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Summary: The immunosuppressive treatment of immune‐mediated thrombotic thrombocytopenic purpura (iTTP) in patients with intolerance or refractoriness to the B‐cell depleting monoclonal antibody rituximab remains debated. Daratumumab, a plasma cell‐directed monoclonal antibody targeting CD38, represents a therapeutic option, but data are scarce. The French Thrombotic Microangiopathies Reference Center conducted a nationwide survey on iTTP patients treated with daratumumab. Nine episodes from seven patients were identified. Treatment was administered for A Disintegrin And Metalloproteinase with ThromboSpondin‐1 motifs, 13th member (ADAMTS13) relapses while patients were otherwise in clinical response (N = 8), or during the acute phase of the disease following rituximab intolerance (N = 1). Patients have received a median of three previous therapeutic lines. ADAMTS13 activity improved in eight cases following daratumumab administration, including three cases where ADAMTS13 normalized. ADAMTS13 relapses occurred in three patients; in two cases, retreatment with daratumumab was successful. Median ADAMTS13 relapse‐free survival was not reached; 12‐month ADAMTS13 relapse‐free survival was 56%. Daratumumab‐related adverse events occurred in five cases and were non‐severe infusion‐related reactions in all cases. These results suggest that daratumumab may be an effective treatment option for iTTP patients with intolerance or refractoriness to rituximab. [ABSTRACT FROM AUTHOR]

Summary: In Australia, bortezomib‐based induction (V‐IND) is used in >90% of newly diagnosed transplant‐eligible multiple myeloma (MM) patients. Four cycles of V‐IND with bortezomib–cyclophosphamide–dexamethasone or bortezomib–lenalidomide–dexamethasone are available via the Pharmaceutical Benefits Scheme prior to autologous stem cell transplantation (ASCT). Patients who demonstrate suboptimal response or who are refractory to V‐IND demonstrate inferior survival, representing a subgroup of MM where an unmet need persists. We evaluated an early, response‐adapted approach in these patients by switching to an intensive sequential therapeutic strategy incorporating daratumumab–lenalidomide–dexamethasone‐based (DRd) salvage, high‐dose melphalan ASCT followed by DRd consolidation and R maintenance. The overall response rate following four cycles of DRd salvage was 72% (95% credible interval: 57.9–82.4); prespecified, dual, Bayesian proof‐of‐concept criteria were met. Euro‐flow minimal residual disease (MRD) negativity was 46% in the intention‐to‐treat population and 79% in the evaluable population following 12 cycles of DRd consolidation. At the 24‐month follow‐up, median progression‐free survival and overall survival were not reached. DRd salvage was well tolerated with grade 3 and 4 events reported in 24% and 8% respectively. Response‐adapted DRd combined with ASCT achieves high rates of MRD negativity and durable disease control in this functional high‐risk group. [ABSTRACT FROM AUTHOR]

Summary: Chronic refractory primary immune thrombocytopenia (CRITP) is currently defined as refractory to multiple therapeutic of second‐line agents with or without splenectomy, faced with the threat of severe bleeding and challenging to obtain effective treatment. Although stable and effective drug therapy is needed, it is tough to find one. Daratumumab (Dara), an anti‐CD38 monoclonal antibody presented the target cloned plasma cells in multiple myeloma, has also been reported to be effective in refractory autoimmune cytopenia in some case or series reports and ongoing clinical trials for adult patients with CRITP. Here, we report the early and durable response of Dara combination with avatrombopag in three CRITP patients (2 male and 1 female aged 12, 5 and 7 years, respectively) in our centre, with a follow‐up period of more than 25 weeks. Before Dara, the duration of immune thrombocytopenia was 9, 1.4 and 4 years, respectively, a baseline platelet count of 4, 6, 9 × 109/L, the bleeding score was all above level 2 and the number of previous drugs was >3. The time to response (R: Plt ≥30 × 109/L with at least a twofold increase in the baseline count) of Dara was on Day 45, 6 and 4 and achieved complete response (CR: Plt ≥100 × 109/L) on Day 51, 6 and 8, the sustained response (SR: Plt >30 × 109/L following Dara at ≥75% of the platelet count assessment at follow‐up end‐point since the patient achieved response) was 48, 175 and 204 days with the follow‐up time of 39.1, 25.9 and 29.7 weeks. The bleeding score decreased from grade 3 to grade 0 during follow‐up. No significant treatment‐related adverse events were found during follow‐up. Dara combination with avatrombopag may be a safe and efficacious therapy for children with CRITP, but it needs to be further explored. [ABSTRACT FROM AUTHOR]

Summary: Bortezomib is regularly used as frontline therapy for systemic AL amyloidosis. We assess the efficacy of second‐line daratumumab‐bortezomib‐dexamethasone (DVD) in AL amyloidosis in bortezomib‐exposed patients. A total of 116 patients treated with second‐line DVD were identified from a prospective observational study of newly diagnosed AL amyloidosis (ALchemy). DVD was initiated in both the relapsed setting or where there was an inadequate response defined as very good partial response (VGPR) or VGPR with organ progression/lack of organ improvement. A complete response (CR)/VGPR to second‐line DVD was achieved in 81 (69.8%) patients. A CR/VGPR was achieved in 67 (79.7%) in those who achieved a VGPR/CR to first line versus 14/32 (43.8%) in those who did not. Where DVD was initiated due to an inadequate response to first line (vs. at relapse), the median event‐free survival (EFS) was 18 vs. 34 months (p = 0.002). If a CR/VGPR was achieved to DVD, the 2‐year EFS was still lower in those with prior inadequate response 54% vs. 66% (p = 0.062). DVD is an efficacious second‐line treatment in systemic AL amyloidosis in a bortezomib‐exposed population. However, the response to DVD is poorer in those with an inadequate response to first‐line bortezomib. [ABSTRACT FROM AUTHOR]

