalidomide had a median PFS and OS of 4.1 and 14.5 months, respectively. Our observations demonstrate the poor outcome of MM patients when standard regimens based on carfilzomib and/or pomalidomide are utilized directly after daratumumab-based therapy given in the relapsed setting. Novel therapies, including immune therapies, are urgently needed to improve the outcomes of these daratumumab-exposed patients.

Camelid-derived CD38 antibody successfully circumvents epitope blockade by the therapeutic anti-CD38 antibody daratumumab.

To evaluate the efficacy of an anti-CD38 nanobody to detect plasma cells in a flow cytometry myeloma minimal residual disease (MRD) panel in patients treated with daratumumab and other immunotherapies. Twenty-three bone marrow samples from as many patients were collected during or at the end of daratumumab treatment cycles. A 5-tube, 8-color flow cytometry MRD panel was performed. Dotplots were reviewed, and the median fluorescence intensity (MFI) was calculated. Patients' ages ranged from 45 to 77 years, and the cohort was made up of 13 men and 10 women who had undergone 2 to 24 cycles of daratumumab therapy at the time of myeloma MRD testing. In all 23 cases, therapeutic use of daratumumab impaired pathologists' ability to measure CD38 on plasma cells when using a conventional murine monoclonal antibody (anti-CD38 fluorescein isothiocyanate [FITC], clone T16; Beckman Coulter). In 21 of the 23 cases, the measurement of CD38 was restored when the anti-CD38 nanobody was employed. Compared with anti-CD38 FITC, the anti-CD38 Alexa Fluor 488 nanobody (Beckman Coulter) produced higher MFI and allowed measurement of a higher frequency of discernable plasma cells. The camelid-derived CD38 antibody successfully circumvents the steric inhibition of CD38 that the therapeutic use of daratumumab imparts and facilitates myeloma MRD plasma cell detection.

NK Cell Phenotype Is Associated With Response and Resistance to Daratumumab in Relapsed/Refractory Multiple Myeloma.

The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16+ and granzyme B+ NK cells, and higher frequency of TIM-3+ and HLA-DR+ NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells.

Real-world clinical outcomes in patients with multiple myeloma treated with isatuximab after daratumumab treatment

Isatuximab and daratumumab are anti-CD38 monoclonal antibodies used to treat refractory multiple myeloma. Isatuximab is often used after unsuccessful daratumumab treatment; however, the clinical benefits of receiving isatuximab after daratumumab treatment have not been fully evaluated. Therefore, this retrospective cohort study assessed the clinical outcomes of 39 patients with multiple myeloma who were administered isatuximab after daratumumab. The median follow-up period was 8.7months (range 0.1-25.0months). The overall response rate was 46.2% (18 patients). The 1-year overall survival was 53.9%, with a median progression-free survival of 5.6months. The median progression-free survival in patients with high and normal lactate dehydrogenase levels was 4.5 and 9.6months, respectively (P = 0.004). The median progression-free survival in patients with and without triple-class refractory disease was 5.1months and not reached, respectively (P = 0.001). The median overall survival in patients with high and normal lactate dehydrogenase levels was not reached and 9.3months, respectively (P = 0.001). The median overall survival in patients with and without triple-class refractory disease was 9.9months and not reached, respectively (P = 0.038). Our findings provide insight into the optimal use and timing of anti-CD38 antibody therapy.

Chemotherapy May Obviate Prophylactic Femoral Nail Surgery for Multiple Myeloma Patients With High Mirels’ Score Lesions and Impending Pathological Hip Fracture

Bone involvement presents in >80% of patients with multiple myeloma. This causes lytic lesions for which prophylactic surgery is indicated to prevent pathological fractures if the lesion is graded ≥9/12 on Mirels’ score. Although successful, these surgeries have risks and extended recovery periods. We present a case indicating myeloma chemotherapy may obviate prophylactic femoral nailing for high Mirels’ score lesions in the femoral head with impending pathological hip fracture. A 72-year-old woman presented in December 2017 with back pain. A plain X-ray indicated degenerative anterolisthesis in her lumbosacral spine. Serum analysis revealed abnormal protein, globulin, alkaline phosphatase, and albumin levels while protein electrophoresis and serum immunofixation revealed raised immunoglobulin A (IgA) kappa paraprotein and kappa serum free light chains, respectively. Whole-body CT scans showed widespread lytic bone lesions and bone marrow biopsy confirmed infiltration by plasma cells. She was diagnosed with International Staging System (ISS) stage 3 multiple myeloma, which was successfully treated with bortezomib, thalidomide and dexamethasone with regular bisphosphonates that year. She presented again to the hospital in June 2020 with acute back and pelvic pain; Her paraprotein and serum-free light chains had increased significantly from her previous clinic appointment, indicating serological progression. MRI showed a relapse of the myeloma deposits in her right femoral head and spine. The deposit in her femoral head was graded 10/12 on Mirels’ score, which indicated prophylactic femoral nailing. Instead, the patient was treated with daratumumab, bortezomib, and dexamethasone with escalation to monthly zoledronic acid infusions, as it was thought surgery would provide limited cytoreductive effect, preventing chemotherapy for six weeks post-surgery, potentiating pathological hip fracture and disease progression at other sites. This resulted in a complete response, thus reducing the deposits such that the femoral lesion was graded <8 on Mirels’ score, improved her pain, and restored her ability to traverse stairs. She remains in complete response with ongoing daratumumab and denosumab maintenance treatment as of December 2022. Chemotherapy and bisphosphonates substantially reduced the myeloma deposit in the femoral head such that indications of prophylactic surgery were eliminated according to Mirels’ score recommendations. This reduced the risk of pathological hip fracture whilst eliminating surgical complications. Further research should be conducted into the safety and efficacy of this treatment regimen in patients with high Mirels’ score lesions. With this knowledge, consideration can be taken as to whether prophylactic femoral nailing is necessary given strong indications.

The TEMPI syndrome: evolution and response to bortezomib and daratumumab treatment

The TEMPI syndrome: evolution and response to bortezomib and daratumumab treatment

Cytomegalovirus and Epstein-Barr virus infection during daratumumab treatment in patients with multiple myeloma

ABSTRACTS We explored the incidence of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections in 131 patients with multiple myeloma (MM), 53 of whom received daratumumab (Dara) treatments. The Dara group had more RRMM patients than the group without Dara. CMV infection was significantly more common in patients treated with Dara (16.98%) than in patients treated with regimens without Dara (2.56%). During Dara treatments, 24.53% of patients developed CMV and/or EBV infections. Patients who developed infections had significantly lower levels of albumin and lymphocytes in their peripheral blood. The median time from the first Dara infusion to infection was 27 days. We observed NK cell depletion and T cell expansion during Dara-treatment. Patients with CMV and/or EBV infections had significantly lower numbers of NK cells, total T cells, and CD8 + T cells at 1 month, and lower numbers of CD8 + T cells at 2 months after the first Dara infusion than those without infections.