Belantamab mafodotin, lenalidomide, и дексаметазон для пациентов среднего и слабого типа с недавно поставленным диагнозом миэлома.

Introduction

Combinations based on belantamab mafodotin (belamaf) have demonstrated potent antimyeloma activity in relapsed/refractory multiple myeloma (MM). 1 , 2 , 3 , 4 , 5 The results from the DREAMM-7 and DREAMM-8 studies have established belamaf-based combinations at the first and early relapse settings in accordance with the recently updated clinical practice guidelines. 6

The phase 1/2 BelaRd (belantamab mafodotin, lenalidomide, and dexamethasone) study evaluated the efficacy and safety of belamaf combined with lenalidomide and dexamethasone in transplant-ineligible (TI), intermediate-fit, and frail patients with newly diagnosed MM (NDMM). Part 1 established a recommended phase 2 dose (RP2D) of 1.9 mg/kg every 8 weeks. 7 , 8 Herein, we report the prolonged outcomes of part 1 and part 2.

Methods

Study design

This is a phase 1/2, open-label study designed to assess the safety, tolerability, and clinical activity of BelaRd in TI patients with NDMM. The study comprises 2 distinct parts. In part 1 (dose-finding phase), patients were randomized in a 1:1:1 ratio into 3 cohorts receiving belamaf at dose levels of 2.5, 1.9, or 1.4 mg/kg administered every 8 weeks, with an initial safety evaluation after a 4-week follow-up after the first infusion. Based on cumulative safety and efficacy data, the RP2D was established. 7 , 8 In part 2 (dose expansion phase), all patients were treated at the RP2D, and they were randomized (1:1) into 2 groups evaluating different dose modification guidelines for belamaf-related ocular adverse events (OAEs). Patients will be observed for efficacy and safety assessments for up to 5 years after the last participant was randomized. The study was approved by the institutional review board of Alexandra Hospital (Athens, Greece) and is registered on www.clinicaltrials.gov with the identifier NCT04808037 .

Patient population

Eligible participants were adults (≥18 years) with a confirmed diagnosis of MM and measurable disease, defined based on standard criteria (eg, serum M protein, urine M protein, or abnormal serum-free light chain levels). 9 Patients were required to be TI based on the International Myeloma Working Group (IMWG) frailty index 10 with scores of 1 or 2 and have an Eastern Cooperative Oncology Group Performance Status of 0 to 2. Intermediate-fit and frail patients represent a clinically relevant group of patients with MM with particularly challenging characteristics that necessitate tailored management. In addition, patients had to demonstrate adequate hematologic, hepatic, and renal function, as defined in the protocol, and provide written informed consent prior to enrollment. All patients provided written informed consent before entering the study, which was performed in accordance with the Declaration of Helsinki and its amendments.

Treatment protocol

All patients received the BelaRd combination regimen. In part 1, belamaf was administered intravenously on day 1 of every other 28-day cycle at 1 of the 3 dose levels (2.5, 1.9, or 1.4 mg/kg every 8 weeks). Dose adjustments were implemented such that, in the presence of OAEs (best corrected visual acuity [BCVA] change from baseline and keratopathy and visual acuity [KVA] scale), belamaf dosing was held and restarted when all OAEs were less than grade 1, whereas the dosing interval was extended (eg, to every 12 weeks). OAEs were defined as Snellen BCVA decline from baseline and/or corneal findings suggestive of keratopathy. Lenalidomide was given at a standard dose of 25 mg orally on days 1 to 21 of each 28-day cycle, and dexamethasone was administered at 40 mg weekly (with dose reductions to 20 mg for patients aged ≥75 years). Patients with renal impairment at baseline started with a reduced lenalidomide dose. Lenalidomide and dexamethasone dose levels were adjusted according to the highest grade of hematologic and nonhematologic toxicity attributed to each drug. Lenalidomide dose levels were 25, 20, 15, 10, and 5 mg, whereas dexamethasone dose levels were 40, 20, 12, 8, and 4 mg.

In part 2, patients were treated at the RP2D determined in part 1 and randomized to either group A (dose modifications based on the standard corneal adverse event [AE] management guidelines according to the KVA scale) or group B (dose modifications guided by the alternate dose modification guidelines for belamaf-related OAEs). In brief, in both groups, patients with grade 3 or higher corneal AEs (keratopathy and BCVA decrease) as assessed by an ophthalmologist interrupted belamaf and resumed at a lower dose upon resolution (grade 1 or lower). For group A, the same approach was adopted for grade 2 corneal AEs based on the KVA scale. For group B, the vision-related anamnestic (VRA) tool (a patient-reported, 9-question tool capturing ocular symptoms and impact on activities of daily living) was assessed, and the patient could receive belamaf only if all reported ocular symptoms were experienced for <50% of the time (minimal time or no time) in the previous 24 hours.

