Abstract Background T-cell-redirecting therapies, including bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, have substantially improved outcomes in relapsed or refractory multiple myeloma (RRMM). However, infectious complications remain a major safety concern, particularly in real-world settings, where patients are more heterogeneous than those enrolled in clinical trials. Methods We conducted a systematic review and meta-analysis of real-world retrospective studies evaluating severe (grade 3–4) infections in adult patients with RRMM treated with approved BiTEs or CAR-T cell therapies. Pooled event rates were estimated using random-effects models. Heterogeneity was explored through subgroup analyses, meta-regression, and sensitivity analyses. Results Sixteen studies encompassing 2,097 patients were included. Overall, 24.2% of patients developed grade 3–4 infections (pooled event rate 0.24; 95% CI, 0.21–0.28). Among BiTEs-treated patients (n = 1,602), the pooled severe infection rate was 0.26 (95% CI, 0.23–0.30), with higher rates observed for BCMA-directed BiTEs (0.27) compared with GPRC5D-directed BiTEs (0.25). CAR-T cell therapies (n = 495) were associated with a lower pooled infection rate (0.19; 95% CI, 0.12–0.27). Conclusions In real-world practice, severe infections affect approximately one in four patients receiving T-cell-redirecting therapies for RRMM. Observed differences in infection rates across platforms and targets should be interpreted with caution, as they derive from indirect comparisons in non-randomized, heterogeneous cohorts. Nevertheless, these data support incorporating patient frailty and prior infection history into therapeutic decision-making. CAR-T therapy, or GPRC5D-directed BiTEs when CAR-T is not feasible, may represent reasonable options in patients at higher infectious risk, within an individualized and context-dependent treatment strategy.

IntroductionMultiple myeloma (MM) is a hematologic malignancy that predominantly affects older adults and poses substantial therapeutic challenges due to the high prevalence of comorbidities and limited treatment tolerability. This study evaluates the cost-effectiveness of four first-line treatment regimens for elderly MM patients, ineligible for autologous stem cell transplantation (ASCT): bortezomib, melphalan, and prednisone (VMP); daratumumab in combination with VMP (D-VMP); lenalidomide and dexamethasone (Rd); and daratumumab combined with Rd (DARA-Rd).MethodsA state-transition Markov model was developed, with transition probabilities parameterized using data derived from the pivotal ALCYONE and MAIA clinical trials. Cost-effectiveness was assessed from the perspective of the Italian National Health Service using a state-transition model comparing VMP, D-VMP, Rd and DARA-Rd over a 5.25-year horizon. Probabilistic sensitivity analyses (PSA) were conducted to account for parameter uncertainty and summarized through cost-effectiveness acceptability curves (CEACs).ResultsRd generated 1.53 QALYs for €60,483, whereas D-VMP generated 1.70 QALYs at €88,331, resulting in an ICER of €160,804/QALY. DARA-Rd and VMP were dominated.ConclusionThe findings indicate that Rd is the strategy with the highest probability of being cost-effective at willingness-to-pay (WTP) thresholds below €250,000 per quality-adjusted life year (QALY) gained. Conversely, for WTP thresholds exceeding €250,000 per QALY gained, D-VMP emerges as the preferred option, offering the most favorable balance between additional costs and health benefits.

Pompe disease is a rare, progressive lysosomal storage disorder caused by acid α-glucosidase deficiency, leading to glycogen accumulation, proximal muscle weakness, and respiratory decline. Enzyme replacement therapy (ERT) significantly improves survival and stabilizes motor function, but IgE-mediated hypersensitivity reactions (HSRs) can critically compromise treatment, posing a major clinical challenge. Desensitization protocols allow temporary tolerance to ERT, yet breakthrough reactions may occur, necessitating adjunctive strategies such as omalizumab. We report a 40-year-old woman with late-onset Pompe disease who developed severe IgE-mediated HSRs to alglucosidase alfa after years of uneventful therapy. Basophil activation testing (BAT) and serum-specific IgE confirmed an IgE-mediated mechanism. A 15-step, 5-bag desensitization protocol allowed temporary tolerance, but breakthrough reactions required therapy interruption. Upon switching to avalglucosidase alfa, BAT demonstrated IgE cross-reactivity, and a new desensitization protocol was implemented. Initial infusions were complicated by recurrent HSRs. The addition of subcutaneous omalizumab (300 mg monthly), administered two days before ERT, enabled safe reintroduction. Moreover, therapy was resumed gradually, starting at 50

