BACKGROUND:Pomalidomide-daratumumab-dexamethasone (DPd) has been shown to be effective in lenalidomide-exposed patients with multiple myeloma (MM). We aimed to evaluate this combination in patients with del(17p), for whom there is no specific treatment. PATIENTS AND METHODS:The phase II DEDALO study enrolled patients with relapsed/refractory (RR)MM, del(17p), and ≤ 3 previous therapy lines including lenalidomide. Patients received DPd according to the approved schedule. The primary endpoint was minimal residual disease (MRD) negativity (by next-generation sequencing, 10-5 sensitivity). RESULTS:Fifty patients were enrolled, and 45 were eligible. A del(17p) clone size ≥ 55% was observed in 26/45 patients, while TP53 mutations in 10/31. One patient achieved MRD negativity. With a median follow-up of 18.7 months, the median progression-free survival (PFS) was 7.0 months (4.3-13.9) overall, 6.5 in patients with a del(17p) clone size < 55%, 7.6 in those with a clone size ≥ 55%, 3.2 in those with biallelic TP53 alteration, and 11.8 in those with isolated del(17p). Toxicity was consistent with previous studies. CONCLUSION:This is the first study testing a specific treatment for MM patients with del(17p). We confirmed the severity of this abnormality, particularly in the presence of double TP53 inactivation, and the importance of a thorough biological characterization.

The prognostic significance of impaired renal function in Waldenström macroglobulinaemia (WM) remains poorly defined. We conducted a nationwide multicentre study to evaluate its clinical characteristics and prognostic impact in symptomatic patients. We analysed 402 symptomatic WM patients, stratified according to renal function at diagnosis (creatinine clearance <60 mL/min/1.73 m2). Renal dysfunction was identified in 119 patients (29.6%). Renal biopsy was performed in 33 cases. Patients with reduced renal function were older (median age 76 vs. 67 years, p < 0.0001), had lower haemoglobin levels (10.8 vs. 11.8 g/dL, p = 0.008) and higher 24-h proteinuria (0.29 vs. 0.20 g, p = 0.04). Comorbidities of renal interest were similarly distributed between groups. Renal dysfunction was associated with inferior median overall survival (139 vs. 203 months, p < 0.001) and progression-free survival (PFS) (80 vs. 106 months, p = 0.002). Among patients aged <70 years, renal dysfunction remained associated with shorter PFS (77 vs. 121 months, p = 0.005). Importantly, worsening renal function did not correlate with increasing age. In this setting, first-line chemoimmunotherapy was associated with improved median PFS. Thus, renal dysfunction at diagnosis may represent an underrecognized, independent adverse prognostic factor in symptomatic WM.

Background: Frailty in Waldenström's Macroglobulinemia (WM) is poorly-defined and hard to assess objectively, despite its impact on treatment access, tolerability, and outcomes. In WM, commonly affecting elderly, comorbid patients (pts), first-line BTKi are EMA-approved only for pts ineligible to chemoimmunotherapy (CIT), though no standardized definition exists for ineligibility. Based on this, we evaluated weather an integrated geriatric- and quality of life (QoL)-based approach could better define pts fitness and guide treatment in WM. Methods: in this ongoing prospective, multicenter, observational cohort study, consecutive adult patients with WM diagnosis, regardless of age, disease stage or treatment status, completed Practical Geriatric Assessment (PGA) (Dale et al., JCO, 2023) and EORTC QLQ-C30 (Aaronson et al., J Natl Cancer Inst, 1993) questionnaires at enrollment (baseline), 6, 12 and 18 months. PGA domains included: physical, functional, psychological, cognitive function, nutritional status, social support and comorbidities. Primary objective is to define frailty in WM using PGA metrics. Secondary include: PGA feasibility in clinical practice; relationship between clinical/disease characteristics and PGA domains; impact of PGA and EORTC QLQ-C30 on therapy choice, treatment management and outcomes, non-cancer-related survival. The study is conducted according to the Declaration of Helsinki. Here we report preliminary data from baseline assessment. Results: From November 2024 to July 2025, 198 WM pts were enrolled: 78 on active treatment at any line (a-Tx); 62 previously treated and currently in watch and wait (t-ww); 58 untreated in watch and wait (u-ww). Median age for the whole population was 72 years (41-92), 66% were male, 14% had a high-IPSSWM, 17% neuropathy, 13% ECOG-PS>1. Median CIRS was 3 (0-19), with 17% having ≥1 major (grade 3-4) comorbidity (CIRS3+). 