All patients enrolled in the study received antiviral, antibiotic, and antithrombotic prophylaxis as per standard clinical practice. Infection prevention included 500 mg of valacyclovir by mouth daily for the varicella-zoster virus, trimethoprim/sulfamethoxazole 800/160 mg by mouth 3 times weekly for Pneumocystis jirovecii , and 500 mg of levofloxacin by mouth daily during the first 3 months of treatment. Additionally, patients were instructed to be vaccinated for COVID-19, Streptococcus pneumoniae , and influenza. Intravenous/subcutaneous immunoglobulins were administered in patients with hypogammaglobulinemia (immunoglobulin G [IgG] <400 mg/dL) and/or frequent or severe infections.

Study outcomes

The primary end points for part 1 of the study included the determination of safety and tolerability through the number of participants experiencing dose-limiting toxicities, AEs, and serious AEs. The primary end point for part 2 of the study was the overall response rate (ORR) as defined by the IMWG criteria as assessed by the investigator.

For both parts of the study, key secondary end points included time to response (TTR) and duration of response (DoR) per IMWG criteria, complete response rate per IMWG criteria, minimal residual disease (MRD) negativity rate in the bone marrow assessed via next-generation flow cytometry (sensitivity threshold of 10 −6 ), progression-free survival (PFS) and overall survival (OS), treatment dose intensity, the number of participants with abnormal ocular findings on ophthalmic examination, changes from baseline, and the proportion of participants with within-participant meaningful change in ocular symptoms as measured using the Ocular Surface Disease Index (OSDI) questionnaire 11 in part 1 and the VRA tool in part 2.

Efficacy assessments

Efficacy was evaluated according to the IMWG response criteria. 12 Assessments were performed on day 1 of each 28-day cycle and included measurements of serum and urine M protein levels, free light chain assays, and imaging studies as needed. In addition, MRD was assessed in patients achieving a complete response (CR) using next-generation flow cytometry (sensitivity threshold of 10 −6 ) on bone marrow samples. Response evaluations were conducted by the investigators and were used to determine ORR, TTR, DoR, PFS, and OS.

AE assessments

Safety evaluations included the monitoring and recording of all AEs, serious AEs, and specific AEs of special interest. OAEs were closely monitored using a combination of clinical ophthalmologic assessments (including BCVA testing, slit lamp examination, and corneal evaluations) and patient-reported outcomes. In part 1, ocular symptoms and the impact of these symptoms on activities of daily living were quantified using the OSDI questionnaire, whereas in part 2, the VRA tool was used to assess the frequency and impact of ocular symptoms on vision-related activities. The severity of ocular findings was graded using the KVA scale, and modifications were implemented according to predefined guidelines to manage ocular toxicity, as described previously.

Statistical methods

The analyses were primarily descriptive, with no formal statistical hypothesis testing performed. Categorical variables are expressed using absolute and relative frequencies, whereas continuous variables are described using median and range or mean and standard deviation. Efficacy outcomes such as ORR, TTR, DoR, PFS, and OS were summarized using medians and corresponding ranges or confidence intervals (CIs) as appropriate. Kaplan-Meier methodology was used to estimate time-to-event end points such as PFS, time to progression (TTP), and OS. All time-to-event end points were calculated from the time of randomization. PFS was calculated until the date of disease progression or death from any cause, whichever occurred first. TTP was calculated until the date of myeloma progression or death due to myeloma progression, whereas OS was calculated until the date of death due to any cause. Patients who did not experience any event at the time of the analysis were censored at the date of their last available disease assessment denoting absence of progression (for PFS/TTP) or last follow-up (for OS). All analyses were performed on the safety population defined in the protocol. Statistical analysis was conducted using SAS (version 9.4). The data cutoff date for this analysis was 1 March 2025.

Results

Updated part 1 results: dose-finding phase

In part 1 of the study, 36 TI patients with NDMM were enrolled and randomized equally among 3 dosing cohorts from 22 February 2021 to 10 December 2021 ( Table 1 ; Figure 1 ). Detailed results are presented in the supplemental Results (available on the Blood website). The ORR was 100% across all cohorts. The median follow-up time was 39.3 months (range, 3.2-47.5). Twenty-five of the 36 patients (69.4%) were still on treatment at the data cutoff, whereas 11 patients (30.6%) had discontinued. Among the discontinuations, 2 patients (5.6%) withdrew consent, 8 patients (22.2%) died, and 1 patient (2.8%) discontinued due to progressive disease. After the completion of the dose-limiting toxicity window, the safety review committee of the study concluded that the RP2D of belamaf was 1.9 mg/kg every 8 weeks, extended to every 12 weeks to account for toxicity. This dose optimally balanced the toxicity/efficacy profile of the BelaRd regimen as equally deep responses and fewer OAEs were reported compared to the higher dose of 2.5 mg/kg.