OBJECTIVES:Using suboptimal imaging modalities on the detection of bone and extra-bone myeloma lesions affects disease status recognition and early treatment decisions. Moreover, a systematic search of the evidence was not provided alongside the recommendations. The objective of this study was to assess the current real world imaging practices in Italy, influencing factors, and barriers to adopting international imaging guidelines for MGUS and MM (reported as plasma cell disorders, PCD) and to develop evidence-based, country-specific recommendations for imaging assessment of PCD patients. METHODS:A national project was launched in 2024, involving experts from 32 hematology centers and 5 radiology services. A survey was conducted and a Delphi panel comprising 23 experts was used to reach a consensus on the developed recommendations. A total of 25 recommendations were finally formulated. RESULTS:The survey revealed that suboptimal imaging modalities were significantly contributing to the under-recognition of bone and extra-bone lesions in myeloma, leading to suboptimal disease status assessment and treatment decisions. CONCLUSIONS:The study emphasizes the importance of adopting effective imaging modalities to improve disease detection and guide treatment decisions in PCD patients. A country-specific, evidence-based set of imaging recommendations has been developed to address existing challenges in the adoption of international imaging guidelines.

BACKGROUND:Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis characterized by eosinophilic inflammation and potential cardiovascular involvement. The relationship between eosinophil burden and subclinical cardiopulmonary vascular dysfunction remains unclear. METHODS:27 EGPA patients were evaluated. Peripheral eosinophil counts (PEC) at diagnosis were analysed in relation to echocardiographic markers of pulmonary vascular load and right ventricular-pulmonary artery (RV-PA) coupling. Patients initiating anti-IL-5/R therapy (mepolizumab or benralizumab) underwent echocardiography assessing pulmonary artery systolic pressure (PAPs), tricuspid annular plane systolic excursion (TAPSE), TAPSE/PAPs ratio, and tricuspid regurgitation velocity (TRV) at diagnosis, treatment initiation (Baseline), and 24-month follow-up (T24) to assess temporal changes. Patients were stratified by median PEC. Multivariable regression and ROC analyses were performed. RESULTS:At Baseline, 33% of patients exhibited elevated PAPs (>25 mmHg) despite absence of clinical pulmonary hypertension. Higher PEC were associated with increased PAPs (p = 0.04) and reduced TAPSE/PAPs ratio (p = 0.03). Pulmonary vascular load worsened from diagnosis to T0 and improved after anti-IL-5/R therapy, with PAPs decreasing from 27.5 [18.0-30.0] mmHg to 18.0 [11.75-20.0] mmHg (p = 0.002) and TRV from 2.30 [1.65-2.48] to 1.80 [1.28-1.92] m/s (p = 0.005). Baseline PEC moderately discriminated patients with intermediate/high echocardiographic probability of pulmonary hypertension (AUC 0.751). CONCLUSION:Elevated PEC may signal early pulmonary vascular dysfunction and RV-PA uncoupling EGPA, which may be partially reverted with anti-IL-5/R therapy. These findings support the importance of early cardiovascular surveillance in eosinophil-rich EGPA.

Perioperative hypersensitivity reactions to neuromuscular blocking agents (NMBAs) remain diagnostically and therapeutically challenging. We report a 21-year-old woman who developed severe perioperative hypersensitivity during general anaesthesia, with intradermal testing identifying cisatracurium as the most likely culprit agent. Because no unequivocally safe alternative NMBA could be identified, a simplified 3-bag, 5-step desensitization protocol was successfully performed under continuous monitoring. The procedure and subsequent anaesthesia were completed without adverse reactions. This report highlights the diagnostic limitations of perioperative NMBA hypersensitivity and suggests that a simplified desensitization protocol may be a pragmatic risk-reduction strategy for selected high-risk patients requiring urgent anaesthesia.