139/158 (88%) had MYD88 and 8/61(13%) CXCR4 mutations. When comparing the 3 groups, a-Tx pts were significantly older (median 74 vs 69 vs 69 y), had higher IgM levels, lower hemoglobin and more concomitant medications (conc-med). Among a-Tx, 73% were on targeted agents; 15% on CIT; 12% on clinical trials; median prior lines was 1 (range 0-7). All t-ww had prior CIT (median 1 prior line, range 1-2). Overall, 96% had ≥1 impaired PGA domain (median 3, range 0-6) with no significant differences across the 3 groups. In a range 0-100 (higher range score representing higher response level) median EORTC QLQ-C30 global health status (GHS) was 67 (67, 67 and 75 in a-Tx, t-ww, u-ww respectively, p=.628). Among 38 pts with CIRS >6 and/or CIRS3+, 97% perceived a significative impact of comorbidities on QoL on the PGA comorbidity domain. Notably, 90% of 145 pts without severe objective comorbidities also reported a significant impact at the PGA. At univariate analysis, conc-med, ECOG-PS and respiratory, neurologic and psychiatric CIRS items were associated with worse QLQ-C30 GHS, but not significant on multivariate. Independent PGA domains affecting QLQ-C30 GHS were: functional and psychological status (both p<.001) and lack of social support (p.002). Cumulative number of impaired domains was significantly higher at multivariate analysis in pts with neuropathy (p.052), presence of comorbidities (p.009), ECOG-PS≥1 (p.001) and vascular CIRS item (p .023). Analyzing individual PGA domains, prior CIT was detrimental on cognitive function only (p.018). Age and conc-med were the baseline pts characteristics most frequently affecting single PGA domains. When stratifying pts by traditional CIT fitness criteria (CIRS >6 and/or CrCl <70 mL/min), “unfit” had higher median number of impaired PGA domains than “fit” (4.0 vs 3.0; p.023) and were older (median age 77.4 vs 65.9 years; p<.001). A median of 3 altered domains still persisted in the “fit” group, highlighting the PGA's added value beyond conventional indices. Median time needed to complete PGA + QLQ-C30 was 20 minutes for pts and 5 minutes for physicians. Conclusion: Preliminary data suggest this approach is feasible, time-efficient, and may improve fitness stratification. Despite the small sample, baseline PGA and EORTC-QLQC30 GSH were comparable across the 3 groups. Impaired functional and psychological status and lack of social support emerged as major detrimental factors for QoL. Ongoing enrollment aims to identify key PGA-based fitness determinants, track longitudinal changes, and assess therapeutic implications.

Based on the results of the ASPIRE trial, the KRd regimen (carfilzomib, lenalidomide and dexamethasone) has been approved in Italy for relapsed/refractory multiple myeloma (RRMM) patients since 2016. The published KRd schedule indicates this combination for 18 cycles, followed by continuous Rd until progression. However, in Italy, there are no limits to the number of KRd cycles, fully refunded based on negotiation with the Italian regulatory agency, and in some centers this combination has been used continuously, beyond the 18th cycle (continuous KRd, cKRd). To evaluate and compare safety and efficacy of both continuous and fixed KRd, we retrospectively collected real-world data from 356 patients treated in 20 EMN (European Myeloma Network) Italian centers from October 2016 to September 2023 and we patients treated with cKRd with those treated with the ASPIRE schedule. After a median follow-up of 48.59 months (CI 27.24-61.24), the overall response rate (ORR) of the entire series was 83% with 35% of complete responses(CR). The mPFS was 23.1 months (CI 20.11-28.62) and mOS was 62.85 months (CI 53.75-70.34), longer than the mOS of the ASPIRE study (48.3 months). The landmark analysis of the cKRd population shows non-significant benefit both in terms of PFS and OS compared to patients where the administration of KRd was stopped at the 18th cycle as in the ASPIRE trial, to note, in the cKRd group patients had a more aggressive disease based on ISS and R-ISS stage. Therefore, although we did not observe additional toxicities, our retrospective analysis, while confirming the validity of the KRd regimen in RRMM, does not indicate any general advantage in keeping the administration of carfilzomib beyond the ASPIRE schedule.

