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The International Myeloma Working Group (IMWG) guidelines recommend using electrophoresis and immunofixation to define response and progressive disease (PD) in immunoglobulin (Ig) secretory multiple myeloma (Ig-MM), whereas the role of serum-free light chain (sFLC) is controversial. We retrospectively analyzed the value of adding sFLC assays in the definition of response and PD according to IMWG criteria in 339 Ig-MM patients treated with a first-line novel agent-based therapy (median follow-up 54 months). sFLC PD was defined according to conventional criteria plus increased sFLC levels, or sFLC escape (sFLCe); progression/sFLCe-free survival (ePFS) was the time from the start of treatment to the date of first PD or sFLCe, or death; overall survival after PD/sFLCe (OS after Pe) was the time from first PD or sFLCe to the date of death. 148 (44%) patients achieved a complete response and 198 (60%) a normal sFLC ratio (sFLCR). sFLCR normalization was an independent prognostic factor for extended PFS (HR=0.46, p=0.001) and OS (HR=0.47, p=0.006) by multivariable analysis. 175 (52%) patients experienced PD according to the IMWG criteria, whereas 180 (53%) experienced PD or sFLCe. Overall, a sFLCe was observed in 31 (9%) patients. Median PFS and ePFS were both equal to 36 (95% CI=32–42, and 32–40, respectively) months. sFLC PD adversely affected the OS after Pe compared to PD with increasing monoclonal Ig only (HR=0.52, p=0.012). Our results support the inclusion of the sFLC assay for defining response and PD in Ig-MM.

Several studies showed that age alone should not be used as an arbitrary parameter to exclude patients from allogeneic hematopoietic cell transplantation (HCT). The accessibility to allogeneic HCT programs for older patients with hematological diseases is growing up constantly. The Center for International Blood and Marrow Transplant Research has recently shown that over 30% of allogeneic HCT recipients are at least 60 years old and that nearly 4% are aged 70 or more. Historically, the use of allogeneic HCT among elderly patients has been limited by age restrictions, reflecting physicians' concerns regarding prohibitive transplant-related mortality and HCT-associated morbidity.The introduction of reduced intensity/toxicity conditioning regimens has allowed transplant Centers to carry out allogeneic HCT on patients previously considered not ideal candidates. The integration of specific risk scores could lead to better capture mental and physical frailties of older patients. Older adults less frequently have available medically fit siblings, able to donate, so, unrelated donors, familial haploidentical donors or umbilical cord blood grafts could potentially abrogate such a difficulty, allowing the curative potential of allogeneic HCT.The appropriate assessing of allogeneic HCT feasibility for elderly patients should be the resonate application of different clinical and biological principles.

