Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who progress to the third-line setting face a lack of standardized treatment, despite the presence of multiple available therapies. In this context, antibody-drug conjugates represent a relatively new class of anticancer agents; among them, loncastuximab tesirine is a second-in-class agent approved for the treatment of patients with R/R DLBCL after ≥ 2 lines of systemic therapy. Because many patients with R/R DLBCL are ineligible for intensive therapies due to advanced age and comorbidities, the availability of any new agent is particularly important. We present an overview of the clinical evidence for loncastuximab tesirine and offer practical guidance on its use in R/R DLBCL. Additionally, three clinical cases are described to illustrate its efficacy in transformed DLBCL, the management of treatment and safety when used as a bridge to allogeneic stem cell transplantation, and its role in the sequencing of therapies for R/R DLBCL. Findings from our Italian experience may be informative on the clinical application of loncastuximab tesirine in other countries where it is approved and available.

Cancer immunotherapies have shown significant promise in multiple myeloma (MM). However, their long-term efficacy is limited by immune evasion, and MM remains incurable. A key evasion strategy involves upregulating inhibitory phagocytosis checkpoints (IPCs), which prevent antigen-presenting cells (APCs) from phagocytosing cancer cells. This pathway is critical for the immune effects of standard anti-MM agents, including bortezomib (BTZ), an inducer of immunogenic cell death (ICD), and the monoclonal antibody daratumumab (DARA). Yet, the mechanisms regulating IPCs in MM remain poorly understood. To address this gap, we screened IPC axes in MM cells and APCs using bone marrow (BM) aspirates from MM patients (n=39) and healthy donors (n=5) via multiparametric flow cytometry. Immunophenotyping included 9 parameters for MM cells and 16 for APCs, covering IPC and lineage markers. We identified the B2 microglobulin (B2M) / leukocyte immunoglobulin-like receptor B1 (LILRB1) axis as the dominantly expressed IPC in MM. B2M, expressed on MM cells, binds LILRB1 on APCs. Notably, B2M is a known adverse prognostic factor in MM. Computational analysis of flow-cytometry data using a semi-automated pipeline allowed us to define 8 distinct myeloid cell clusters, with consistently high LILRB1 abundance, especially in conventional type 1 dendritic cells (DCs). Single-cell RNA-seq data from 90 MM BM samples confirmed LILRB1 expression in DCs, monocytes (Mo) and macrophages (MΦ). qRT-PCR of BM Mo-derived DCs found that LILRB1 mRNA levels increased from healthy donor to smoldering MM to overt MM, suggesting a link to disease progression. To functionally assess the B2M/LILRB1 axis, we knocked out B2M in MM cell lines (n=3) and re-expressed a chimeric B2M mutant (B2MMUT) lacking functional LILRB1-binding site by introducing 16 missense mutations. B2M functions as an MHC-I subunit, so this mutant allowed us to isolate its checkpoint role without the confounding effects from complete B2M loss. Yeast 2-hybrid assays confirmed a direct interaction between B2M and LILRB1, but not for B2MMUT. Phagocytosis assays found that B2MKO and B2MMUT cells were more susceptible (more than 2-fold) than WT to phagocytosis by DCs and MΦ after BTZ or DARA treatment (p<0.01). LILRB1 knockdown (KD) in APCs, using an antisense oligonucleotide, similarly enhanced the phagocytic potential after BTZ treatment (p<0.05). Since MM cells actively secrete B2M (s-B2M), we analyzed the media from MM cell lines with different B2M statuses: B2M WT, B2MKO, and B2MMUT. We found s-B2M in the media from B2M WT cells, but no B2M in the KO cells and s-B2MMUT in the B2MMUT. Exposure of DCs to the conditioned media of WT s-B2M, but not s-B2MMUT, reduced phagocytosis after BTZ or DARA (p<0.05) of B2MKO cells, suggesting that s-B2M impairs APC function in a LILRB1-dependent manner. Treatment of APCs with His-tagged recombinant B2M (rB2M) confirmed activation of downstream LILRB1 signaling, assessed by modulation of p-SHP1. Interestingly, APCs internalized rB2M in a LILRB1-dependent manner, as both LILRB1 KD and treatment with rB2MMUT resulted in reduced internalization. Correlative light and electron microscopy (CLEM) and TEM revealed that internalized rB2M localized to perinuclear vesicles near the microtubule-organizing center (MTOC). Confocal imaging found that rB2M uptake increased microtubule stability, as assessed by a higher acetylated-to-tyrosinated tubulin ratio. Functionally, this correlated with impaired APC maturation following lipopolysaccharide stimulation (assessed by phalloidin staining) and a reduced ability to activate T cells after ICD, as measured shown by reduced T cell-mediated MM cell lysis. To evaluate the in vivo relevance, we generated a murine MM cell line (5TGM1) expressing a chimeric B2M (B2Mmut), which cannot bind the murine LILRB1 ortholog. Mice injected with B2Mmut cells exhibited reduced tumor engraftment and growth compared to those injected with WT cells, accompanied by increased infiltration of CD3⁺ and CD8⁺ T cells.Ongoing studies are assessing the effect of the B2M/LILRB1 axis on BTZ or DARA efficacy in vivo and will be presented at the meeting. This work provides fundamental insight into the immune role of B2M in MM, revealing the B2M/LILRB1 axis as a novel immune checkpoint in MM driven by impaired APC function. Targeting this axis represents a new therapeutic vulnerability to restore immune competence and improve MM outcomes.