The prolonged survival of patients with Waldenström Macroglobulinemia (WM), together with the increasing use of chemoimmunotherapy and novel agents, has raised concern about long-term complications, including the development of secondary primary malignancies (SPMs). However, real-world data on the incidence and characteristics of SPMs in WM are scarce.The aim of our study was to evaluate, in a real-life multicenter cohort, the incidence, type, and risk factors associated with SPMs in WM patients treated with various therapeutic strategies, including bendamustine-rituximab (BR), dexamethasone-rituximab-cyclophosphamide (DRC), other chemoimmunotherapy (CIT) schemes including fludarabine or chlorambucil or cladribine, BTK inhibitors (BTKis), and rituximab or steroids.This retrospective analysis included 489 patients diagnosed with WM and treated across 14 Italian hematology centers from 2008 to 2024. A total of 57 SPMs were identified with a median time to diagnosis of 34.1 months (range 2.3–192 months) from the beginning of the treatment. Hematologic SPMs represented 22.8% (13/57) of all SPMs.Analyzing the entire cohort, 12.7% (21/165) of patients treated with BR developed a SPM, compared to 10.5% (16/152) with DRC, 21% (13/62) with other CIT and 5.9% (1/17) with BTKi alone. Similarly, among those treated with DRC alone (n=73), 10 SPMs occurred (13.7%) and the addition of BTKi as second line was not associated with an increased risk (4/53, 7.5%). A higher incidence was observed in patients treated with other CIT scheme as first line: 6 SPMs were registered among 22 patients (27.3%). Patients who received BTKi alone (n=16) had the lowest rate of SPMs (1/16, 6.2%).In patients receiving BR without further treatment, the median time to SPM was 30.3 months (range 3.1–89.2), while for those receiving DRC it was 21.0 months (range 2.3–137.8) and those receiving other CIT it was 34.4 months (range 13.3-186.6). Notably, patients receiving BR followed by BTKi had a median time to SPM of 42.6 months, and those receiving DRC followed by BTKi had a longer latency (61.5 months).Although BR and DRC had similar overall SPM rates, other CIT regimens were associated with a higher risk, often appearing late. Conversely, BTKis, both in untreated patients and in sequential therapy, showed a favorable SPM profile.When adjusting the SPM incidence by the competing risk of death and age at diagnosis, the risk of SPM was significantly higher for the BR/DRC group respect to the BTKi (p=0.04, HR=2.68, 95% CI: 1.07-6.38, Fine-Gray model).In our cohort, patients treated with BTKi exhibited the lowest incidence of SPMs (6.2%), in comparison to that observed with BR, DRC, or other CIT regimens. Even when BTKi was administered as second-line therapy following initial cytotoxic regimens, it did not increase the risk compared to the CIT exposure (BR: 13.8% vs 9.5%; DRC: 13.7% vs 7.5%).The pharmacodynamic profile of BTKi, targeting the MYD88-BTK axis with minimal off-target DNA damage, contrasts with alkylating agents or nucleoside analogues that pose greater mutagenic risk.Unlike fixed-duration CIT, continuous BTKi exposure does not appear to culminate in cumulative carcinogenic risk. Based on lower SPM incidence, favorable latency profiles, and minimal contribution to hematologic second cancers, BTKi seemed to emerge as a strategic therapeutic choice in patients with prolonged expected survival, where minimizing long-term toxicity is crucial. In conclusion, our large real-world multicenter study confirms that SPMs are a relevant long-term complication in WM, with variable incidence according to treatment exposure, despite the limitation of a smaller BTKi group and its shorter median follow-up time. BR and DRC are associated with moderate SPM risk, not increased by subsequent BTKi. Other CIT schemes, nowadays less administered, appeared to confer a too high risk of SPMs. BTKi seemed to demonstrate a significant advantage in limiting SPM, both solid and hematological. Although retrospective, our findings support the integration of BTKi early in treatment algorithms to reduce SPM risk. Prospective registries, longer-term follow-up and comparison with other casistics will be critical to define cumulative risk, especially as next-generation BTKi show promising results with even better selectivity and tolerability.