Summary: Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant‐eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment‐emergent adverse events. In summary, these findings suggest a benefit of D‐RVd front‐line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients. [ABSTRACT FROM AUTHOR]

This article discusses a case report of a patient with sickle cell disease (SCD) who underwent a donor-specific antibody desensitization treatment using daratumumab prior to a hematopoietic cell transplant. The patient had a history of red cell antibodies and high levels of HLA antibodies, which increased the risk of graft failure. Traditional pretransplant immune suppression methods were ineffective, so the patient received daratumumab along with other treatments, resulting in a reduction in antibody levels. The patient successfully underwent the transplant and achieved full donor chimerism with no evidence of graft-versus-host disease. This is the first reported use of daratumumab for this indication in SCD. The document also includes a table summarizing three different studies on patients who underwent allogeneic hematopoietic cell transplantation (AlloHCT), providing information on various factors such as desensitization regimens and donor chimerism. The authors acknowledge funding support and declare any conflicts of interest. [Extracted from the article]

Summary: Induction therapy followed by CD34+ cell mobilisation and autologous transplantation represents standard of care for multiple myeloma (MM). However, the anti‐CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. In this study, we investigated the effect of three different regimens (dara‐VCd, isa‐KRd and VTd) on CD34+ cells using flow cytometry and transcriptomics. Decreased CD34+ cell peak concentration and yields, longer collection and delayed engraftment were reproduced after dara‐VCd/isa‐KRd versus VTd induction in 34 patients in total. Using flow cytometry, we detected major changes in the proportion of apheresis product and bone marrow CD34+ subsets in patients treated with regimens containing anti‐CD38 therapy; however, without any decrease in CD38high B‐lymphoid progenitors in both materials. RNA‐seq of mobilised CD34+ cells from 21 patients showed that adhesion genes are overexpressed in CD34+ cells after dara‐VCd/isa‐KRd and JCAD, NRP2, MDK, ITGA3 and CLEC3B were identified as potential target genes. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion‐related interactions, rather than killing of CD34+ cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti‐CD38 therapy. [ABSTRACT FROM AUTHOR]

Access to upfront daratumumab for AL amyloidosis is expanding, but it is not universal. Bomsztyk et al. show that patients who do not receive front‐line daratumumab can be effectively rescued with this agent, indicating that deep haematological response should be pursued tenaciously. Commentary on: Bomsztyk et al. Response rates to second‐line treatment with daratumumab bortezomib dexamethasone (DVD) in relapsed/refractory light chain (AL) amyloidosis after initial bortezomib‐based regime. Br J Haematol 2024;205:138–145. [ABSTRACT FROM AUTHOR]

Summary: As daratumumab use in AL amyloidosis increases, more patients will either relapse after or become refractory to daratumumab. We present the outcome of 33 patients with AL who failed on daratumumab (due to haematological relapse in 21 [64%] patients and inadequate haematological response in 12 [36%]) and received further treatment. Overall response rate in the post‐daratumumab failure treatment was 55% (CR/VGPR: 14 [42%] and PR: 3 [9%] patients). Patients retreated with daratumumab and patients harbouring +1q21 had lower rates of response. Treatment of patients with AL who fail daratumumab therapy is feasible when non‐cross‐resistant drugs or other targeted therapies are available. [ABSTRACT FROM AUTHOR]

Summary: Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease. Such agents include the neonatal Fc receptor antagonist efgartigimod, the Bruton tyrosine kinase inhibitor rilzabrutinib, the complement inhibitors sutimlimab and iptacopan and anti‐CD38 monoclonal antibodies such as daratumumab and mezagitamab, among others. Each of these agents exploits therapeutic targets or other aspects of ITP pathophysiology currently not targeted by the existing approved agents (thrombopoietin receptor agonists and fostamatinib). This manuscript offers an in‐depth review of the current available data for novel therapeutics in ITP presently undergoing phase 2 or 3 studies in patients with heavily pretreated or refractory ITP. It additionally highlights the future directions for drug development in refractory ITP, including discussion of innovative clinical trial designs, health‐related quality of life as an indispensable clinical trial end‐point and balancing potential toxicities of drugs with their potential benefits in a bleeding disorder in which few patients suffer life‐threatening bleeding. [ABSTRACT FROM AUTHOR]

