Supp. Table S14. Multivariable logistic regression analyses: Treatment response (≥ PR vs. MR/SD/PD)

Supp. Table S10. Cytopenias before and during treatment – m-EASIX ≤ median vs. > median

INTRODUCTION:Molecular tumor boards (MTBs) integrate clinical, pathological, and molecular data to prioritize therapy options. Because MTB-guided treatment starts at varying time points after MTB discussion, vulnerabilities to immortal time bias occur if treatment delay is ignored. METHODS:Retrospective survival analysis of 949 consecutive individuals discussed at the University Cancer Center Hamburg MTB (2016-2022). Index date (t0) was the first MTB discussion. Therapy initiation was modeled as a time-dependent exposure using Mantel-Byar methods and visualized with Simon-Makuch plots. Therapy strata were priority 1 targeted, priority 2 targeted, and non-targeted therapy. RESULTS:Among solid tumors (n = 854), targeted therapy was implemented in 24% and was off-label in 51%. ORR/DCR were 30.8%/61% for priority 1, 11.4%/36.4% for priority 2, and 37.5%/52.1% for non-targeted therapy (P = .017). The progression-free survival ratio (MTB-directed therapy vs immediately preceding line) exceeded 1.3 in 63% of targeted therapy recipients. From the MTB date, median survivalMTB was 16.5 months (priority 1), 15.5 months (priority 2), and 11.0 months (non-targeted). In Mantel-Byar analysis, progression-free survivalSimonMakuch favored priority 1 (P = .002) with 1-year rates of 28%, 12%, and 15% for priority 1, priority 2, and non-targeted therapy, respectively. One-year overall survivalSimonMakuch was 52%, 34%, and 42%. In a time-dependent Cox model, priority 1 was associated with lower risk of death versus no targeted post-MTB therapy (hazard ratio 0.80, 95% confidence interval 0.64-0.99, P = .038). CONCLUSIONS:After correction for immortal time bias, implementation of the top-priority MTB recommendation was associated with improved disease control and survival signals, although confounding and selection effects remain key limitations.

Advancements in frontline therapies have substantially improved outcomes in newly diagnosed multiple myeloma (NDMM); however, many patients will not achieve deep responses and will relapse. Teclistamab, a BCMA×CD3 bispecific antibody, in combination with daratumumab, has demonstrated strong efficacy in relapsed/refractory multiple myeloma versus standard of care as early as first relapse. This ongoing phase 2 GMMG-HD10/DSMM-XX (MajesTEC-5) study evaluates teclistamab-based regimens in transplant-eligible NDMM. In this prespecified pooled analysis of three cohorts, 49 patients received teclistamab/daratumumab/lenalidomide (Tec-DR; arms A and A1) or Tec-DR with bortezomib (Tec-DVR; arm B). Primary endpoints were incidence and severity of adverse events (AEs) and serious AEs; secondary endpoints included overall response rate (ORR), minimal residual disease (MRD) negativity and MRD-negative complete response (CR). The current analysis spans the induction and autologous stem cell transplantation phases until the premaintenance timepoint. Grade 3 or 4 treatment-emergent AEs (TEAEs) occurred in 91.8% (45/49); most were hematologic (lymphopenia (59.2%; 29/49), neutropenia (59.2%; 29/49) and leukopenia (18.4%; 9/49)). No grade 5 TEAEs were reported. Serious AEs occurred in 55.1% (27/49); pyrexia (12.2% (6/49)) was most common. Any-grade and grade 3 or 4 infections occurred in 81.6% (40/49) and 36.7% (18/49), respectively, the most common grade 3 or 4 infections being COVID-19 and pneumonia (6.1% (3/49) each). Cytokine release syndrome occurred in 67.3% (33/49); all were grade 1 or 2, all resolved and none led to discontinuation of any study treatment. No treatment-related immune effector cell-associated neurotoxicity syndrome (ICANS) events occurred. Across arms, the MRD-negative CR rate was 91.8% (45/49) by the premaintenance timepoint; the MRD negativity rate was 100% in evaluable samples at postinduction cycle 3 (1 × 10-5 (46/46)), cycle 6 (1 × 10-5 (46/46) and 1 × 10-6 (46/46)) and premaintenance (1 × 10-5 (40/40)); the ORR was 100% (49/49). Total median stem cell yield was 8.1 × 106 per kg. Data support the feasibility of Tec-D(V)R induction in transplant-eligible NDMM, with a consistent safety profile compared with individual regimen components and notable early MRD negativity rates. ClinicalTrials.gov identifier: NCT05695508 .