Infections are a major source of morbidity and mortality in patients with Waldenström Macroglobulinemia (WM). During the last years, treatments with Bruton's Tyrosine Kinase inhibitors (BTKis) have increased in WM, with a perceived reduction on infection rates but data on infection incidence are generally extrapolated from clinical trials, and real-world evidence remains limited.The aim of our study is to describe in a real-world setting the infectious complications in patients with WM treated with chemo-immunotherapy (CIT) or BTKis to evaluate their incidence in first and second line of treatment and to identify additional factors of infectious risk.This retrospective multicentre study included 489 patients diagnosed with WM and treated since 2008 across 14 Italian hematological centres.In the first-line setting, treatments were distributed as follows: bendamustine-rituximab (BR, n=165), dexamethasone-rituximab-cyclophosphamide (DRC, n=152), other CIT regimens (n=62), rituximab or steroids alone (n=52), chemotherapy alone (n=41), and BTKis (n=17). A total of 111 infections were recorded, with the following rates per regimen: BR 32.1% (53/165), DRC 14.5% (22/152), other CIT 24.2% (15/62), rituximab/steroids 9.6% (5/52), chemotherapy 29.3% (12/41), and BTKis 23.5% (4/17).When evaluating hospitalization and exposure-adjusted infection rates for the main schemes, BR had a hospitalization rate of 34% (18/53), with an infection rate of 5.65 per 100 person-months and 1.92 per 100 person-months for infections requiring hospitalization; other CIT 26.7% (4/15), 4.25 and 1.13. In contrast, DRC showed lower rates: 22.7% hospitalization, 2.49, and 0.56 per 100 person-months respectively. BTKis showed the lowest rates: 25% hospitalization, 0.72, and 0.18 per 100 person-months.In the second-line setting, 203 patients received subsequent therapies: BTKis (n=102), BR (n=26), DRC (n=16), bortezomib-based regimens (n=19), chemotherapy (n=22), and rituximab alone (n=18). A total of 63 infections occurred, distributed as follows: BTKis 35.3% (36/102), BR 30.8% (8/26), DRC 12.5% (2/16), bortezomib 42.1% (8/19), chemotherapy 31.8% (7/22), and rituximab 11.1% (2/18).BTKis in second line had a hospitalization rate of 27.8% (10/36), with an infection rate of 1.0 per 100 person-months and 0.28 for those requiring hospitalization. BR showed higher rates: 37.5% (3/8) hospitalization, 5.52, and 2.07 per 100 person-months, respectively. DRC 0% (0/2), 2.53 and no hospitalization, bortezomib-based regimens 62.5% (5/8), with 1.11 and 0.69 infections per 100 person-months.Overall, infection rates were similar between first and second-line therapies within the same treatment group. BTKis showed lower infection rates respect to those of BR and other CIT regimens, (in first line BTKis vs BR: <0.001; vs DRC: 0.012; vs other CIT: <0.001; in second line BTKis vs BR: <0.001)) and severity, measured by hospital admissions (BTKis vs BR 0.002). These rates became significantly lower when adjusted for drug exposure time. Notably, DRC demonstrated the lowest infection rate among CIT schemes, especially in first-line therapy.This large retrospective real-world study highlights the favourable infectious safety profile of BTKis in the treatment of WM, particularly when compared to traditional chemo-immunotherapy regimens both in the small group of WM patients treated in first line and the greater population of WM relapsed patients. The lower incidence of infections and related hospitalizations with BTKis was observed in both first- and second-line settings, suggesting their potential as a safer long-term option in WM management. Among CIT regimens, DRC also emerged as a well-tolerated alternative with a lower risk of infectious complications, especially in the elderly population. These findings underscore the importance of incorporating infection risk into treatment decisions and support the broader use of BTKis in appropriate clinical contexts.

BACKGROUND:Fluorescence in situ hybridization (FISH) is the standard technique for the prognostic detection of cytogenetic abnormalities (CA) in multiple myeloma (MM). In Italy, the application of practical guidelines for FISH testing in clinical studies and the degree of standardization of laboratory techniques are largely unknown. METHODS:We conducted a survey from April to July 2023 among 70 MM-treating centers associated with the European Myeloma Network Italy and geographically well distributed across Italy. We aimed to record laboratory and clinicians' perspectives about FISH application in Italy, with a focus on 1q alterations. RESULTS:FISH was widely accessible across the country, with 71% of centers performing it locally, while the remaining centers (predominantly those with <30 newly diagnosed MM cases/year) sent samples to external laboratories. Variability in laboratory techniques, such as CD138+ cell purification and CA detection thresholds, was observed among centers. The centers analyzed del(17p) (100%), t(4;14) (100%), t(14;16) (98%), 1q+ (96%, with 70% distinguishing between gain and amplification), t(11;14) (90%), del(1p32) (88%), del(13q) (68%), and hyperdiploidy (52%). FISH emerged as a crucial prognostic technique, since 94% of centers used the Revised International Staging System (R-ISS) at diagnosis, and 69% implemented the recent R2-ISS. Most centers performed FISH at diagnosis in all patients, while others did not routinely perform FISH in some categories of patients (e.g., aged >80 years). At relapse, 53% of centers routinely repeated FISH testing, 9% did not, while others repeated it selectively. CONCLUSIONS:This overview of FISH use in Italy provides a basis for future standardization efforts.