Keywords: daratumumab; plasma cell; refractory; thrombotic thrombocytopenic purpura (TTP) EN daratumumab plasma cell refractory thrombotic thrombocytopenic purpura (TTP) 429 433 5 07/14/23 20230715 NES 230715 INTRODUCTION Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition usually associated with IgG antibody-mediated destruction of the disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) enzyme. ADAMTS13 activity was typically performed within 24 h of sample collection, whereas ADAMTS13 antigen and anti-ADAMTS13 IgG antibody titres were analysed in batches, delaying incorporation of the results into the clinical management. ADAMTS13 activity B ( b TECHNOZYM® ADAMTS13 Activity ELISA Kit), ADAMTS13 antigen (TECHNOZYM® ADAMTS13 Antigen ELISA Kit) and anti-ADAMTS13 IgG antibody titres (TECHNOZYM® ADAMTS13 INH ELISA Kit) were determined by ELISA method. Both had a reduction in anti-ADAMTS13 IgG antibody titres after daratumumab and had negative anti-ADAMTS13 IgG antibody titres by 90 days. [Extracted from the article]

Summary: Although Dara–VCD (daratumumab–bortezomib–cyclophosphamide–dexamethasone) has revolutionized the treatment of newly diagnosed Amyloid Light chain (AL) amyloidosis, patients with stage IIIb disease were excluded in the pivotal trial. We performed a multicentre retrospective cohort study to investigate the outcomes of 19 consecutive patients treated with Dara–VCD front‐line therapy who had stage IIIb AL at diagnosis. More than two thirds presented with New York Heart Association Class III/IV symptoms, and had a median of two organs involved (range, 2–4). The haematologic overall response rate was 100%, with 17/19 patients (89.5%) achieving a very good partial response (VGPR) or better. Haematologic responses were achieved rapidly, as evidenced by 63% of evaluable patients with involved serum free light chains (iFLC) < 2 mg/dl and the difference between involved and uninvolved serum free light chains (dFLC) <1 mg/dl at three months. Among 18 evaluable patients, 10 (56%) achieved a cardiac organ response and six (33%) cardiac VGPR or better. The median time to first cardiac response was 1.9 months (range, 0.4–7.3). At a median follow‐up of 12 months for surviving patients, estimated one‐year overall survival was 67.5% [95% confidence interval (CI), 43.8–84.7]. The incidence of grade 3 or higher infections was 21%, with no infection‐related mortality thus far. In summary, Dara–VCD has a promising efficacy and safety profile in stage IIIb AL, and should be studied in prospective trials. [ABSTRACT FROM AUTHOR]

Summary: The CD38‐targeting monoclonal antibodies (CD38 mAbs) are well‐established therapies in multiple myeloma (MM), but responses to treatment are not always deep or durable. Natural killer (NK) cells deficient in Fc epsilon receptor gamma subunits, known as g‐NK cells, are found in higher numbers among individuals exposed to cytomegalovirus (CMV) and are able to potentiate the efficacy of daratumumab in vivo. Here, we present a single‐centre, retrospective analysis of 136 patients with MM with known CMV serostatus who received a regimen containing a CD38 mAb (93.4% daratumumab and 6.6% isatuximab). CMV seropositivity was associated with an increased overall response rate to treatment regimens containing a CD38 mAb (odds ratio 2.65, 95% confidence interval [CI] 1.17–6.02). However, CMV serostatus was associated with shorter time to treatment failure in a multivariate Cox model (7.8 vs. 8.8 months in the CMV‐seropositive vs. CMV‐seronegative groups respectively, log‐rank p = 0.18, hazard ratio 1.98, 95% CI 1.25–3.12). Our data suggest that CMV seropositivity may predict better response to CD38 mAbs, although this did not correspond to longer time to treatment failure. Larger studies directly quantitating g‐NK cells are required to fully understand their effect on CD38 mAb efficacy in MM. [ABSTRACT FROM AUTHOR]

Summary: Daratumumab, bortezomib and dexamethasone (DVd) is approved for patients with relapsed multiple myeloma following the CASTOR phase 3 clinical trial. This retrospective multicentre analysis assesses the overall response rate (ORR) and progression‐free survival (PFS) in routine clinical practice for patients at first relapse treated with DVd incorporating weekly bortezomib. Data were collected from 296 sequential patients treated across 15 UK centres. After a median follow‐up of 21 months, the ORR was 82% (26% partial response, 56% very good partial response or better) and the median PFS was 16 months [95% confidence interval (CI) 12–20 months]. Results were similar regardless of prior lenalidomide exposure. The median time to next treatment was 20 months (95% CI 15–25 months) and the estimated overall survival at two years was 74%. Patients with high‐risk features (by cytogenetics, International Staging System or extramedullary disease) and those treated within 18 months of initiation of progression‐free treatment, or within 12 months of autologous stem cell transplant, had significantly inferior outcomes. The grade 2 and 3 peripheral neuropathy rate was 7%. DVd with weekly bortezomib was effective in a heterogenous real‐world population at first relapse with a low rate of peripheral neuropathy. However, high‐risk patients had inferior outcomes and should be considered for alternative treatments. [ABSTRACT FROM AUTHOR]