INTRODUCTION:The treatment landscape for relapsed refractory (RR) follicular lymphoma (FL) is rapidly evolving, and chemo-free immunotherapeutic strategies represent the major players in the field. CD20×CD3 bispecific antibodies are effective and easily manageable agents that are able to redirect the cytotoxic activity of T-cells against lymphoma cells by creating an immunological synapse. AREAS COVERED:In this paper we will review the efficacy and safety profile of the bispecific antibody epcoritamab in RR FL, either as monotherapy (as it was recently approved in the United States and Europe) and in combination with other agents. We will discuss its potential role among the existing treatment options in this setting, particularly in relation with other approved bispecific antibodies and with CAR-T cell therapy. Presented data were obtained by literature search on PubMed and updated with most recent evidence presented at international hematology meetings (2022-2024). EXPERT OPINION:The optimal treatment sequencing in FL is still an open issue; however, epcoritamab effectively combines key aspects such as high, rapid and durable responses, good tolerability, predictable cytokine release syndrome (CRS) kinetics, and ease of administration, representing an appealing option for patients and clinicians. Future efforts should aim at positioning epcoritamab-based treatments in earlier lines of FL.

Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients ineligible for autologous stem cell transplant (ASCT) or chimeric antigen receptor (CAR)-T-cell therapy remain limited. The PI3K inhibitor copanlisib has shown activity as a single agent in DLBCL. This phase II, single-arm, multicentre trial evaluated copanlisib with rituximab and bendamustine (copa-BR) in ASCT- and CAR-T-ineligible R/R DLBCL. Patients received six cycles of copa-BR, followed by up to 12 cycles of copanlisib maintenance. The primary end-point was 12-month progression-free survival (PFS). Thirty-seven patients (aged 68-87 years, R/R after 1-2 prior lines) were enrolled. The overall response rate was 24.3%, with complete responses in 13.5%. After a median follow-up of 20 months, the 12-month PFS and overall survival rates were 25.1% and 44.5% respectively. Grade ≥3 toxicities included neutropenia (56.8%), infections (27.0%, including 6 death due to COVID-19 infection with 25% fatality) and thrombocytopenia (16.2%). Due to limited efficacy, poor tolerability and emerging alternative treatments, the trial was terminated prematurely. Copa-BR showed limited activity and an unfavourable safety profile, discouraging further investigation of this combination in ASCT- and CAR-T-ineligible R/R DLBCL.