Autologous stem cell transplantation (ASCT), doubled in selected cases, followed by lenalidomide maintenance (LM) remains the standard treatment after induction therapy for newly diagnosed, transplant eligible patients with multiple myeloma (TEMM). Notwithstanding, evidences about how these approaches have been applied and how they have performed in the real-life setting, before the introduction of daratumumab within the induction regimens, are quite limited. Herein, we report the outcome of 300 MM patients, who underwent single (45%) or double (55%) ASCT, and received (42%) or not (58%) lenalidomide maintenance, outside of clinical trials, between December 2001 and February 2020, within the "Rete Ematologica Pugliese". After a median follow-up of 65 months (range: 9-186), median PFS was significantly longer in patients who underwent double ASCT compared to those who received single ASCT (66 vs. 53 months, respectively, p = 0.01). Likewise, after a median follow-up of 62 months (range: 9-174), patients who received LM had a significantly better PFS respect to those who did not (72 vs. 36 months, respectively p < 0.001). Concerning OS, it was not influenced by single or double ASCT (although a trend favoring double ASCT was observed), while LM significantly improved OS (142 vs. 108 months, p = 0.01). At multivariable analysis factors influencing PFS were achievement of complete remission after first ASCT, double ASCT and LM, while those impacting on OS were high risk cytogenetics, LDH and LM. In the context of a rapidly changing therapeutic scenario, our data might contribute to a real-life, historical benchmark for current and future treatments of TEMM patients.

Bone disease associated with multiple myeloma (MM) is characterized by osteolytic lesions and pathological fractures, which remain a therapeutic priority despite new drugs improving MM patient survival. Antiresorptive molecules represent the main option for the treatment of MM-associated bone disease (MMBD), whereas osteoanabolic molecules are under investigation. Among these latter, we here focused on the myokine irisin, which is able to enhance bone mass in healthy mice, prevent bone loss in osteoporotic mouse models, and accelerate fracture healing in mice. Therefore, we investigated irisin effect on MMBD in a mouse model of MM induced by intratibial injection of myeloma cells followed by weekly administration of 100 mu g/kg of recombinant irisin for 5 wk. By micro-Ct analysis, we demonstrated that irisin improves MM-induced trabecular bone damage by partially preventing the reduction of femur Trabecular Bone Volume/Total Volume (P = .0028), Trabecular Number (P = .0076), Trabecular Fractal Dimension (P = .0044), and increasing Trabecular Separation (P = .0003) in MM mice. In cortical bone, irisin downregulates the expression of Sclerostin, a bone formation inhibitor, and RankL, a pro-osteoclastogenic molecule, while in BM it upregulates Opg, an anti-osteoclastogenic cytokine. We found that in the BM tibia of irisin-treated MM mice, the percentage of MM cells displays a reduction trend, while in the femur it decreases significantly. This is in line with the in vitro reduction of myeloma cell viability after 48 h of irisin stimulation at both 200 and 500 ng/mL and, after 72 h already at 100 ng/mL rec-irisin. These results could be due to irisin ability to downregulate the expression of Notch 3, which is important for cell-to-cell communication in the tumor niche, and Cyclin D1, supporting an inhibitory effect of irisin on MM cell proliferation. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot. Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of a plasma cell clone in the BM. The main clinical complication of MM is represented by Bone Disease (BD) often determining pathological fractures and increased mortality risk. To date, MMBD treatment is based on molecules able to avoid bone resorption, but many patients continue to fracture; thus, molecules involved in new bone deposition are under investigation. Among these, we focused on irisin, produced by skeletal muscle during physical exercise, which is able to enhance bone mass and accelerate fracture healing in mice, and prevent bone loss in osteoporotic mice. Therefore, by using a mouse model of MM, we demonstrated that irisin improves MM-induced trabecular bone damage, downregulates the expression of the inhibitor of bone formation, Sclerostin, and modulates bone resorption molecules in favor of bone protection. We also found that irisin reduces MM cell invasion in the femoral BM of mice and reduces myeloma cell viability in vitro, presumably by irisin ability to downregulate the expression of Notch 3 and the regulator of cell proliferation Cyclin D1. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot. Graphical AbstractWe thank Servier Medical Art (https://smart.servier.com/) for providing free image software to build the figure.

The ELOQUENT-3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18-month follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 17.7 months, 213 patients (66.4%) experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 7.5 and 19.2 months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three-fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow-up. In conclusion, our real-world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab.