Background. Multiple myeloma (MM) is associated with profound immune dysfunction, predisposing patients to severe infections. Immunoglobulin replacement therapy (IgRT) may reduce infection risk, but evidence is heterogeneous and mainly limited to intravenous administration. Its impact, particularly in patients receiving modern therapies such as bispecific T-cell engagers (BiTEs), remains unclear. Methods. We performed a systematic review and meta-analysis of studies comparing MM patients receiving IgRT as preemptive or primary prophylaxis versus those receiving secondary or no IgRT. MEDLINE and LILACS were searched up to December 30, 2025. Both intravenous (IVIg) and subcutaneous (SCIg) routes were included. Comparative studies reporting hazard ratios (HRs) for severe infections or sufficient data to derive them were included, with HRs pooled using random-effects models. Results. Eight studies (358 IgRT-treated, 430 controls) were included, predominantly using IVIg; one study exclusively used SCIg and one included both IVIg and SCIg. IgRT prophylaxis was associated with a 75% reduction in severe infections (pooled HR 0.25, 95% CI 0.13–0.49, p < 0.0001). In BiTEs-treated patients, HR was 0.32 (95% CI 0.18–0.56, p < 0.0001). Results were robust across study designs and sensitivity analyses, with low heterogeneity after leave-one-out analysis. Conclusions. IgRT prophylaxis substantially reduces severe infections in MM, including high-risk BiTEs-treated patients. The benefit is clinically meaningful and mainly reflects IVIg use, though limited evidence suggests SCIg is also effective. These findings support systematic consideration of IgRT in high-risk MM populations, with prospective studies needed to optimize timing, patient selection, and administration.

Abstract Bispecific antibodies (BiTEs) have transformed the therapeutic landscape of relapsed/refractory multiple myeloma (RRMM), offering deep and durable responses even in heavily pretreated patients. However, their use carries substantial infectious risk due to immunosuppression, particularly hypogammaglobulinemia, induced by T-cell-redirecting therapy. To define the real-world incidence of grade 3–4 infections, we conducted a systematic review and meta-analysis of retrospective studies including RRMM patients treated with BiTEs currently approved for clinical use. Ten studies encompassing 1,373 patients were analysed using a random-effects model of pooled proportions. The overall rate of grade 3–4 infections was 0.25 (95% CI, 0.22–0.30) after a median follow-up of 8.3 months, with moderate heterogeneity (I²=52.9%). Subgroup analyses showed comparable pooled event rates for teclistamab—anti-CD3/BCMA—(0.26; 95% CI, 0.22–0.31) and talquetamab—anti-CD3/GPRC5D—(0.23; 95% CI, 0.14–0.33). Meta-regression revealed an inverse association between infection rates and mean number of prior therapy lines (p = 0.002) and prior BCMA exposure (p = 0.0019), likely because, in real world setting, clinicians select fitter, immunologically stable patients for BiTEs therapy. In summary, approximately one in four RRMM patients receiving BiTEs experiences severe infection. These findings underscore the need for proactive monitoring and standardized preventive measures, including immunoglobulin replacement, prophylaxis, vaccination, to ensure safe, effective integration of BiTEs into routine MM care.

BACKGROUND:Multiple myeloma (MM) is a malignancy characterized by the proliferation of abnormal plasma cells in the bone marrow, leading to osteolytic lesions. This condition is accompanied by a serum accumulation of monoclonal immunoglobulin. Zoledronic acid (ZA) is a new-generation bisphosphonate commonly used to prevent bone complications. However, allergic reactions can pose challenges, potentially leading to ZA discontinuation. Thus, rapid desensitization (RD) has been proposed as a solution to continue treatment in patients with severe HR. RD consists in the induction of a temporary state of tolerance by administering increasing doses of the offending medication. METHODS:We present the case of a 57-year-old woman with MM who developed face angioedema, flushing with itching, dizziness and fever to ZA. Thus, an allergy work-up with skin prick test and intradermal test (IDT) with ZA were performed. Subsequently, considering the necessity of maintaining ZA treatment, a 3-dilution, 12-step RD infusion protocol was implemented. Skin tests were also repeated after three RD infusions. RESULTS:Skin tests showed positive IDT reactions to ZA confirming the hypersensitivity state of the patient to the medication. Then, the patient underwent RD procedures without any HR. Skin tests performed after three RD procedures were deemed negative. CONCLUSIONS:Here, we demonstrate successful management with RD in an MM patient with HR to ZA, providing a valuable therapeutic option for patients experiencing such reactions. The effectiveness of RD to ZA was confirmed by the negative response to skin tests after 3 RD procedures. Nevertheless, further research is needed to refine RD protocols and establish their safety and efficacy for patients with HR to ZA. Standardized in vitro testing may also improve the diagnosis and management of ZA hypersensitivity.