Background The advent of B-cell maturation antigen (BCMA)-targeted immunotherapies has markedly transformed the prognosis for patients with relapsed/refractory multiple myeloma (r/r MM). However, the emergence of therapeutic resistance, frequently driven by tumor-intrinsic alterations in the TNFRSF17 (tumor necrosis factor receptor superfamily member 17) gene encoding BCMA, remains a critical clinical challenge. While the event of complete antigen loss via biallelic gene deletion is well-described, the functional impact of novel, non-truncating variants of uncertain significance (VUS) discovered through comprehensive sequencing is often unclear, complicating therapeutic decisions. Methods Whole-genome sequencing (WGS) was performed on purified CD138 + plasma cells from two patients with r/r MM who experienced disease progression after treatment with the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel). We developed a novel AI-based computational workflow to assess the impact of identified TNFRSF17 mutations on protein structure response to treatment across a panel of clinically relevant BCMA-directed agents. Our method combines AI-based protein-complex structure prediction with binding free energy calculations. Results WGS revealed a monoallelic deletion of 16p13, encompassing the TNFRSF17 gene locus, in both patients, accompanied by distinct subclones on the remaining allele: three VUS (p.Cys37Tyr, p.Cys24_Cys28del, and p.Pro23delins9) in patient #1, and the p.Cys8Trp VUS in patient #2. All detected variants in the protein sequence are localized within the extracellular, epitope-bearing domain of BCMA. Our AI-driven structural analysis predicted that these mutations induce significant conformational changes, primarily by disrupting the stabilizing disulfide bond network. Quantitative energetic calculations demonstrated that these variants would severely impair or completely abrogate binding of specific therapeutic agents, including ide-cel and belantamab cilta-cel, consistent with the patients’ clinical course of relapse. Notably, our analysis showed differential effects across various agents, with the binding affinity of some therapeutics predicted to remain robust to the structural changes. Conclusion The integration of WGS into diagnostics with AI-driven structural and energetic modeling provides a powerful framework for the functional interpretation of VUS in TNFRSF17 . This approach can rapidly elucidate patient-specific, epitope-dependent resistance mechanisms and has the potential to guide the rational sequencing of BCMA-targeted therapies. By transforming VUS from a diagnostic challenge into an actionable clinical biomarker, this methodology represents a critical step toward precision immunotherapy in MM.

Supp. Table S6. Univariable logistic regression analysis: Hospitalization ≥ 14 days

Background Malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH) carries a poor prognosis and is often complicated by overlapping infection, cytopenias, organ failure, and progressive disease. Methods We retrospectively analyzed 49 adults with M-HLH at a single tertiary cancer center (2013-2026), summarizing malignancy spectrum, diagnostic features, treatment, and survival outcomes. HLH probability was assessed by HScore and modified HLH-2004 criteria. Results Lymphoma was the main underlying disease (34/49; 69.4%), led by aggressive B-cell (17/49; 34.7%) and T-cell NHL (12/49; 24.5%). HLH coincided with initial malignancy recognition in 17 of 49 patients (34.7%). The median HScore was 231 (IQR 202-256); 44 of 49 patients (89.8%) met the ≥ 169 threshold, and 42 of 49 patients (85.7%) fulfilled ≥ 5 of 7 modified HLH-2004 criteria. HLH-directed therapy included corticosteroids (41/49; 83.7%), etoposide (21/49; 42.9%), and anakinra (16/49; 32.7%); 21 of 49 patients (42.9%) received concurrent malignancy-directed chemotherapy. Mortality was 59.2% (29/49) with a median overall survival of 56 days (median follow-up 612 days for the cohort; 574 days among survivors, n = 20). De novo presentation carried substantially lower mortality than HLH in previously known malignancy (23.5% vs. 78.1%; hazard ratio [HR] 5.38, 95% confidence interval [CI], 1.85-15.61; P = .002). Malignancy-directed chemotherapy was associated with lower mortality than HLH-directed therapy alone (HR 3.11, 95% CI, 1.36-7.09; P = .007). All 6 patients with invasive mold infection died. Conclusions M-HLH was predominantly lymphoma-associated, met diagnostic criteria with high probability, and carried poor short-term survival. De novo presentation had better outcomes, likely because lymphoma-directed chemotherapy can simultaneously address the underlying malignant trigger and the hyperinflammatory state. Invasive mold infection was uniformly fatal, illustrating the lethal combination of profound immunosuppression and uncontrolled opportunistic infection in this setting.