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

In the setting of relapsed patients affected by Waldenström Macroglobulinaemia (WM) chemo-immunotherapy (CT) has been substantially substituted by BTKis. Previous trials have investigated efficacy and safety of BTKis in second line without a direct comparison to CT. The aim of our retrospective study was to assess responses and outcomes with the treatment of BTKi or CT in second line. We enrolled 169 WM patients relapsed in the period 2008-2022 from 15 FIL centres: 85 patients were treated with ibrutinib and 84 patients with CT; of whom 34 patients with BR (bendamustine-rituximab), 21 DRC (dexamethasone-rituximab-cyclophosphamide), 15 bortezomib-based regimens and 14 palliative regimens (i.e. alkylants). The two cohorts of ibrutinib and CT showed similar basal clinical characteristics, prognostic factors, comorbidities and also times of retreatment between first and second line (42 vs 39 months, p=0.64). Overall response rate (ORR) was achieved in 84.7% of patients after ibrutinib and in 69% after CT (p=0.026), ibrutinib patients showed a better progression free survival (PFS) than CT patients (4-y PFS of 67% vs 48%, p=0.0045), but we did not find statistical differences in terms of time to next treatment (TTNT) and overall survival (OS); in particular 4-y TTNT was 67% for ibrutinib and 55% for CT, 4-y OS was 78% for both. ORR for both the groups was independent from presence of treatment modifications and toxicities. Considering the 4 different groups within the CT cohort, they showed the same characteristics except for the median age at treatment (bortezomib-based: 69 yy, BR: 70 yy, DRC: 75 yy, palliative: 83 yy; p=0.007). Non-significant difference among the 4 groups was seen in terms of ORR and PFS nor of TTNT and OS, even if we registered a better PFS for BR with a median PFS of 58.2 months, followed by bortezomib-based (PFS 53.6 mo), DRC (PFS 44.6 mo) and palliative (PFS 33.6 mo). When comparing ibrutinib to each of the 4 CT groups, different ORR were observed in each group with Ibrutinib reporting the highest rate (84.7%; p=0.023). PFS of ibrutinib was superior to PFS of DRC, bortezomib-based and palliative regimens (p=0.028, p=0.023 and p=0.04, respectively) and it showed a trend versus PFS of BR (p=0.055). Analysis showed the significant trend (p=0.057) in terms of better PFS of ibrutinib in comparison to the other 4 curves. For TTNT and OS none difference was reported based on ibrutinib and type of CT. No differences were noted in the two subgroups of ibrutinib patients who were treated with BR or DRC as first line therapy in terms of PFS, TTNT, OS, ORR and withdrawal or dose reduction due to toxicity. Multivariate analysis found choice of the treatment (ibrutinib vs CT), beta2microglobulin and female gender as significant variables that favourably impact on PFS, choice of the treatment, age and female gender on TTNT, age and female gender on OS. This large retrospective real-life study showed advantages of ibrutinib versus CT in terms of ORR and PFS, except for BR, but not in terms of TTNT and OS.

Waldenström Macroglobulinaemia (WM) is an indolent lymphoma still primarily managed with chemo-immunotherapy, which remains a key first-line treatment option, although recently BTKIs have emerged as potential therapies for untreated patients. The aim of our study was to evaluate and compare efficacy and safety of different chemo-immunotherapeutic regimens commonly used in Italy for frontline WM treatment. A retrospective analysis was conducted on 547WM patients enrolled between 2008-2022 from 14 Italian haematological centres. Among them, 245 received the BR scheme (bendamustine-rituximab), 116 were treated with DRC (dexamethasone-rituximab-cyclophosphamide), and 129 were treated with various other regimens including monotherapy with chlorambucil or cyclophosphamide as well as more aggressive combinations, such as Chl-R (chlorambucil-rituximab), FCR (fludarabine-cyclophosphamide-rituximab) or R-CHOP (rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone), 48 patients received rituximab monotherapy for neurological symptoms. The main focus of our analysis was on the two major treatment groups: BR and DRC. There were notable differences between these two groups in terms of age at treatment (69 vs 70 years old, respectively), CIRS (more patients with CIRS>6 in DRC) and revised IPSSWD (higher risk rates in BR). Patients treated with BR tended to be younger, more fit but also had a more aggressive disease. Overall survival (OS) curves did not show significant differences between the two schemes (5-year OS 87.5% for BR and 93.0% for DRC, p=0.42). Similarly, the analysis of progression free survival (PFS) curves demonstrated a better PFS at 5 years for BR (79.2%) compared to DRC (54.5%) (p<0.001; figure 1A). The median PFS was 63.6 months for DRC, while it was not reached for BR. When analysing BR-treated patients separately (standard dose and reduced initial dose) both groups showed better PFS curves than DRC (p<0.001; figure 1B). Multivariate analysis identified the choice of the treatment (BR vs DRC) as the sole significant variable impacting PFS (RR 1.76). Notably, approximately 33% of the patients treated with BR received an initial bendamustine dose lower than the standard dose of 90 mg/m 2 for first-line therapy with 91% of these cases receiving 70 mg/m 2. The two schemes BR and DRC were well tolerated with no significant reduction in administered cycles (16.3% for BR vs 20.7% for DRC). However, dose reduction was more common for BR (14.3%) compared to DRC (6.0%). In conclusion, this large Italian retrospective real-life study showed excellent outcomes for unselected WM patients treated with chemo-immunotherapy. Despite the emergence of new treatment options, chemo-immunotherapy remains a highly effective treatment modality for these patients. The long-term follow-up confirmed better PFS for BR-treated patients, while OS, remained comparable between BR and DRC. Moreover, the BR scheme exhibited excellent PFS even with a reduced initial bendamustine dose.