Systemic immunoglobulin light-chain (AL) amyloidosis is a rare plasma cell disorder caused by a clone producing unstable misfolded light chains that form amyloid fibrils, causing organ damage, mostly in kidneys and heart. The disease is progressive and early treatment is crucial to prevent irreversible injury. In January 2021, based on the ANDROMEDA trial, the anti-CD38 antibody Daratumumab combined with the CyBorD regimen (bortezomib/cyclophosphamide/dexamethasone) became the new up-front standard of care for AL amyloidosis. Few real-world studies assessed Daratumumab alone or with bortezomib or lenalidomide; however, data on its combination with CyBorD outside clinical trials remain limited. The “CyBor_Dq trial” was designed to retro- and prospectively evaluate the efficacy and safety of Daratumumab-CyBorD in newly diagnosed Italian AL amyloidosis patients. We present data from the first interim analysis. A multicenter observational study across multiple haematology Italian Centers started in June 2024. Eligible patients had biopsy-confirmed systemic AL amyloidosis, with deposits verified by immunohistochemistry and/or immune-electron microscopy. All patients received “CyBor_Dq” regimen upfront (subcutaneous bortezomib 1.3 mg/m², cyclophosphamide 300 mg/m² orally or IV, and dexamethasone 40 mg orally or IV weekly for six 28-day cycles, plus subcutaneous Daratumumab 1800 mg—weekly in cycles 1-2, every two weeks in cycles 3-6, then monthly up to 24 cycles or progression—in a real-world setting). Hematological responses were assessed at 3 and 6 months; cardiac and renal responses at 6 months post treatment initiation. Responses followed consensus criteria: Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), with cardiac and renal response (International Society of Amyloidosis criteria). Age, sex, Charlson comorbidity index, fluorescence in situ hybridization (FISH) abnormalities, European modification of the Mayo 2004 staging system, NYHA functional class, and creatinine clearance were also recorded as baseline variables. Hematologic and non-hematologic adverse events were also monitored. Logistic regression was used for associations; p<0.05 was significant. Between June 2024 to June 2025, 117 patients were enrolled at 22 Italian Centers. Up to July 2025, data were available from 95 patients showing a median age of 64 years, with a prevalence of lambda chain isotype (77%). Cardiac involvement was seen in 39 (41%) patients; of them, 12 (12.6%) were IIIa and 7 (7.4%) IIIb stage. Kidney involvement was seen in 54 patients (56.8%). A total of 35 patients (36.8%) had both cardiac and renal injury, while 6 patients (6.3%) having 3 or more organs involved. FISH was available in 43 (45%) subjects of whom 21 (48.8%) harbored the t(11;14). The overall hematologic response rate (ORR) was 91.4% with 27 (32.9%) patients obtaining a VGPR, 3 (3.7%) a PR and 45 (54.8%) a CR. Overall, 44.4% achieved hematologic response within 6 months. At 6 months, renal response was observed in 14 of 36 evaluable patients (38.8%) and cardiac response in 16 of 39 patients (41%). None of the classical baseline variables was significantly associated with hematological, cardiac, or renal response. As of today, no serious adverse events (AE) were reported and the most commonly treatment-associated symptoms (diarrhoea, fatigue, peripheral edema, anemia, constipation, dyspnea, thrombocytopenia, worsening of renal function) were reported in <7% of patients. No AE resulted in permanent treatment discontinuation. To our knowledge, the present study describes one of the largest RW cohort of newly diagnosed AL amyloidosis patients treated with Daratumumab-CyborD. The study population reflects the clinical heterogeneity of real-life patients, including those with severe cardiovascular conditions and/or critical renal impairment, who would not have met the inclusion criteria of the “ANDROMEDA” trial. Nevertheless, this interim evidence confirms “CyBor_Dq” as an effective and manageable frontline treatment for AL amyloidosis, resembling results of the “ANDROMEDA” trial. The challenge is to find early predictors of treatment response and improve patient outcomes. Additional follow-up data are needed to confirm these initial results and guide the development of future personalized treatment approaches.