Summary: The prognosis of multiple myeloma (MM) has dramatically improved with the development of new drugs, and it has become important to determine the appropriate combinations of these novel agents. This study was a systematic review and network meta‐analysis (NMA) of randomized trials in patients with relapsed and/or refractory (RR) MM. The PubMed, Cochrane, and Embase databases were searched for randomized trials from 1 January 2002 to 28 February 2022 of patients treated for MM. The primary end‐point was progression‐free survival (PFS), evaluated as a hazard ratio (HR) with a 95% confidence interval (95% CI) compared to dexamethasone (DEX). The p‐score was used to rank treatments. Of a total of 1136 abstracts screened, 37 studies were selected, including 34 treatment options for RRMM. Daratumumab, lenalidomide and DEX was found to be the best treatment for RRMM, with the best HR compared to DEX (HR, 0.13; 95% CI, 0.08–0.20; p‐score 0.9796). There was no evidence of significant heterogeneity (I2, 41.3%; p = 0.146). The current NMA confirmed the excellent efficacy of three‐drug regimens including anti‐CD38 antibodies to treat RRMM and provides background data to evaluate the efficacy of chimeric antigen receptor T‐cell treatments and bispecific T‐cell engager therapies. [ABSTRACT FROM AUTHOR]

This article, published in the British Journal of Haematology, discusses the successful treatment of scleromyxoedema, a rare mucinous disease associated with monoclonal gammopathy. The case study focuses on a 51-year-old female patient who had been diagnosed with scleromyxoedema in 1992 and had accompanying monoclonal gammopathy of undetermined significance (MGUS). The patient underwent various treatments, including topical steroids, retinoids, laser therapy, and systemic treatments commonly used in myeloma therapy. However, these treatments only provided short-lived responses. Eventually, the patient was started on daratumumab monotherapy, which led to an undetectable M protein level, significant improvement in skin manifestations, and the absence of seizures. This is the first report of antiCD38-antibody treatment for scleromyxoedema. [Extracted from the article]

Summary: Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D). Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT) received D‐RVd/RVd induction, high‐dose therapy and ASCT, D‐RVd/RVd consolidation and up to 2 years of lenalidomide maintenance therapy ± D. VTE prophylaxis was recommended (at least aspirin, ≥162 mg daily) in accordance with International Myeloma Working Group guidelines. In the safety population (D‐RVd, n = 99; RVd, n = 102), VTEs occurred in 10.1% of D‐RVd patients and 15.7% of RVd patients; grade 2–4 VTEs occurred in 9.1% and 14.7%, respectively. Median time to the first onset of VTE was longer for D‐RVd versus RVd patients (305 days vs 119 days). Anti‐thrombosis prophylaxis use was similar between arms (D‐RVd, 84.8% vs RVd, 83.3%); among patients with VTEs, prophylaxis use at time of first VTE onset was 60.0% for D‐RVd and 68.8% for RVd. In summary, the addition of daratumumab to RVd did not increase the incidence of VTEs, but the cumulative VTE incidence was relatively high in this cohort and anti‐thrombotic prophylaxis use was suboptimal. [ABSTRACT FROM AUTHOR]

CANDOR compared the safety/efficacy of carfilzomib with dexamethasone and daratumumab (KdD) to carfilzomib with dexamethasone (Kd) in adults with relapsed/refractory multiple myeloma (RRMM). This CANDOR subgroup analysis evaluated outcomes based on cytogenetic risk. Overall response rates (KdD vs. Kd) were 81% versus 56% in high‐risk and 87% versus 79% in standard‐risk groups. Median progression‐free survival was 11.2 versus 7.4 months in high‐risk (hazard ratio, 0.56 [95% CI, 0.34, 0.93]) and not reached versus 16.6 months in standard‐risk groups (0.56 [95% CI, 0.39, 0.80]). These data support the efficacy of KdD in RRMM treatment, including in patients with high‐risk cytogenetics. [ABSTRACT FROM AUTHOR]

A reduced dose of lenalidomide can be an important factor for treatment continuation, since systemic AL amyloidosis patients are often intolerant to lenalidomide over 15 mg/day.13 One patient without haematological response at 6 months from DRd treatment had chromosome 1q21 amplification. Approximately 12%-15% of multiple myeloma (MM) patients develop systemic light chain amyloidosis (AL amyloidosis) during the clinical course.1 Treatment with daratumumab, cyclophosphamide, bortezomib and dexamethasone is becoming a standard of care for systemic AL amyloidosis patients according to the recently published phase-3 ANDROMEDA trial.2 However, patients with coexisting MM have been excluded from the trial. [Extracted from the article]

Summary: Daratumumab (dara) has significantly altered the therapeutic landscape of multiple myeloma (MM), especially in the relapsed setting. This study aimed to evaluate the outcomes of dara‐containing regimens in the Canadian real‐world setting among relapsed and refractory MM available within the national Canadian Myeloma Research Group Database (CMRG‐DB). A total of 583 MM patients who received dara‐based therapy in second‐line or later treatment were included. After a median follow‐up of 17.5 months, the median progression‐free survival (PFS) and overall survival (OS) for the entire cohort were 13.1 and 32.9 months, respectively. The median PFS and OS were 23.5 and 49.1 months in second‐line treatment and decreased to 12.8 and 43.0 months in third‐line and 7.0 and 20.5 months in fourth‐line treatment respectively. Dara in monotherapy with or without corticosteroids after a median of four prior lines of therapy resulted in a median PFS of 3.9 months and a median OS of 17.1 months. The addition of bortezomib, lenalidomide or pomalidomide to dara resulted in an improved median PFS and OS of 8.3 and 26.2 months; 26.8 and 43.0 months; and 9.7 and 31.4 months respectively. These retrospective data from the CMRG‐DB suggest that outcomes are superior when dara is used in combination and in earlier lines of treatment. [ABSTRACT FROM AUTHOR]