COVID-19-related mortality in the onco-hematological setting is higher than in general population and patients with multiple myeloma (MM) are reported to be particularly vulnerable to SARS-CoV-2 infection, due to compromised humoral and cellular immunity (related to disease itself) and to anti-tumor treatments. Thus, along with general measures, vaccines against SARS-CoV-2 have become, from their approval, the most important strategy to prevent poor outcome from COVID-19 in MM patients. However, limited data have been so far published about epidemiology and outcome of breakthrough COVID-19 in MM patients after three anti-SARS-CoV-2 vaccine doses. We performed a retrospective analysis of 54 consecutive patients with active MM who experienced SARS-CoV-2 infection between December, 2021, and December, 2022 at our Institution (Table 1). Among them, four cases of “reinfection” were documented. All patients had received three doses of anti-SARS-CoV2 vaccines (mostly mRNA) and 6 of them had also received a fourth, “second booster” dose. SARS-CoV-2 infections were diagnosed by RT-PCR or by antigen rapid test on nasopharyngeal swabs. Data about sex, age, ongoing treatment, symptoms, hospitalization, mortality, and additional use of antiviral drugs or monoclonal antibodies for the treatment of COVID-19 were collected. The median age of the whole group was 65 years (IQR: 60-76; range: 39-84), with male preponderance (59.3%). Half of the patients (27) had at least one underlying comorbidity, with chronic cardiopathy (i.e., hypertension, atrial fibrillation) being the most reported. The most frequent isotype was IgG, followed by IgA, light chain and non-secreting subtype. Median number of days between the last dose of vaccine and infection was 136.5 (IQR: 89-199.2; range: 11-381). About disease status at SARS-CoV-2 breakthrough infection, 27 cases (50%) were newly diagnosed/first line MM, 20 (37%) were first relapses, 7 (13%) were further relapsed MM. Forty-eight patients (88.9%) were under treatments including dexamethasone (64.8%), proteosome inhibitors (25.9%), IMiDs (75.9%), anti-CD38 monoclonal antibodies (44.4%) or other therapies (7.4%). Six patients (11.1%) in complete response, three of whom after autologous transplantation and one after CAR-T treatment, were in follow-up, without active therapy. Infection was symptomatic in 35 patients (64.8%) and the most common symptoms were fever, cough, sore throat and runny nose. Overall, 4 patients (7.4%) were hospitalized: among them, 1 (1.8%) was admitted to an intensive care unit (ICU) due to respiratory distress. Fourteen patients (25.9%) received specific anti-SARS-CoV-2 treatment: 7molnupivar, 5 PF-07321332/ritonavir, 1 PF-07321332/ritonavir + sotrovimab, 1 sotrovimab. After a median follow-up of 258 days (IQR: 181-294; range: 43-356), 3 patients (5.6%) had died and no patient reported long-lasting symptoms. Our data indicate that SARS-CoV-2 infection remains frequent even in “triple vaccinated” MM patients, but also that the clinical outcome of COVID-19 appears to be significantly improved by a “booster” dose of vaccine with respect to pre-vaccination era in this high risk population exposed to novel Omicron variants. The role of new antiviral agents and monoclonal antibodies, currently used to reduce the risk of progression of COVID-19 to severe disease, warrants to be further investigated in larger series. Table 1 - Characteristics of 54 full vaccinated MM patients with SARS-CoV-2 infection Age, years Median (IQR)Range 65 (60-76)39-84 Sex, n. (%)MaleFemale 32 (59.3)22 (40.7) Comorbidities, n. (%)012≥3 27 (50)16 (29.7)5 (9.2)6 (11.1) MM subtype, n. (%)IgGIgALight chainNon-secreting 33 (61.1)12 (22.2)7 (13)2 (3.7) Days from last vaccine dose to SARS-CoV-2 infection Median (IQR)Range 136.5 (89-199.2)11-381 Disease status, n. (%)Newly diagnosed/First line1st RelapseRelapse-Refractory 