Laura Paris

Summary: The extensive use of lenalidomide (Len) in the first‐line treatment of multiple myeloma (MM) has resulted in an increased frequency of patients who have been exposed or are refractory to Len (Len‐R) at first relapse. However, the outcome of Len‐R patients treated at first relapse after autologous haematopoietic stem cell transplantation (AHSCT) remains unclear. The aim of this real‐life study is to evaluate the effectiveness of the regimens licensed in Italy and used in a cohort of patients who relapsed during Len maintenance after AHSCT. We collected 306 patients with these features. Considering the different regimens used, most patients received isatuximab–carfilzomib–dexamethasone (Isa‐KD) (45.4%) followed by daratumumab–pomalidomide–dexamethasone (D‐PD) (19.3%) and daratumumab–bortezomib–dexamethasone (D‐VD) (12.4%). Overall, a reduced progression‐free survival (PFS) and overall survival (OS) were observed in patients with high‐risk disease features at relapse, including high lactate dehydrogenase (LDH) ( p = 0.0003 and p < 0.0001), International Staging System (ISS) ≥2 ( p < 0.0001 and p < 0.0001) and early relapse (p = 0.0017 and p = 0.0009). Considering the type of treatment, anti‐cluster of differentiation 38 (CD38) monoclonal antibodies (anti‐CD38 MoAb)‐based regimen displayed improved survival compared to the other treatment, with Isa‐KD reporting the longest PFS (22.8 months). Our data in a homogenous cohort of Len‐R patients treated at first relapse demonstrated that the anti‐CD38 MoAb‐based combinations, particularly Isa‐KD, represented the standard of care before the approval of anti‐B cell maturation antigen (BCMA) immunotherapy.

The management of transplant-eligible, newly diagnosed multiple myeloma is evolving with the adoption of antiCD38-based quadruplet regimens and the potential earlier use of anti-BCMA CAR T-cell therapy in lenalidomiderefractory disease. In this context, the national macroregional syMMphony project (covering Northern, Central, and Southern Italy) was developed to coordinate clinical and organizational pathways across the continuum of care, from initial autologous stem cell transplantation (ASCT) to referral for CAR T-cell therapy. The project involved structured multidisciplinary discussions within three Italian macroareas focused on four key areas: the impact of anti-CD38 quadruplets, criteria for ASCT eligibility, early identification of patients who may qualify for CAR T-cell therapy based on CARTITUDE-4, and organizational requirements for equitable access to advanced treatments. Each macroarea produced written agreements, which were then compared and harmonized during a national plenary meeting to create a final cross-regional consensus. Across all macroareas, ASCT remained central, with eligibility based mainly on overall fitness rather than age alone, and tandem transplantation reserved for select high-risk cases. Daratumumab combined with lenalidomide maintenance was recognized as an emerging post-transplant strategy, while MRD-guided modulation appeared promising but required methodological standardization and the establishment of dedicated laboratory networks. Early referral pathways for CAR T-cell therapy were increasingly seen as relevant for certain patients with lenalidomide-refractory relapse, highlighting the importance of hub-and-spoke models, resource planning, sustainable funding, and systematic collection of real-world data. Overall, the syMMphony project produced a macroregional agreement aimed at supporting more consistent and timely care pathways, aligned with evolving evidence and regulatory frameworks.

B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.

PURPOSE: High levels of circulating tumor plasma cells (CTC-high) in patients with multiple myeloma are a marker of aggressive disease. We aimed to confirm the prognostic impact and identify a possible cutoff value of CTC-high for the prediction of progression-free survival (PFS) and overall survival (OS), in the context of concomitant risk features and minimal residual disease (MRD) achievement.METHODS: CTC were analyzed at diagnosis with two-tube single-platform flow cytometry (sensitivity 4 × 10^–5) in patients enrolled in the multicenter randomized FORTE clinical trial (ClinicalTrials.gov identifier: NCT02203643 ). MRD was assessed by second-generation multiparameter flow cytometry (sensitivity 10^–5). We tested different cutoff values in series of multivariate (MV) Cox proportional hazards regression analyses on PFS outcome and selected the value that maximized the Harrell's C-statistic. We analyzed the impact of CTC on PFS and OS in a MV analysis including baseline features and MRD negativity.RESULTS: CTC analysis was performed in 401 patients; the median follow-up was 50 months (interquartile range, 45-54 months). There was a modest correlation between the percentage of CTC and bone marrow plasma cells ( r = 0.38). We identified an optimal CTC cutoff of 0.07% (approximately 5 cells/µL, C-index 0.64). In MV analysis, CTC-high versus CTC-low patients had significantly shorter PFS (hazard ratio, 2.61; 95% CI, 1.49 to 2.97, P < .001; 4-year PFS 38% v 69%) and OS (hazard ratio, 2.61; 95% CI, 1.49 to 4.56; P < .001; 4-year OS 68% v 92%). The CTC levels, but not the bone marrow plasma cell levels, affected the outcome. The only factor that reduced the negative impact of CTC-high was the achievement of MRD negativity (interaction P = .039).CONCLUSION: In multiple myeloma, increasing levels of CTC above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact.

Background: The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). Methods: The analysis included all patients with MM from the CALM study who underwent ≥1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0–100 days, 101 days–1 year, and >1 year after the first transplant. Results: The analysis included a total of 3552 patients followed up for a median of 56.7 months (range 0.4–108.1). Complication rates decreased with the time from ASCT with 24.85 cases per 100 patient-years from day 0 to 100 days after the transplant, and <2.31 cases per 100 patient-years from the 101st day. At 100 days after ASC T, 45.7% of patients had complications, with infectious events being twice as frequent as non-infectious complications. Bacterial infections (6.5 cases per 100 patient-years, 95% CI: 6.1–7.0) and gastrointestinal complications (4.7 cases per 100 patient-years, 95% CI: 4.3–5.1) were the most common early events. The pattern of complications changed with time from ASCT. The presence of complications after ASCT was not associated with overall survival. Conclusions: Our data provide a solid basis for comparing ASCT-related complications to those caused by emerging treatments in multiple myeloma, such as CAR T-cell therapy and other immunotherapies.