Supp. Table S16. Univariable Cox regression analysis: Overall survival

Use of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy to treat relapsed/refractory multiple myeloma is increasing. Studies suggest that effective bridging therapy (BT) prior to anti-BCMA CAR-T therapy can enhance efficacy and safety outcomes. Through qualitative interviews and a consensus workshop, 10 European experts shared their clinical experience regarding optimal BT selection, efficacy, safety and outcomes post-CAR-T, focussing on heavily pretreated patients and emerging BT options, such as bispecific T-cell engagers. Experts agreed that BT should aim to reduce tumour burden and maintain or improve patient performance status, while avoiding treatment-related toxicity that could delay or prevent CAR-T infusion. The balance between treatment duration and achieving an adequate response is important, and patient characteristics are key for BT selection, especially in difficult-to-treat populations. Here, we discuss the unique therapy talquetamab, a GPRC5DxCD3 bispecific antibody, which demonstrates robust efficacy and rapid response rates in clinical trials, and is being considered as a BT option before anti-BCMA CAR-T therapy based on expert experience and real-world data. This consensus, based on clinical experience, aims to provide guidance on BT for healthcare professionals (HCPs) involved in anti-BCMA CAR-T therapy and aid standardisation of care in this rapidly advancing field.

Abstract Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care Rd (Revlimid [lenalidomide] and dexamethasone; D-Rd) or to VMP (Velcade [bortezomib], melphalan, and prednisone; D-VMP), respectively, vs Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP vs Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to the first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in the D-Rd/D-VMP and Rd/VMP groups, respectively. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. These trials were registered at www.ClinicalTrials.gov as NCT02252172 (MAIA) and NCT02195479 (ALCYONE).

In previous analyses of MAIA, daratumumab plus lenalidomide/dexamethasone (D-Rd) significantly improved progression-free survival and overall survival (OS) versus lenalidomide/dexamethasone (Rd) in transplant-ineligible newly diagnosed multiple myeloma (NDMM). We report results on long-term OS and subsequent antimyeloma therapies from the MAIA final analysis. A protocol amendment (July 20, 2021) led to a long-term extension of MAIA, during which patients were followed for OS. A total of 737 patients were randomized to D-Rd (n = 368) or Rd (n = 369). At a median follow-up of 89.3 months (range, 0.0-102.2; interquartile range, 85.3-93.0), median OS was 90.3 months (95% confidence interval [CI], 80.8-not estimable [NE]) with D-Rd versus 64.1 months (56.0-70.8) with Rd (hazard ratio [HR], 0.67; 95% CI, 0.55-0.82); estimated 7-year OS rates were 53.1% (95% CI, 47.8-58.2) and 39.3% (34.1-44.5), respectively. Median time to subsequent antimyeloma treatment was not reached (95% CI, 84.1-NE) for D-Rd versus 42.4 months (33.5-50.6) for Rd (HR, 0.51; 95% CI, 0.41-0.63; P < 0.0001). Death due to adverse events occurred in 84 patients (D-Rd, n = 44/364 [12%]; Rd, n = 40/365 [11%]). With >7 years of follow-up, D-Rd demonstrated a new benchmark for median OS (7.5 years) in transplant-ineligible NDMM, further supporting frontline D-Rd use to maximize survival.