High-dose melphalan plus autologous stem cell transplantation (ASCT) is a standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM), and adequate hematopoietic stem cell (HSC) collection is crucial to ensure hematologic recovery after ASCT. In this prospective, observational study we evaluated HSC mobilization with granulocyte colony-stimulating factor (G-CSF), cyclophosphamide, and 'on-demand' plerixafor (in patients with <20×106 CD34+ cells/L after at least 4 days of G-CSF or failing to collect ≥1×106 CD34+ cells/kg after the first apheresis) in NDMM patients treated with novel agent-based induction therapy. The primary endpoint was the rate of poor mobilizers (patients collecting <2×106 CD34+ cells/kg or requiring plerixafor rescue to reach an adequate HSC harvest). Secondary endpoints included the rate of patients collecting ≥2×106 CD34+ cells/kg after plerixafor administration and the identification of factors predicting mobilization failure or plerixafor need. Overall, 301 patients (median age 60 years) were enrolled. Two hundred and eighty-seven of 301 (95%) and 274 of 301 (93%) patients collected ≥2×106 and ≥4×106 CD34+ cells/kg, respectively, with a median of 9.9×106 CD34+ cells/kg collected. Poor mobilizers were 48 of 301 (16%): 34 of 301 (11%) required plerixafor rescue, and 14 of 301 (5%) failed HSC collection regardless of plerixafor. Thirty-four of 38 (90%) patients receiving plerixafor collected ≥2×106 CD34+ cells/kg. Bone marrow plasmacytosis at diagnosis >60% (odds ratio [OR]=4.14), lenalidomide use (OR=4.45), and grade 3-4 hematologic toxicities during induction (OR=3.53) were independently associated with a higher risk of mobilization failure or plerixafor need. Cyclophosphamide plus G-CSF and 'on-demand' plerixafor is an effective strategy in NDMM patients treated with novel agents, resulting in a high rate of HSC collection and high HSC yield (clinicaltrials gov. identifier: NCT03406091).

Background: Diffuse Large B-cell lymphoma (DLBCL) is a heterogeneous disease, with different clinical behaviors and biological characteristics. High-grade B-cell lymphomas (HGBL) with MYC and BCL2 and/or BCL6 rearrangement represent a separate entity with lower response to R-CHOP like regimens and poorer outcome. Additional molecular risk stratification of DLBCL/HGBL carrying MYC alterations could provide further prognostic information for an optimal choice of therapy. Major issues affecting risk stratification are characterization of MYC translocation partners, presence of TP53 gene alterations and determination of Cell of Origin (COO). Aim: to provide preliminary data on additional molecular risk factors in patients with DLBCL/HGBL with MYC alterations and treated with R-CHOP-like regimens with curative intent. Cytogenetic and molecular findings will be correlated with clinical features and treatment outcome. Methods: this is a retrospective multicentric study on DLBCL/HGBL patients with MYC gene involvement (MYC rearrangement and/or MYC anomalies identified by Fluorescent In Situ Hybridization, FISH). The following analyses were performed: a) immunohistochemical staining b) FISH to determine MYC, BCL2 and BCL6 rearrangements, MYC partner gene, MYC copy number and TP53 deletion, c) Targeted Next Generation Sequencing (NGS) to identify the unknown gene partner in non-immunoglobulin (IG)/MYC rearrangements and additional molecular alterations d) GEP Study to determine COO. Biological findings were correlated with baseline clinical data and response to therapy/survival. Results: 42 patients were included in the study. All patients received first line treatment with R-CHOP like regimens. Median follow-up was 36 months. Median age was 65 years; 15/42 (36%) patients were low/intermediate IPI and 26/42 (62%) were intermediate-high/high IPI risk (1/42 data not available). MYC increased copy number was detected in 8/42 (19%) patients, whereas MYC rearrangement (MYC-r) in 34/42 (81%). Of the MYC-r patients, 31/34 patients had sufficient material for subsequent analyses. MYC-r with an IG gene was observed in 19/31 (61%) patients. BCL2 and BCL6 rearrangements were reported in 20/39 (51%) and 14/39 (36%) cases, respectively. The co-occurrence of MYC and BCL2 rearrangement was detected in 12/31 (39%) patients, MYC and BCL6 in 6/31 (19%) patients and 4/31 (13%) patients were positive to all three genes. A TP53 deletion was present in 7/40 (18%) patients for whom the analysis was available. COO was Germinal Centre B-Cell (GCB) subtype in 31/40 (78%) patients, Activated B-Cell (ABC) in 6/40 (15%) and unclassified in 3/40 (7%). Three-year overall survival (OS) rate was 52% in all patients with MYC-r and 75% in patients with MYC gain (p=0.19). As expected, patients with MYC and BCL2 and/or BCL6 rearrangements showed a trend to worse OS (3-years OS rate 46%) as compared with patients with MYC-r only or with MYC gain (3-year OS rate 75% in both groups, p= 0.39). Patients with MYC-r and TP53 deletion showed a significant inferior OS (3-year OS 20%) as compared to patients without TP53 deletion and with MYC-r (3-year OS 59%) or MYC gain (3 year OS 75%) (p = 0.047). Most prevalent pathogenic variants detected by NGS (i.e detected in >15% patients) were TP53 (33%), CREBBP (31%), MYC (31%), BCL2 (19%), TNFRS14 (19%), CIC (17%), EZH2 (17%) and NF1 (17%). Updated data and clinical correlation will be presented at the meeting. Conclusion: With the limitations of the small sample size and retrospective nature of the study, our findings underline the adverse prognostic impact of TP53 deletion on OS in a cohort of high-risk large B cell lymphoma (LBCL) patients harboring MYC alterations (structural and/or numerical). The adverse clinical impact of the co-occurrence of MYC and/or BCL2/BCL6 rearrangements was confirmed. Evaluation of TP53 status should be included in standard diagnostic work-up of DLBCL/HGBL to further refine the prognosis. Identifying these high risk patients could potentially help to tailor treatments, for example considering novel immunotherapies earlier in the disease course in dedicated clinical studies. NGS may provide further insights. A full integration of clinical and biological data could ultimately allow better stratification of LBCL patients. This study was funded by FPRC 5xmille 2017 MUR (INTERONC project) and FPRC 5xmille Ministero della Salute 2019 IDEE