Dupilumab, a monoclonal antibody targeting the interleukin (IL)-4 receptor alpha subunit and IL-13, has markedly advanced the treatment of atopic conditions such as dermatitis, asthma, and chronic rhinosinusitis. However, its expanding use has brought increased attention to a range of ocular adverse events—conjunctivitis, blepharitis, keratitis, corneal ulcers, and cicatricial conjunctivitis—that remain underrecognized and frequently underestimated in clinical practice. These manifestations often emerge in patients with atopic dermatitis and display varying severity, posing diagnostic and therapeutic challenges. Rather than isolated phenomena, these effects appear to stem from a complex interplay of goblet cell depletion, mucin deficiency, immune dysregulation, and microbiome alterations, including Demodex proliferation. Current management strategies remain largely empirical, lacking standardized protocols, and are often guided by anecdotal evidence. In this review, we critically appraise the existing literature, synthesize emerging pathogenic hypotheses, and highlight the unmet clinical need for evidence-based treatment algorithms. We advocate for a multidisciplinary approach and future research aimed at elucidating mechanisms, refining risk stratification, and minimizing ocular toxicity without compromising the therapeutic benefits of dupilumab. Furthermore, we intend to provide a more practical and straightforward resource for the reader based on the current literature on approaching the topic.

Background. Daratumumab-bortezomib-melphalan-prednisone (DVMP) and daratumumab-lenalidomide-dexamethasone (DRd) are standard treatments for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts). No prospective randomized trial has directly compared DVMP vs DRd. Moreover, real-life older NTE pts are underrepresented in clinical trials. Aims. We conducted a randomized multicenter phase IV trial (NCT03829371; funded by the Italian Medicines Agency AIFA - Independent Research) to compare safety and efficacy of VMP +/- daratumumab (DVMP) vs Rd +/- daratumumab (DRd) in an unselected real-life population of NTE NDMM pts. Methods. In the first part of the trial,NDMM pts who were NTE due to age ≥65 years or comorbidities were randomized 1:1 to 9 VMP cycles vs continuous Rd (standard approved schedule). As of July 2022, the protocol was amended to randomize 1:1 pts to DVMP vs DRd. Pts were enrolled regardless of performance status, comorbidities, renal function or baseline laboratory values. Stratification was based on IMWG frailty score and cytogenetic risk [high risk: 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 overall survival (OS) and safety. Centralized measurable residual disease by next-generation flow (NGF-MRD) was analyzed by the ITT principle in daratumumab-treated pts. Results. At data cut-off (July 9, 2025), 231 pts received VMP (n=114) or Rd (n=117), and 170 pts received DVMP (n=87) or DRd (83). Results of the VMP vs Rd comparison were recently published (Bringhen et al. Haematologica 2025; median follow-up: 28.9 months). With an extended follow-up (median: 45.8 months), the median PFS in the ITT population was 29 vs 31 months with VMP vs Rd (HR 1.41, 95% CI 0.95–2.09, p=0.09). A significantly better OS was observed with VMP vs Rd, with 3-year OS rates of 82% vs 68% in the ITT population (HR 0.57, 95% CI 0.33–0.98, p=0.04). The difference in OS between VMP and Rd was particularly evident in high–cytogenetic-risk pts (median: not reached vs 19 months, p=0.067). Regarding the second part of the study (DVMP vs DRd), baseline characteristics were balanced between the DVMP and DRd arms: median age was 76 (range 64–90) vs 76 years (range 63–87), respectively; 18% vs 13% of pts were aged >80 years; 37% vs 34% were frail; 27% vs 32% had high-risk cytogenetics. Median follow-up was 19.3 months. PFS was significantly better in the daratumumab (DVMP + DRd) vs non-daratumumab (VMP + Rd) cohorts (HR 0.57, 95% CI 0.36–0.89, p=0.01). Despite the short follow-up, an OS advantage was already observed with the addition of daratumumab to Rd (DRd vs Rd: HR 0.26, 95% CI 0.09–0.77, p=0.02) but not to VMP (DVMP vs VMP: HR 1.71, 95% CI 0.74–3.94, p=0.20), suggesting a synergistic effect of daratumumab with Rd. Regarding the comparison DVMP vs DRd in the ITT population, the 6-month and 1-year PFS rates were 90% vs 97% and 83% vs 90%, respectively, with no significant differences (HR 1.56 95% CI 0.72–3.33, p=0.30). In the first 6 months, 9 PFS events (2 progressive disease and 7 deaths) were observed [7/9 (78%) pts were frail; 7/9 (78%) events were observed in the DVMP arm]. No significant differences in PFS with DVMP vs DRd were observed across the age (> or ≤80 years), IMWG frailty score or cytogenetic-risk subgroups. In the ITT population, the 12-month NGF-MRD negativity rate was 25% with DVMP vs 30% with DRd (OR 1.79, 95% CI 0.81–3.94, p=0.15). Reaching a MRD-negative vs -positive status within 12 months led to an improved PFS (HR 0.12, 95% CI 0.03–0.50, p=0.004) with no significant differences between the two arms in MRD-negative or -positive pts. No new safety concerns were reported. Conclusion. The extended follow-up of the VMP vs Rd cohorts confirmed an OS advantage of VMP over Rd, highlighting a possible detrimental effect of lenalidomide refractoriness at relapse. In the second part of the study, we confirmed the efficacy of DVMP and DRd in an older real-life NTE NDMM population including ~35% of frail pts. Centralized MRD assessment in this real-life setting was feasible, and MRD negativity rates were comparable to those in registrational trials. The addition of daratumumab to VMP and Rd led to improved PFS with DRd, already showing an OS benefit vs Rd. The benefit of VMP vs Rd in high–cytogenetic-risk pts was not observed when daratumumab was added to both regimens.