Introduction Despite advances in multiple myeloma treatment, most patients (pts) will relapse, highlighting the need for new drug classes to improve outcomes in RRMM. Further, extensive use of lenalidomide (LEN), an immunomodulatory drug (IMiD), as frontline and maintenance therapy has increased LEN refractoriness, decreasing responses to subsequent treatment. G protein-coupled receptor class C group 5 member D (GPRC5D) is a promising therapeutic target for RRMM as the receptor is highly expressed on malignant plasma cells with little to no expression in non-plasma immune cells and limited expression in healthy tissues. Arlocabtagene autoleucel (arlo-cel), a GPRC5D-directed autologous CAR T-cell therapy, has demonstrated safety and efficacy in pts with RRMM in a first-in-human phase 1 study. Following a single infusion of arlo-cel (150 × 106 CAR T cells), overall response rate (ORR) was 96% (23/24) and 91% (21/23) in those with 1-3 and ≥3 prior lines of therapy (pLOT), respectively. Objective To present the study design for QUINTESSENTIAL-2 (NCT06615479), a randomized, open-label, multicenter, phase 3 confirmatory study comparing the efficacy and safety of arlo-cel vs standard of care (SOC) in adults with RRMM. Methods Pts must be aged ≥18 years, with a confirmed MM diagnosis per International Myeloma Working Group criteria, 1-3 pLOT (may include a proteasome inhibitor, IMiD, and anti-CD38 antibody), measurable disease, and ECOG performance status 0 or 1. Pts with prior GPRC5D-targeted therapy are excluded. Eligible pts must have prior LEN exposure (with ≥2 consecutive cycles, unless best response of progressive disease to LEN-containing treatment or in cases of LEN intolerance or unacceptable toxicity) and will be randomized 1:1 to Arm A or Arm B. Arm A includes leukapheresis within 3-4 days of randomization, bridging therapy of DPd (daratumumab, pomalidomide, dexamethasone) or Kd (carfilzomib, dexamethasone) per investigator choice within 6 days of randomization, and lymphodepleting chemotherapy prior to a single arlo-cel infusion. Arm B includes SOC of DPd or Kd per investigator choice, dosed per labeling, until disease progression. Primary endpoints are progression-free survival and minimal residual disease (MRD) negativity in complete response. Secondary endpoints include overall survival, ORR, MRD-negative status, complete response rate, time to response, duration of response, pharmacokinetics, and patient-reported quality of life outcomes. Pts will be followed for ≤5 years after the last pt is randomized, with a subsequent long-term follow-up study (≤15 years post-infusion) for pts receiving arlo-cel. Results This is a trial in progress and is expected to enroll 440 pts at ∼126 sites globally. The first pt was enrolled in March 2025. Conclusion This phase 3 study will compare the efficacy and safety of arlo-cel vs SOC in adult pts with RRMM refractory to LEN.

Supp. Table S18. Multivariable Cox regression analyses: Overall survival

The significant clinical benefit of bispecific T-cell engagers (TCE) for the treatment of relapsed/refractory multiple myeloma (RRMM) may be offset by serious toxicities and treatment failure. Risk scores such as the CAR-HEMATOTOX (HTX), Endothelial Activation and Stress Index (EASIX), and modified EASIX (m-EASIX) can identify patients at risk for complications before chimeric antigen receptor (CAR) T-cell therapy, but their utility prior to TCE therapy remains elusive. We analyzed associations with outcomes and toxicities in independent discovery (n = 123) and validation (n = 155) cohorts treated with TCEs. Patients with HTX ≥3 or m-EASIX > median (>0.86) had a significantly increased risk of prolonged hospitalization, antibiotic treatment, and fever during step-up dosing. We also observed associations with cytopenias requiring therapeutic intervention, higher severe infection and intervention densities, as well as inferior response rates and reduced progression-free and overall survival. Our findings highlight the potential of these clinical scores to improve risk stratification before TCE therapy. SIGNIFICANCE:Scores such as HTX, EASIX, and m-EASIX have emerged as helpful tools to enable risk stratification before CAR T-cell therapy. In this study, we demonstrate their utility in patients with RRMM receiving TCEs. HTX ≥3 and m-EASIX > median (>0.86) proved to be risk markers for infections, therapeutic interventions, and poor outcomes. See related commentary by Banerjee and Dhodapkar, p. 345.