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 patients with VEXAS for CH in their peripheral blood (PB) and correlated the findings with clinical outcomes in 77 of them. UBA1mut were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mut was the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed 2 major patterns: with either typical CH preceding UBA1mut selection in a clone (pattern 1) or occurring as an UBA1mut subclone or in independent clones (pattern 2). VAF in the PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

Background: Until the recent introduction of daratumumab (Dara), bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) have been standards of care for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts) in the frontline setting. Nonetheless, no prospective randomized trial has directly compared VMP with Rd, and only few data on real-life experiences in older NTE pts are available. Methods: In this multicenter randomized phase IV trial (NCT03829371; funded by the Italian Medicines Agency AIFA - Independent Research), real-life NDMM pts ineligible for transplant due to comorbidities or age ≥65 years were randomized 1:1 to VMP (nine 42-day [dd] cycles [cc], V: 1.3 mg/m2 dd 1,4,8,11,22,25,29,32 cc 1-4 and dd 1,8,22,29 cc 5-9; M: 9 mg/m2 dd 1-4; P: 60 mg/m2 dd 1-4) vs continuous Rd (28-day cc, R: 25 mg dd 1-21; d: 40 mg dd 1,8,15,22), according to standard practice. Upon written informed consent, pts were enrolled regardless of comorbidities, performance status, baseline laboratory values, or renal function. Stratification was performed according to the International Myeloma Working Group frailty score and to cytogenetic risk by fluorescence in situ hybridization [high risk with del(17p), t(14;16), or t(4;14)]. Progression-free survival (PFS) in the intention-to-treat (ITT) population was the primary endpoint. Overall survival (OS), response rates, and safety were key secondary endpoints. Results: The data cut-off was July 4, 2022: 231 pts were randomly assigned to VMP (n=114) or Rd (n=117). Baseline characteristics were balanced in VMP vs Rd: median age 77 (IQR 73-80) and 76 years (IQR 73-79); frail pts 49% vs 50%; pts with high-risk cytogenetics 17% vs 19%. After a median follow-up of 19 months, median PFS in the ITT population was 29.6 vs 26.2 months with VMP vs Rd (hazard ratio [HR] 0.82, 95% CI 0.51-1.31, P=0.41; Fig. 1A). HR was 0.21 (95% CI 0.04-0.99) in pts with high-risk cytogenetics vs 1.24 (95% CI 0.70-2.18) in standard-risk pts (interaction P=0.036). No differences in terms of age or frailty status were observed. In the ITT population, 2-year OS was 89% with VMP vs 75% with Rd (HR 0.53, 95% CI 0.26-1.07, P=0.08; Fig. 1B). No safety concerns were reported. Thrombocytopenia (15%) and neuropathy (7%) were the most frequent grade 3-4 adverse events with VMP; neutropenia (23%), infections (12%), and dermatologic toxicities (9%) with Rd. At least 1 dose reduction (any drug) was reported in 66% of pts in the VMP and 59% in the Rd arms, including 35% of pts in the VMP arm switching to once-weekly V before cc 5. Conclusion: Overall, the advantage of Rd over VMP was lower than anticipated in this older real-life NTE NDMM population with 50% of frail patients. However, a strong effect modification by cytogenetic risk was found, with high-risk pts benefiting more from VMP vs Rd in terms of PFS (HR 0.21). Safety data were consistent with those previously reported. Of note, only 1/3 of real-life pts were able to receive full-dose VMP or Rd. Despite the limited follow-up, the poor outcomes in pts failing R-based treatment could explain the different OS rates in the two arms. As of July 2022, pts have been randomized to Dara-VMP vs Dara-Rd. With longer follow-up, an analysis of the addition of Dara will further improve decision-making.