The treatment landscape in multiple myeloma (MM) has changed drastically in the past two decades with new treatment paradigms evolving. In this issue Sborov et al. provide the first study investigating the frequency, severity, onset of vascular thrombotic events (VTEs) and use of prophylactic therapies in a trial applying a contemporary myeloma treatment protocol and highlight that prevention of VTEs needs to be revisited in the era of modern myeloma treatment. Commentary on: Sborov et al. Daratumumab plus lenalidomide, bortezomib and dexamethasone in newly diagnosed multiple myeloma: Analysis of vascular thrombotic events in the GRIFFIN study. Br J Haematol. 2022;199:355–365. [ABSTRACT FROM AUTHOR]

One patient's therapy was stopped after three administrations because of a very good response.3 In two patients, therapy was temporarily interrupted after two doses for the same reason and later completed because of imminent relapse.3 Patient 3 later received another six doses of daratumumab as maintenance at an external hospital (Figure S2). Autoimmune haemolytic anaemia (AIHA) is an autoantibody-mediated autoimmune disorder characterized by red blood cell (RBC) destruction by the host's immune system. While patient 1 had insufficiently controlled graft-versus-host disease, patient 2 had a relapse of chronic myelomonocytic leukaemia associated with the occurrence of AIHA. [Extracted from the article]

Two patients with autoimmune thrombocytopenia (Patients #4 and 8) and patient #9 with AIHA did not respond to daratumumab within a median follow-up of 89 days (range 20-412 days) from the first dose of daratumumab. Prior treatments are summarised in Table I. Seven of nine patients received corticosteroids at a median of 18 days (range 1-677 days) before daratumumab and four of nine patients received rituximab at a median of 36-5 days (range 10-72 days) before daratumumab (Table SII). Keywords: daratumumab; autoimmune cytopenias; plasma cell depletion; CD38 and autoimmunity EN daratumumab autoimmune cytopenias plasma cell depletion CD38 and autoimmunity e84 e89 6 09/02/21 20210901 NES 210901 Autoimmune haemolytic anaemia (AIHA), immune thrombocytopenia and autoimmune neutropenia comprise a heterogenous group of disorders collectively referred to as autoimmune cytopenias.1 First-line therapy generally consists of treatment with corticosteroids, intravenous immune globulin, rituximab and sirolimus.1 Despite this initial therapy, up to 60% of patients fail to exhibit a complete response.2 Following B cell-directed therapies, refractory autoimmune manifestations could be due to antibodies secreted by autoreactive plasma cells,3 suggesting that targeting autoreactive plasma cells may be an effective treatment approach. Three patients developed autoimmune cytopenia(s) in the setting of an inborn error of immunity, four patients developed autoimmune cytopenia(s) following an allogeneic HSCT, one patient had idiopathic bone marrow failure and one patient developed autoimmune cytopenia(s) following solid organ transplant (Table I, Appendix S1 and Table SI). [Extracted from the article]

For patients with one prior LOT, the PFS HR (95% CI) was 0-90 (0-48-1-70) for lenalidomide-naive patients, 0-30 (0-10-0-86) for lenalidomide-exposed patients and 0-11 (0-02-0-52) for lenalidomide-refractory patients. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Keywords: cancer; clinical studies; clinical trials; multiple myeloma EN cancer clinical studies clinical trials multiple myeloma 784 788 5 08/18/21 20210815 NES 210815 Bortezomib- and lenalidomide-based therapies have become standard front-line treatment for multiple myeloma (MM),1 resulting in many patients being refractory to bortezomib or lenalidomide at first relapse.2,3 This may negatively impact the efficacy of later lines of therapy (LOT)4 and makes optimal sequencing of MM therapies challenging. [Extracted from the article]

Summary: In the phase 3 POLLUX trial, daratumumab in combination with lenalidomide and dexamethasone (D‐Rd) significantly improved progression‐free survival in patients with relapsed/refractory multiple myeloma (RRMM) compared with lenalidomide and dexamethasone (Rd) alone. Here, we present patient‐reported outcomes (PROs) from POLLUX, assessed using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30‐item (EORTC QLQ‐C30) and the EuroQol 5‐dimensional descriptive system (EQ‐5D‐5L) questionnaires. Changes from baseline are presented as least‐squares mean changes with 95% confidence intervals (CIs) derived from a mixed‐effects model. PRO assessment compliance rates were high and similar in both D‐Rd and Rd groups through cycle 40 (week 156). In this on‐treatment analysis, mean changes from baseline were significantly greater in EORTC QLQ‐C30 global health status, physical functioning, and pain scores in the D‐Rd group versus the Rd group at multiple time points; however, magnitude of changes was low, suggesting no meaningful impact on health‐related quality of life (HRQoL). Subgroup results were similar to those in the overall population. In the POLLUX study, baseline HRQoL was maintained with prolonged D‐Rd treatment. These findings complement the sustained and significant improvement in progression‐free survival observed with D‐Rd and supports its use in patients with RRMM. Clinical trial registration: NCT02076009. [ABSTRACT FROM AUTHOR]