Multiple myeloma (MM) is a malignancy of plasma cells, originating from B lymphocytes and accumulating within the bone marrow. The prevalence of MM has increased in industrialized countries, representing 1-1.8% of all cancers and 15% of hematologic malignancies. Immunotherapy has broadened therapeutic options for MM, offering treatments with generally improved efficacy and reduced toxicity compared to conventional therapies. Daratumumab, a monoclonal antibody recently granted regulatory approval, exemplifies this advancement, demonstrating improved patient outcomes. However, the substantial cost of daratumumab has significantly increased per-patient treatment expenditures. Consequently, the economic burden associated with this new class of therapies warrants careful evaluation of their cost-effectiveness. To address this, a six-state non-stationary Markov model was developed for cost-effectiveness analysis of immunotherapy in newly diagnosed MM patients and, more broadly, in the oncohematological patient population. This model aims to provide healthcare professionals and policymakers with actionable insights into cost-effective interventions, supporting informed decisions regarding optimal treatment strategies.

INTRODUCTION:Acyclovir is a synthetic purine nucleoside analog that is used to treat infections caused by herpes simplex virus (HSV) and varicella zoster virus (VZV) by targeting the viral enzyme thymidine kinase. However, its use can lead to hypersensitivity reactions (HR) in rare cases, resulting in treatment discontinuation. Rapid drug desensitization (DD) by intravenous or oral administration protocols are used in these patients in order to avoid treatment discontinuation. This approach has been proven to be effective and safe. Here, we review all the desensitization strategies adopted so far, and also report our experience. METHODOLOGY:We reviewed all reports related to acyclovir desensitization; focusing on skin test results, protocols and premedication performed, and their effectiveness. We also report on the case of a 74-year-old woman affected by multiple myeloma who developed HR to acyclovir. She underwent skin tests, and lymphocyte proliferation test (LPT) with acyclovir, and was subsequently subjected to oral desensitization. RESULTS:Six articles met the inclusion criteria and were analyzed in this review, along with a case report. All DD procedures were well-tolerated, with only mild reactions reported in one patient. Skin tests gave negative results but one result was deemed doubtful response. Moreover, the LPT performed in our case had positive result, indicating a hypersensitive immune response to acyclovir. CONCLUSIONS:Acyclovir desensitization is a safe and effective approach for patients experiencing HR. Standardized in vivo and in vitro testing are required to better estimate the risk of DD and find the safest individualized DD protocol.