PURPOSE:Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+.PATIENTS AND METHODS:The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated.RESULTS:In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value.CONCLUSION:The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables.

BACKGROUND. Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) have represented standards of care for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts) until the recent introduction of daratumumab (Dara) in the frontline setting. However, no prospective randomized trial has directly compared VMP with Rd. Moreover, real-life older NTE pts are underrepresented in clinical trials, and only few data on safety and efficacy in this population are available. AIMS. We conducted a randomized multicenter phase IV trial (NCT03829371; funded by the Italian Medicine Agency AIFA - Independent Research) to compare safety and efficacy of the two standard regimens, VMP vs Rd, in an unselected real-life population of NTE NDMM pts. METHODS. NDMM pts ineligible for transplant due to age ≥65 years or comorbidities were randomized 1:1 to: 9 VMP cycles (42-day cycles, V: 1.3 mg/m2, days (dd) 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1-4 and dd 1, 8, 22, and 29, cycles 5-9; M: 9 mg/m2, dd 1-4; P: 60 mg/m2, dd 1-4) vs continuous Rd (28-day cycles, R: 25 mg, dd 1-21; d: 40 mg, dd 1, 8, 15, and 22) according to standard practice. Pts gave written informed consent and were enrolled regardless of performance status, comorbidities, renal function, or baseline laboratory values. Pts were stratified according to the International Myeloma Working Group (IMWG) frailty score and cytogenetic risk by fluorescence in situ hybridization [high risk if positive for del(17p), t(14;16), or t(4;14)]. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population. Key secondary endpoints included response rates, overall survival (OS), and safety. RESULTS. At the data cut-off (July 4, 2022), 231 pts were randomly allocated to receive VMP (n=114) or Rd (n=117). Baseline characteristics were evenly balanced between the two arms: median age was 77 (IQR 73-80) and 76 years (IQR 73-79); 49% vs 50% of pts were frail; 17% vs 19% pts had high-risk cytogenetics, respectively. After a median follow-up of 19 months, the median PFS in the ITT population was 29.6 vs 26.2 months with VMP vs Rd (hazard ratio [HR] 0.82, 95% CI 0.51-1.31, P=0.41; Figure - panel A). However, the HR was not constant over time: from 0.65 (95% CI 0.36-1.19, P=0.16) during the first year of treatment (suggesting a slight benefit of VMP vs Rd) to 1.37 (95% CI 0.65-2.86, P=0.40) after the first year of treatment (suggesting a slight benefit of continuous Rd therapy). The subgroup analysis according to cytogenetic risk showed a significant effect modification of the comparison VMP vs Rd in terms of PFS, with an HR=0.21 (95% CI 0.04-0.99) in the high-risk group vs an HR=1.24 (95% CI 0.70-2.18) in the standard-risk group (interaction P=0.036). No significant effect modification was observed in terms of age or frailty status. In the ITT population, the 2-year OS was 89% with VMP vs 75% with Rd (HR 0.53, 95% CI 0.26-1.07, P=0.08; Figure - panel B). No safety concerns were reported. The most frequent grade (G)3-4 adverse events (AEs) with VMP were thrombocytopenia (15%) and neuropathy (7%), while neutropenia (23%), infections (12%), and dermatologic toxicities (9%) were the most frequent G3-4 AEs observed in the Rd arm. Sixty-six percent of pts in the VMP and 59% in the Rd arms had ≥1 dose reductions of any drug, including 35% of pts in the VMP arm switching to once-weekly V before cycle 5. CONCLUSION. We confirmed the efficacy of VMP and Rd in an older real-life population of NTE NDMM pts including ~50% of frail pts. VMP and Rd were equally effective in standard-risk pts and in all frailty subgroups in terms of PFS. However, high-risk pts benefited more from VMP (HR 0.21), suggesting that the doublet Rd is suboptimal in this subgroup. Safety data were consistent with those previously reported. Of note, only one third of real-life pts were able to receive full-dose VMP