mRNA vaccines BNT162b2 and mRNA1273 are highly effective in preventing SARS-CoV-2 infection and mortality in healthy adults. However, their immunogenicity in immunocompromised Multiple Myeloma (MM) patients is less clear. We performed an observational prospective study of 96 MM patients (pts) treated at our centre, aimed at assessing the humoral and cell-mediated immune (CMI) response following the full immunization schedule. To this aim, we measured serum levels of neutralizing IgG anti Spike-protein (IgG anti S-RBD) at 1, 3, 6, 9 and 12 months after the 2 nd dose of vaccination, using the electrochemiluminescence (ECLIA) platform (Elecsys® Anti-sars-Cov-2 ECLIA assay) and evaluated CMI response in terms of pts with a SARS-CoV-2 specific IFNγ T cell response by IGRA (Interferon-Gamma Release Assays) test at 3 and 12 months after 2 nd dose. A concentration level of IgG anti S-RBD ≥0.80 U/ml was considered a seropositive result. Herein, we report preliminary data on the development of humoral response in 96 MM pts who reached the first study timepoint (1 month after 2 nd dose), compared to 54 health-care workers as controls. At vaccination, the median age of the 96 patients (51 males/45 females) was 66.5 (range 47-83) years. The median number of previous lines of therapy was 1 (range 1-11) and only 7 (7.3%) pts were not receiving active treatment. 44.8% (n=43) pts had relapse/refractory MM. Among 72 (75%) transplant-eligible pts, 63 patients had previously received autologous stem-cell transplantation (ASCT) with a median time between ASCT and vaccine of 31 (range 3-274) months. 70 (72.9%) pts had received immunomodulatory drugs (IMIDs) containing regimens, 30 (31.3%) proteasome inhibitors (PIs), 11 (11.5%) IMIDs + PIs, 32 (33.3%) anti-CD38 monoclonal antibodies (anti-CD38 moAbs). 33 (34.4%) pts were in lenalidomide (R) maintenance therapy. At vaccination, 67 (68.8%) pts were in VGPR or higher, 18 (18.7%) in PR and 11 (11.3%) in SD or PD. Immunoparesis (≥1 uninvolved Ig below lower level limit) was observed in 78 (88.6%) pts, of whom 59 (67.1%) showed a reduction of two Ig classes. All pts had completed the 2 planned doses of BNT162b2 (40.6%) or mRNA1273 (59.4%) vaccine 3 or 4 weeks apart, respectively. Control cohort (n=54; median age of 51 [range 40-66] years) received mRNA vaccine during the same period. People with previous SARS-CoV-2 infection (positive IgG anti S-RBD or anti-nucleocapsid N antibody titer before vaccines) were excluded from the analysis. At 1 month post 2 nd dose, (median 30 days, IQR 28-32) seropositive response rate to vaccination was 91.7% (n=88) for MM pts vs 100% for controls, p=0.05; the median IgG anti S-RBD titer was 435 (range 0.4-2500) vs 1040.5 U/ml (range 160-2500), respectively; p=0.008. No difference in the rate of seropositive response between those who received the 2 type of vaccines was found (p=0.09). Pts with response level ≥ CR had a median antibody (Ab) titer (1242 U/ml, range 0.4-2500) significantly higher than those with ≤CR (221.5 U/ml, range 0.4- 2500), p Pts receiving PI (median Ab titer 156; range 0.4- 2500) and anti-CD38 MoAbs (median titer 265 U/ml; 0.4- 2500) containing regimens had a lower Ab titer than all the other pts (p=0.003 and p A distribution analysis of the Ab titer revealed a significant correlation between better humoral response and hematological response ≥ CR (p Multivariate analysis confirmed ≥ CR [OR 2.54, 95% CI 93-756], being in first line treatment [OR 2.10, CI 22-722] and R maintenance therapy [OR 4.53, CI 484-1233] as independent predictors of better humoral response at 1 month after 2 nd vaccine dose. In conclusion, mRNA vaccines provided a high seropositivity rate in pts in active MM treatment, with a better humoral response in pts achieving CR, those who received ASCT and receiving R maintenance. Immunoparesis was confirmed to be an unfavourable factor for the development of humoral response, as well as treatment with anti-CD-38 moAbs. Disclosures Mancuso: Celgene: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Zamagni: Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers-Squibb: Honoraria; Janssen: Honoraria. Pantani: Amgen: Honoraria; Janssen: Honoraria. Rocchi: Amgen: Honoraria; GalxoSmithKline: Honoraria; Janssen: Honoraria. Rizzello: Amgen: Honoraria; GlaxoSmithKline: Honoraria; Sanofi: Honoraria. Tacchetti: Amgen: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria. Zinzani: JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; TG Therapeutics: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; ROCHE: Other, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; Incyte: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; ADC Therap.: Other; Beigene: Other, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Cavo: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

The effectiveness of ceftolozane/tazobactam for the treatment of infections in neutropenic patients caused by hypervirulent multidrug-resistant (MDR) Pseudomonas aeruginosa has not been previously reported. We identified seven cases of MDR P. aeruginosa infection in neutropenic patients over a four-month period within the same hematology ward. Four cases were associated with rapid progression despite piperacillin-tazobactam or meropenem therapy, and three patients developed sepsis or extensive skin/soft tissue necrosis. In three of the four cases, patients were empirically switched from meropenem to ceftolozane/avibactam before carbapenem susceptibility test results were available, and all four patients underwent extensive surgical debridement or amputation of affected tissues and survived. Further investigation revealed a common bathroom source of MDR P. aeruginosa clonal subtypes ST175 and ST235 that harbored genes for type III secretion system expression and elaboration of ExoU or ExoS exotoxin. We conclude that ceftolozane/tazobactam plus early source control was critical for control of rapidly progressing skin and soft infection in these neutropenic patients caused by highly virulent ST175 and ST235 clones of MDR P. aeruginosa.