27 (50)20 (37)7 (13) Current MM treatment, n. (%) Dexamethasone Contains Proteosome inhibitor Bortezomib Carfilzomib Ixazomib Contains IMiD (including maintenance therapy) Thalidomide Lenalidomide Pomalidomide Contains CD38 mAb Daratumumab Isatuximab Contains other Elotuzumab, Belantamab Mafodotin Melphalan No therapies 48 (88.9)35 (64.8)14 (25.9)93241 (75.9)632324 (44.4)2224 (7.4)211 6 (11.1) COVID-19 outcome, n. (%)Presence of symptomsHospitalizationHospitalization in ICUDeath to COVID-19 35 (64.8)4 (7.4)1 (1.8)3 (5.6) COVID-19 symptoms, n. (%)FeverCoughSore throatRunny noseFatigueDiarrhea 28 (80)14 (40)11 (31.4)11 (31.4)6 (11.1)3 (8.6) Treatment, n. (%)MolnupiravirPF-07321332/RitonavirPF-07321332/Ritonavir + SotrovimabSotrovimabNone 7 (13)5 (9.3)1 (1.8)1 (1.8)40 (74.1)

Introduction: Deletion of the short arm of chromosome 17 (del(17p)) is a well-established high-risk feature in multiple myeloma (MM) and is included in current disease staging criteria. Treatment of del(17p) MM is a major challenge due to rapid development of chemoresistance and short survival. The size of del(17p) clone correlates with prognosis, and the 55-60% threshold has the worst prognosis. Approximately 1/3 of pts have a concomitant TP53 mutation, with a complete abolition of the protein function. TP53 biallelic inactivation is defined as double-hit myeloma. Pomalidomide-dexamethasone showed promising results in this setting (Leleu et al, Blood 2014). Daratumumab is an attractive strategy for treatment of MM pts with del(17p). In the phase II DEDALO trial (NCT04124497), we assessed daratumumab-pomalidomide-dexamethasone (DPd) in RRMM pts with del(17p). Methods: Key eligibility criteria included: RRMM; up to 3 prior lines of therapy, del(17p) observed by FISH in at least 10% of plasma cells at any time of MM history, previous exposure to lenalidomide, no refractoriness or intolerance to pomalidomide, nor previous exposure to an anti-CD38 monoclonal antibody. Continuous DPd treatment consisted of daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter; oral pomalidomide (4 mg, once daily on days 1–21); and oral or intravenous dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for pts ≥75 years) at each 28-day cycle. The primary endpoint was MRD 10-5 negativity within the first 12 months of treatment. NGF and NGS MRD analyses were performed. The key secondary endpoints were PFS, ORR and OS. Results: Forty-five pts were enrolled. The median age was 63 (range 43-83) years (yrs), and 60%/29%/11% of pts had ISS stage I/II/III. All pts had >10% del(17p) and 14 pts had ≥55% del(17p); t(4;14) was observed in 6, t(14;16) in 6, del(1p) in 10, and 1q+ in 16 pts. Median number of prior lines of therapy was 1 (range 1-3); 100% had been previously exposed to lenalidomide and 86% to a proteasome inhibitor. Three pts achieved MRD negativity by NGF, while NGS analysis is ongoing. ORR was 60%, including 13 pts with PR, 12 with VGPR, and 2 with ≥CR. Median time-to-response was 2.5 months. With a median follow-up of 8.5 months (range 6.3-13.9), median PFS was 7.1 months (range 5.9 – not reached [NR]; Figure). By subgroup analysis, PFS was: 8.4 months in pts with del(17p) clone size <60% and 6.5 months in pts with del(17p) clone size ≥60% (HR, 0.75; 95% CI 0.33-1.7; P=0.48); 12.4 months in pts with ISS I vs 4.2 months in pts with ISS II-III (HR, 2.48; 95% CI 1.12-5.51; P=0.02); 6.6 months in pts at first relapse vs 7.1 months beyond first relapse (HR 0.95; 95% CI 0.42-2.12; P=0.89); 7.1 months in pts <65 yrs and 7.6 months in those ≥65 yrs of age (HR 0.84; 95% CI 0.37-1.92; P=0.68). Median OS was NR. No new safety concerns were observed. TP53 mutational analysis is underway. Conclusion: In this difficult-to-treat population, DPd is a therapeutic option for pts of all ages and can be considered as a bridge to other immunotherapies, such as T-cell engagers and CAR-T cells.