or Rd therapy according to their schedule. Despite the limited follow-up, the difference in terms of OS between the two arms may be explained by the poor outcomes of patients failing lenalidomide-based treatments. Importantly, following a recent amendment, as of July 2022, enrolled pts will be randomized to Dara-VMP vs Dara-Rd. Decision-making and treatment selection will be further supported by a future analysis of this addition of Dara, based on patient and disease characteristics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Background: High-dose melphalan and autologous stem-cell transplant (ASCT) are pillars for the upfront treatment of ASCT-eligible newly diagnosed multiple myeloma (ND)MM patients (pts) or as salvage strategy at relapse. Failure to collect an adequate number of hematopoietic stem cells (HSC) to receive ASCT (<2×106 CD34+ cells/kg) occurs in 5%-15% of MM pts undergoing HSC mobilization with granulocyte colony-stimulating factor (G-CSF) or G-CSF+cyclophosphamide (G-CSF/CY). Aims: We report the final results of the observational MOZOBL06877 study (NCT03406091; partially supported by Sanofi investigation funds) to prospectively assess the performance of HSC mobilization with G-CSF/CY plus on-demand CXCR4 inhibitor plerixafor (PLX) in NDMM pts treated with novel agents. Methods: NDMM pts undergoing HSC mobilization with CY (2-4 g/m2) and G-CSF (5-10 mcg/kg/day) were enrolled and observed up to 30 days after mobilization. According to its label, “on-demand” PLX was administered in pts with <20 CD34+ cells/ul after ≥4 days of G-CSF or in case <1×106 CD34+ cells/kg were collected on the first apheresis day. Pts gave written informed consent. The primary endpoint was the poor mobilizer rate, defined as the rate of pts collecting <2×106 CD34+ cells/kg or requiring PLX. Secondary endpoints were the identification of predictive factors for PLX use and safety during mobilization. Results: 301 NDMM pts were enrolled and analyzed; 72% received induction with bortezomib-thalidomide-dexamethasone, 9% a lenalidomide (Len)-based and 3% a daratumumab (Dara)-based regimen. Overall, 48 pts (16%) were poor mobilizers: 14 (5%) failed to yield ≥2×106/Kg CD34+, while 34 (11%) required rescue with PLX. Among pts yielding <2×106/Kg CD34+ cells, 4 received PLX, while 10 did not. Among pts who successfully collected ≥2×106/Kg CD34+ (n=287, 95%), 34 (12%) required PLX: 23 (68%) due to a CD34+/uL count ≤20 after ≥4 days of G-CSF and 11 (32%) to a collection <1×106/Kg after the first apheresis day. In pts mobilized with PLX, median number of CD34+×106/L cells increased from 17.5 (IQR 10.8-25.6) before PLX to 58.3 (IQR 34.2-100.2) after PLX. Median number of CD34+/Kg collected in pts who did not require PLX was 10.2×106 (IQR 8.3-13.2). In pts who required PLX, a median of 6.5×106 CD34+/Kg (IQR 4.6-9.6) was collected. An adequate HSC yield for ≥2 ASCTs (≥4×106/Kg) was obtained in 96% and 85% of pts not receiving or receiving PLX, respectively. Median number of apheresis days was 1 (IQR 1-2) in pts not requiring PLX and 2 (IQR 1-2) in pts requiring PLX. In a multivariate analysis (Table), factors predicting PLX use were advanced disease stage (R-ISS 3 vs 1-2, OR 5.5, P=0.01), bone marrow (BM) plasma cell (PC) infiltration at diagnosis (PC>60% vs ≤60%, OR 4.2, P<0.001), pre-mobilization absolute neutrophil count (ANC, < vs >2500/mmc, OR 2.8, P=0.01), and the use of Len-based (Yes vs No, OR 3.4, P=0.02) or Dara-based induction regimens (Yes vs No, OR 5.3; P=0.04). Grade 3 infections occurred in 3 pts (1%), with no grade 4-5 reported. Image:Summary/Conclusion: Among NDMM pts treated with novel-agent-based induction and undergoing HSC mobilization with CY/GCSF, “on-demand” PLX in case of low CD34+ cell count or insufficient HSC yield was a safe and effective rescue strategy, reducing mobilization failure from 16% to 5%. Predictive factors for PLX use were advanced disease stage, high BM plasmacytosis, low ANC values before mobilization and the use of Len/Dara during induction. Preemptive PLX in pts with ≥1 risk factors should be investigated to further reduce the risk of mobilization failure.