Spinal malignant lesions are a common feature in multiple myeloma (MM) and often require surgical intervention. Accurate survival prediction is critical for guiding treatment decisions in these patients. While PATHFx is a widely used, machine-learning-based prognostic tool for skeletal metastases, it has not been validated for malignant bone lesions in MM so far. To evaluate the predictive performance and clinical utility of PATHFx 3.0 in a well-characterized cohort of MM patients with spinal malignant lesions. A retrospective cohort of 100 MM patients with radiologically confirmed spinal malignant lesions treated between 2009 and 2024 at a tertiary care center was analyzed. 51 patients underwent surgery for the local treatment of spinal lesions, while 49 were treated with non-operative treatment regimes. Clinical data were entered into PATHFx 3.0 to generate survival estimates at 1, 3, 6, 12, 18, and 24 months. Model performance was assessed using Receiver Operating Curves (ROC) with Area under the Curve (AUC), Brier scores, calibration plots, and decision curve analysis (DCA), and compared to the actual survival in this cohort. PATHFx achieved good discriminatory performance at all time points, with AUC values ranging from 0.72 (1 month) to 0.79 (18 months). Calibration improved with longer prediction intervals, and Brier scores ranged from 0.09 to 0.20, with best accuracy at 3 months. DCA showed net clinical benefit for all models except the 1-month estimate. The inclusion of both surgical and non-surgical patients enhanced the generalizability of results. PATHFx 3.0 is a reliable and clinically useful tool for survival estimation in MM patients with spinal disease. Its flexible design and acceptable predictive performance support its use in multidisciplinary treatment planning, especially where traditional scoring systems fall short.

Patients with multiple myeloma undergoing dorsal spinal instrumentation for malignant spinal lesions remain at high risk for postoperative complications and limited survival. Acute kidney injury (AKI) is common in myeloma and after major surgery, but its prognostic relevance in surgically treated myeloma patients and its association with subsequent CT-based body composition and bone density trajectories, remains insufficiently defined. We performed a retrospective cohort study of consecutive multiple myeloma patients undergoing dorsal spinal instrumentation between 2011 and 2024 at a tertiary referral center. Postoperative AKI was defined and staged according to KDIGO criteria based on serum creatinine changes within 7 postoperative days. Clinical outcomes included overall survival (OS), surgical site infection (SSI), and length of hospital stay (LOHS). CT-based morphometry was assessed on non-contrast whole-body CT at L3 level on a preoperative baseline scan (tCT1) and a postoperative follow-up scan. The follow-up CT scan (tCT2) was obtained approximately 9 months postoperatively as part of routine oncologic follow-up or clinical indication rather than a fixed imaging schedule, reflecting real-world clinical practice. The mean interval between tCT1 and tCT2 was 9.1 ± 1.2 months. Analysis included skeletal muscle index (SMI), skeletal muscle density (SMD), visceral adipose tissue (VAT), and vertebral trabecular bone status assessed by Hounsfield Units (HU). Multivariable Cox regression, logistic regression, and log-linear regression were used to evaluate the independent association of AKI with OS, SSI, and LOHS, adjusting for clinically relevant covariates. 59 patients were included (median age 69.0 years; 40.7

Supp. Table S11. Univariable Cox regression analysis: Time to severe infection

Supp. Table S3. Complications and toxicities

Supp. Table S9. Cytopenias before and during treatment – CAR-HEMATOTOX (HTX) < 3 vs. ≥ 3