In our limited evaluation of four patients, the novel regimen D-ICE, was safe and effective with all four patients achieving a CR after three to four cycles of therapy. Keywords: chemotherapy; daratumumab; monoclonal antibodies; non-Hodgkin lymphoma; plasmablastic lymphoma EN chemotherapy daratumumab monoclonal antibodies non-Hodgkin lymphoma plasmablastic lymphoma e32 e34 3 07/18/22 20220715 NES 220715 Plasmablastic lymphoma (PBL) is a rare and aggressive form of non-Hodgkin lymphoma (NHL) that arises from a post-germinal centre B-cell that has taken on many characteristics of a fully differentiated plasma cell. Although outcomes are worse for PBL, at least some data support taking a similar approach.2 A standard lymphoma salvage regimen consists of ifosfamide, carboplatin, and etoposide (ICE).3 In order to improve the CR rate, we combined this regimen with daratumumab (D-ICE). [Extracted from the article]

IFLC levels just before the first daratumumab administration are as follows: Patient number (no.) 1, 68-4 mg/l; no. 2, 20-8 mg/dl; no. 3, 66-4 mg/l; no. 4, 447 mg/l; no. 5, 33900 mg/l; no. 6; 23-8 mg/l; no. 7, 598 mg/l; no. 8, 2435-3 mg/l; no. 9, 401 mg/l; no. 10, 283 mg/l; no. 11, 12 700 mg/l; no. 12, 664f0 mg/l. gl The most common adverse event (in four patients) was Grade 1/2 infusion reaction after the first dose. Pre-treatment CD38-positive regulatory T cells affect the durable response to daratumumab in relapsed/refractory multiple myeloma patients. In general, adverse events of daratumumab in patients with severe RI are similar to those in patients without RI. There has been considerable improvement in the treatment of multiple myeloma (MM), but severe renal impairment (RI) owing to cast nephropathy (CN) is still one of the frequent complications requiring prompt treatment. [Extracted from the article]

Summary: In the phase III CASTOR trial, daratumumab, bortezomib and dexamethasone (D‐Vd) significantly extended progression‐free survival compared with bortezomib and dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Here, we present patient‐reported outcomes (PROs) from the CASTOR trial. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30‐item (EORTC QLQ‐C30) and the EuroQol 5‐dimensional descriptive system questionnaire. Treatment effects through Cycle 8 were measured by a repeated measures mixed‐effects model. After Cycle 8, PROs were only collected for patients in the D‐Vd group who continued on daratumumab monotherapy. Compliance rates for PRO assessments were high and similar between treatment groups. Mean changes from baseline were generally similar between treatment groups for EORTC QLQ‐C30 global health status (GHS), functioning and symptoms, and did not exceed 10 points for either treatment group. Subgroup analyses were consistent with the results observed in the overall population. There was no change in patients' health‐related quality of life for the first eight cycles of therapy; thereafter, patients treated with daratumumab over the long‐term reported improvements in GHS and pain. These results complement the significant clinical benefits observed with D‐Vd in patients with RRMM and support its use in this patient population. [ABSTRACT FROM AUTHOR]

Summary: Real‐world outcomes of daratumumab monotherapy (DM) for relapsed/refractory multiple myeloma (RRMM) have remained unclear. We conducted a multicentre retrospective study of 107 patients receiving DM for RRMM. The cohort included 64 trial‐unfit patients whose characteristics could not meet inclusion criteria in two previous clinical trials (GEN501 and SIRIUS). The overall response rate (ORR), and median first and second progression‐free survival (PFS1 and PFS2) and overall survival were 42·1%, and 3·6, 8·1 and 11·9 months, respectively. Refractoriness to carfilzomib and/or lenalidomide, and neutropenia (<1.0 × 109/l) resulted in poorer ORRs. An Eastern Cooperative Oncology Group Performance Status of ≥3, neutropenia (<1.0 × 109/l), thrombocytopenia (<75 × 109/l), and renal failure (glomerular filtration rate of <20 ml/min/1·73 m2) were associated with poor PFS1 and PFS2 in respective univariate analysis. The modified trial‐unfit group, based on the above factors, showed significantly negative impacts on PFS1 and PFS2 (hazard ratio 2·823 and 3·677, all P < 0·001) in multivariate analysis despite having a 34% ORR. Fatal infections occurred more often in the modified trial‐unfit group than in the others (16·1% vs. 4·3%; P = 0·099). Despite failure of DM, subsequent therapy with pomalidomide‐based therapy or carfilzomib‐dexamethasone provided a 66·6% ORR. Real‐world DM showed favourable efficacies for RRMM and, potentially, additional benefits with subsequent therapies. However, characteristics corresponding with trial‐unfitness might offset the efficacy of DM. [ABSTRACT FROM AUTHOR]

Summary: Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab‐based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow‐up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non‐measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next‐generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab‐based therapy is a new option for patients with MGRS. [ABSTRACT FROM AUTHOR]

Summary: Daratumumab is a CD38‐targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard‐of‐care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D‐VRd) for transplant‐eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D‐VMP) for transplant‐ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D‐Rd) for relapsed/refractory MM. In total, 199 patients were treated (D‐VRd, n = 67; D‐VMP, n = 67; D‐Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21‐day induction cycles for D‐VRd was 71·6% [90% confidence interval (CI) 61·2–80·6%], and the overall response rates (ORRs) for D‐VMP and D‐Rd were 88·1% (90% CI 79·5–93·9%) and 90·8% (90% CI 82·6–95·9%). With longer median follow‐up for D‐VMP and D‐Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease–negativity (10‒5) rates were 16·4% and 15·4%. Infusion‐related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard‐of‐care regimens demonstrated comparable clinical activity to DARA IV–containing regimens, with low infusion‐related reaction rates and reduced administration time. [ABSTRACT FROM AUTHOR]