Background:The anti-CD38 monoclonal antibody daratumumab is the backbone of most anti-multiple myeloma (MM) regimens. To mitigate the risk of infusion-related reactions (IRRs), intravenous daratumumab administration requires 7 hours for the first infusion and 3.5-4 hours thereafter, thus making daratumumab-containing regimens burdensome for patients and health care resources. Preliminary data suggest that a rapid (90-minute) infusion of daratumumab is safe and does not increase IRRs. The rapid schedule was adopted by our centers since 2019.Methods:We conducted an observational multi-center, real-life study to assess the safety of rapid daratumumab infusion protocol from the third administration in relapsed MM patients receiving daratumumab alone or in combination with lenalidomide-dexamethasone or bortezomib-dexamethasone. The primary endpoint was the safety of the rapid infusion protocol, particularly in terms of IRRs.Results:A total of 134 MM patients were enrolled. IRRs occurred in 7 (5%) patients and were mostly mild (6/7 of grade 1-2), with only 1 patient experiencing a grade 3 IRR. Due to the IRRs, 5 (3.7%) patients discontinued the rapid infusions and resumed daratumumab at the standard infusion rate, while 1 patient permanently discontinued daratumumab. In 4/7 patients (57%), IRRs occurred while resuming rapid daratumumab infusions after a temporary interruption (2-4 months). No other adverse event was considered related to the rapid infusion protocol.Conclusions:Our findings confirmed the safety of rapid daratumumab infusions starting from the third administration. In case of prolonged daratumumab interruption, it is advisable to resume infusions at the standard rate (3.5 hours) before switching to the rapid infusion.

Multiple Myeloma (MM) is a hematologic malignancy characterized by a wide clinical and biological heterogeneity leading to different patient outcomes. Various prognostic tools to stratify newly diagnosed (ND)MM patients into different risk groups have been proposed. At baseline, the standard-of-care prognostic score is the Revised International Staging System (R-ISS), which stratifies patients according to widely available serum markers (i.e., albumin, β 2-microglobulin, lactate dehydrogenase) and high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization. Though this score clearly identifies a low-risk and a high-risk population, the majority of patients are categorized as at "intermediate risk". Although new prognostic factors identified through molecular assays (e.g., gene expression profiling, next-generation sequencing) are now available and may improve risk stratification, the majority of them need specialized centers and bioinformatic expertise that may preclude their broad application in the real-world setting. In the last years, new tools to monitor response and measurable residual disease (MRD) with very high sensitivity after the start of treatment have been developed. MRD analyses both inside and outside the bone marrow have a strong prognostic impact, and the achievement of MRD negativity may counterbalance the high-risk behavior identified at baseline. All these techniques have been developed in clinical trials. However, their efficient application in real-world clinical practice and their potential role to guide treatment-decision making are still open issues. This mini review will cover currently known prognostic factors identified before and during first-line treatment, with a particular focus on their potential applications in real-world clinical practice.

Abstract Minimal residual disease (MRD) techniques are essential to identify the small clonal fraction within and outside the bone marrow. In the last years, evidence regarding their prognostic role for the evaluation of the depth of response of current treatment strategies has grown rapidly. Consequently, MRD was incorporated in an increasing number of clinical trials for multiple myeloma patients, also as primary endpoint, and even to guide therapeutic choices. A robust correlation between MRD negativity and survival was established. Yet, several issues regarding MRD evaluation remain to be addressed: from the optimal and more cost-effective techniques for its assessment and its harmonization worldwide to its use in clinical practice to its impact on treatment modulation. This review focuses on the available evidence supporting the use of MRD status for the management of multiple myeloma patients and on open issues that still need an answer.

Lenalidomide-dexamethasone (Rd) is standard treatment for elderly patients with multiple myeloma (MM). In this randomized phase 3 study, we investigated efficacy and feasibility of dose/schedule-adjusted Rd followed by maintenance at 10 mg per day without dexamethasone (Rd-R) vs continuous Rd in elderly, intermediate-fit newly diagnosed patients with MM. Primary end point was event-free survival (EFS), defined as progression/death from any cause, lenalidomide discontinuation, or hematologic grade 4 or nonhematologic grade 3 to 4 adverse event (AE). Of 199 evaluable patients, 101 received Rd-R and 98 continuous Rd. Median follow-up was 37 months. EFS was 10.4 vs 6.9 months (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.95; P = .02); median progression-free survival, 20.2 vs 18.3 months (HR, 0.78; 95% CI, 0.55-1.10; P = .16); and 3-year overall survival, 74% vs 63% (HR, 0.62; 95% CI, 0.37-1.03; P = .06) with Rd-R vs Rd, respectively. Rate of ≥1 nonhematologic grade ≥3 AE was 33% vs 43% (P = .14) in Rd-R vs Rd groups, with neutropenia (21% vs 18%), infections (10% vs 12%), and skin disorders (7% vs 3%) the most frequent; constitutional and central nervous system AEs mainly related to dexamethasone were more frequent with Rd. Lenalidomide was discontinued for AEs in 24% vs 30% and reduced in 45% vs 62% of patients receiving Rd-R vs Rd, respectively. In intermediate-fit patients, switching to reduced-dose lenalidomide maintenance without dexamethasone after 9 Rd cycles was feasible, with similar outcomes to standard continuous Rd. This trial was registered at www.clinicaltrials.gov as #NCT02215980.

Despite remarkable advances in the treatment of multiple myeloma in the last decades, the prognosis of patients harboring high-risk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with multiple myeloma receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard- versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard- vs. high-risk patients, we observed similar progression-free survival (3-year PFS: 52% vs. 43%, respectively; p=0.50), overall survival (3-year OS: 78% vs. 73%; p=0.38), and overall response rate (88% vs 95%; p=0.47), with no statistical differences between the two groups. No difference in terms of progression-free survival was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed multiple myeloma patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted into similar progression-free survival and overall survival, as compared to standard-risk patients. ClinicalTrials.gov IDs: NCT01857115 (IST-CAR-561) and NCT01346787 (IST-CAR-506).

Elderly transplant-ineligible (NTE) patients represent the majority of patients affected by multiple myeloma (MM). Elderly patients are a highly heterogeneous population, with large variability in health and functional status. Thus, choosing their optimal treatment is challenging. A wide range of first-line treatments is available, and novel-agent combinations, including monoclonal antibodies (mAbs), have recently entered clinical practice. The combination of the anti-CD38 mAb daratumumab with bortezomib, melphalan and prednisone (Dara-VMP) or lenalidomide and dexamethasone (Dara-Rd) demonstrated impressive advantages in terms of progression-free survival and minimal residual disease negativity, as compared to VMP and Rd, without safety concerns. Another anti-CD38 mAb, isatuximab, is showing encouraging results, and new isatuximab-based combinations might enter clinical practice in the future. Nevertheless, available data come from clinical trials with selected patient populations and, to date, the manageability of these regimens in real-life patients or in frail patients remains unknown. Frailty-tailored treatments, including mAbs, are under evaluation in preliminary studies. In this review, we analyze recently approved mAb-based treatments for NTE newly diagnosed MM patients and new combinations under evaluation, focusing on the efficacy and safety of these regimens and on open issues regarding the choice of therapy for elderly patients.