Induction therapy followed by CD34 + cell mobilisation and autologous transplantation represents standard of care for multiple myeloma (MM). However, the anti-CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. In this study, we investigated the effect of three different regimens (dara-VCd, isa-KRd and VTd) on CD34 + cells using flow cytometry and transcriptomics. Decreased CD34 + cell peak concentration and yields, longer collection and delayed engraftment were reproduced after dara-VCd/isa-KRd versus VTd induction in 34 patients in total. Using flow cytometry, we detected major changes in the proportion of apheresis product and bone marrow CD34 + subsets in patients treated with regimens containing anti-CD38 therapy; however, without any decrease in CD38high B-lymphoid progenitors in both materials. RNA-seq of mobilised CD34 + cells from 21 patients showed that adhesion genes are overexpressed in CD34 + cells after dara-VCd/isa-KRd and JCAD, NRP2, MDK, ITGA3 and CLEC3B were identified as potential target genes. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion-related interactions, rather than killing of CD34 + cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti-CD38 therapy., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Summary: A deep elucidation of the mechanisms of action of anti‐CD38 monoclonal antibodies (mAbs), such as daratumumab (DARA), is required to identify patients with multiple myeloma (MM) who are more responsive to this treatment. In the present study, an autologous ex vivo approach was established, focussing on the role of the monocytes in the anti CD38‐mediated killing of MM cells. In bone marrow (BM) samples from 29 patients with MM, we found that the ratio between monocytes (CD14+) and MM cells (CD138+) influences the response to DARA. Further, the exposure of the BM samples to DARA is followed by the formation of a CD138+CD14+ double‐positive (DP) population, that quantitatively correlates with the anti‐MM cells killing. These effects were dependent on the presence of a CD14+CD16+ monocyte subset and on high CD16 expression levels. Lastly, the addition of a mAb neutralising the CD47/signal‐regulatory protein α (SIRPα) axis was able to increase the killing mediated by DARA. The effects were observed only in coincidence with high CD14+:CD138+ ratio, with a significant presence of the DP population and were correlated with CD16 expression. In conclusion, the present study underlines the critical role of the CD16+ monocytes in DARA anti‐MM killing effects and gives a rationale to test the combination of an anti‐CD47 mAb with anti‐CD38 mAbs. [ABSTRACT FROM AUTHOR]

Summary: Immunoglobulin light‐chain amyloidosis (AL amyloidosis) is a rare disease in which a small plasma cell clone produces toxic misfolded proteins that deposit in organs and impair their function. Currently, the only available treatment approach is the elimination of clonal plasma cells. However, a rapid strike that halts and possibly reverses organ damage is crucial. The development of agents that facilitate the clearance of pathological fibrillar deposits, therefore reducing the frailty of patients, is the needed supplement to plasma cell‐directed therapy. Monoclonal antibodies provide therapy against malignant plasma cells (daratumumab, isatuximab, elotuzumab) but they are also able to target and eliminate the amyloid from organs (NEOD001, CAEL‐101, dezamizumab). From the plasma cell‐directed group, daratumumab in monotherapy has proved to be extremely efficient in relapsed AL amyloidosis, exceeding its results in multiple myeloma. Compared to other agents, monoclonal antibodies possess the advantage of high selectivity and low toxicity and could potentially become future game‐changers in this field. Co‐targetting of the plasma cell clone and amyloid deposits shall together be translated in the revolutionary improved outcome of potentially curable AL amyloidosis. [ABSTRACT FROM AUTHOR]

Summary: Gain of chromosome 1q21 and the gene expression‐based GEP70 risk score are established prognostic markers for newly diagnosed Multiple Myeloma (MM) patients. Here we addressed the prognostic impact of these two markers in 81 relapsed/refractory (RR) MM patients treated with the CD38‐antibody daratumumab. Fluorescence in situ hybridization for 1q21 was performed at initial presentation, while the GEP70 score was determined at initial presentation and prior to daratumumab treatment. While the GEP70 at initial presentation showed a trend for inferior survival, the GEP70 collected prior to daratumumab treatment was significantly associated with poor outcome (P < 0·05). The worst outcome was seen for patients who were positive for gain(1q) and classified as GEP70 high risk prior to daratumumab [progression‐free (PFS) and overall survival (OS) of 0·3 years (95% CI: 0·15–1·4 years) and 0·8 years (95% CI: 0·5–1·9 years) respectively], while the median PFS and OS were not reached by patients without gain(1q) and GEP70 low‐risk status. In conclusion, gain(1q) and the GEP70 are powerful prognostic markers for RR MM patients treated with daratumumab, and patients classified as high risk according to these markers experience shorter treatment response. [ABSTRACT FROM AUTHOR]

Daratumumab is effective in the relapsed or refractory systemic light-chain amyloidosis but associated with high infection burden in a frail real-life population In most cases, the underlying disease is a clonal plasma cell disorder and AL patients have consequently benefited from the vast therapeutic advances in multiple myeloma (MM). As expected, several patients experienced progressive hypogammaglobulinaemia that might add to the risk of infections, Fig D. The median gammaglobulin level before treatment was 4-8 g/l (range, 1-6-9-7) vs. 3-3 g/l (range, 1-2-5-4) afterwards. & Liedtke, M. (2017) Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. [Extracted from the article]

Summary: Single agent daratumumab has shown clinical activity in relapsed, refractory multiple myeloma (RRMM). The Intergroupe Francophone du Myélome 2014‐04 trial was designed to further investigate daratumumab in combination with dexamethasone in triple RRMM patients. Patients received daratumumab infusions in combination with weekly dexamethasone until disease progression or unacceptable toxicity. Fifty‐seven patients were included in the trial and evaluable for response. The overall response rate and the clinical benefit rate were 33% (n = 19) and 48% (n = 27), respectively. Five (8·8%) patients achieved a very good partial response or better. The median time to response was 4 weeks. For responding patients, the median progression‐free survival was 6·6 months, compared to 3·7 months (3·0–5·5) for those with a minimal or stable disease. The median overall survival (OS) for all patients was 16·7 months (11·2–24·0). For responding patients, the median OS was 23·23 months, whereas that of patients with progressive disease was 2·97 months. The incidence of infusion‐related reactions was 37%; all cases were manageable and did not lead to dose reduction or permanent treatment discontinuation. These data demonstrate that treatment with daratumumab and dexamethasone results in a meaningful long‐term benefit with an acceptable safety profile for patients with triple RRMM. [ABSTRACT FROM AUTHOR]

The article focuses on the role of Daratumumab, pomalidomide and dexamethasone (Pd) combination therapy for the treatment of relapsed and refractory multiple myeloma. It mentions the addition of daratumumab to the Pd backbone (DaraPd) for the patients with relapsed and refractory multiple myelom and also discussions on daratumumab that depletes levels of CD38 (cluster of differentiation 38).

Summary: This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D‐VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4–8 induction cycles of bortezomib 1·5 mg/m2, cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split‐first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty‐six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12‐month progression‐free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment‐emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D‐VCd was well tolerated, split‐first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1‐year PFS rate was 87%. [ABSTRACT FROM AUTHOR]

The article informs on a study for analysing the impact of Fc gamma receptor polymorphisms on efficacy and safety of daratumumab in relapsed/refractory multiple myeloma. It examines effect of Fc portion of IgG polymorphisms on response, survival, and infusion-related reactions in multiple myeloma patients treated with daratumumab drug as single agent in the GEN501 and SIRIUS studies.

Summary: CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti‐CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib‐resistant lines) elicited antibody‐dependent cellular cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), antibody‐dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI‐WM1‐xenografted mice. CD38 is reported to augment B‐cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib‐resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single‐agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti‐WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co‐targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second most common haematological malignancy after non-Hodgkin lymphoma. Despite the improvement in outcomes over the last decade with the introduction of novel therapies, such as immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs), MM remains an incurable disease. Patients who are both refractory to IMiDs and PIs carry a particularly dismal prognosis. The development of targeted therapy in the form of monoclonal antibodies has shifted the treatment paradigm of this disease, resulting in unprecedented response rates, even among the highest-risk patients. In this review, we will summarize the mechanism of action and provide an overview of the clinical trials that have led to the US Food and Drug Administration approval of Daratumumab and Elotuzumab, and their current use in the treatment of MM. [ABSTRACT FROM AUTHOR]

The availability of novel therapies for the treatment of multiple myeloma has had a dramatic impact on the depth of response that can be expected on initial treatment. Despite these advances, disease relapse remains inevitable in most patients and brings with it a different set of priorities for therapy. The most recent wave of novel agents may have a particular impact in the relapsed setting. In this review, we examine the evidence currently available from clinical trials for the use of novel agents, particularly in the formation of triplet therapy. We consider data supporting the addition of the proteasome inhibitors carfilzomib and ixazomib, or the monoclonal antibodies elotuzumab or daratumumab, to a treatment backbone of lenalidomide and dexamethasone. The clinical data set is less well developed for the addition of a third agent to the combination of bortezomib and dexamethasone; nonetheless, data are presented supporting the addition of the histone deacetylase inhibitor panobinostat, or elotuzumab or daratumumab. While acknowledging the lack of head-to-head data on which to base comparisons between the numerous regimens, we collate the latest data in order to provide a basis on which to make clinical decisions in this rapidly advancing field. [ABSTRACT FROM AUTHOR]

Ganzel I et al i ([4]), reported transient benefit of daratumumab in a multiply relapsed paediatric Ph-positive B-ALL patient, including failure of anti-CD19 and anti-CD22 chimeric antigen receptor T cell therapy (Ganzel I et al i , [4]). Although our first patient succumbed during the neutropenic period post-transplant, daratumumab was effective in enabling an induction therapy-refractory patient to become MRD-negative pre-transplant. It would be interesting to see if daratumumab therapy can overcome the need for transplant, decrease CNS relapses or become Food and Drug Administration-approved for MRD-positive disease in T-ALL, akin to blinatumomab in B-ALL. [Extracted from the article]