The safety profile in part 1 was characterized by common treatment-emergent AEs such as fatigue, rash, diarrhea, and infections ( supplemental Table 1 ). Notably, 8 patients (22.2%) died during part 1, with 4 due to COVID-19, 2 due to pneumonia, 1 due to intracranial hemorrhage, and 1 due to sudden death. Of the 6 patients who died due to infections, only 1 was categorized as frail. Overall, severe infections (grade 3 or higher) were reported in 9 patients. Hypogammaglobulinemia (defined as IgG <400 mg/dL) was observed in 27 of 36 patients (75.0%).

OAEs were the most frequently observed toxicity, with 35 of 36 patients (97.2%) experiencing ocular symptoms ( Table 3 ). According to Common Terminology Criteria for Adverse Events grading, in the 2.5 mg/kg cohort, grade 1 ocular symptoms were reported in 1 of 12 patients (8.3%), grade 2 ocular symptoms were reported in 1 of 12 patients (8.3%), grade 3 ocular symptoms were reported in 8 of 12 patients (66.7%), and grade 4 ocular symptoms were reported in 1 of 12 patients (8.3%). In the 1.9 mg/ kg cohort, 5 of 12 patients (41.7%) showed grade 2 ocular symptoms, and 7 of 12 patients (58.3%) showed grade 3 ocular symptoms. In the 1.4 mg/kg cohort, 1 of 12 patients (8.3%) showed grade 1 ocular symptoms, 7 of 12 patients (58.3%) showed grade 2 ocular symptoms, and 4 of 12 patients (33.3%) showed grade 3 ocular symptoms. Analysis of BCVA changes revealed that, of 413 ocular assessments in the 2.5 mg/kg cohort, 60 (14.5%) demonstrated a clinically meaningful decline, defined as BCVA worse than 20/50 with at least a 3-line drop in the better-seeing eye. In the 1.9 mg/kg cohort, 40 of 434 assessments (9.2%) showed such declines, and in the 1.4 mg/kg cohort, 22 of 327 assessments (6.7%) showed such declines. The median time to resolution of these BCVA declines was 1.2 months (range, 0.5-5.8) across all cohorts. According to the OSDI assessment, only a minority of the evaluations revealed ocular symptom duration “most or all of the time” in 7 of 399 patients (1.8%) in the 2.5 mg/kg cohort, 8 of 421 patients (1.9%) in the 1.9 mg/kg cohort, and 8 of 321 patients (2.5%) in the 1.4 mg/kg cohort.

Part 2 results: dose expansion phase

Patient disposition and baseline characteristics

In part 2 of the BelaRd study, a total of 30 patients were enrolled from 31 August 2022 to 29 August 2023, with 15 patients assigned to group A and 15 assigned to group B ( Table 1 ; Figure 1 ). The median follow-up time for part 2 was 22.8 months overall, with group A having a median follow-up of 24.7 months (range, 3.9-29.6) and group B having a median follow-up of 21.5 months (range, 7.7-29.6). At the cutoff date, 22 patients (73.3%) remained on treatment, whereas 8 patients (26.7%) had discontinued therapy. Reasons for discontinuation included death (n = 6), disease progression (n = 1), and study withdrawal (n = 1). In group A, 13 patients (86.7%) were still receiving treatment, and 2 patients (13.3%) had discontinued, whereas in group B, 9 patients (60.0%) were still receiving treatment and 6 patients (40.0%) had discontinued.

Regarding demographic data, the median age in part 2 was 76.0 years (range, 65-89), whereas 20 patients (66.7%) were male and 10 (33.3%) were female ( Table 1 ). Most patients were classified as intermediate fit based on the IMWG frailty score (n = 29, 96.7% had a score of 1), and international staging system classifications were distributed as follows: 14 (46.7%) were at stage I, 9 (30.0%) were at stage II, and 7 (23.3%) were at stage III. Baseline ophthalmologic assessments showed that most patients had BCVA of 20 of 20 to 20 of 40 (n = 18, 60.0%) in at least one eye, whereas 3 patients (10.0%) had a BCVA of 20 of 50, 7 patients (23.3%) had a BCVA of 20 of 70, and 1 patient (3.3%) had a BCVA of 20 of 200. In 5 patients (16.7%), there was mild superficial punctate keratopathy at baseline, whereas the other patients with decreased BCVA at baseline had other ocular-related conditions from their past medical history.

Treatment exposure and dose characteristics

Patients in part 2 were treated at the RP2D of 1.9 mg/kg administered every 8 weeks. The median number of belamaf doses administered per patient was 8 (range, 2.0-16.0), whereas the median cumulative dose was 1125.8 mg (range, 250.8-2736.0). The median dose intensity, calculated as milligrams per kilogram per 4-week cycle, was 0.6 mg/kg (range, 0.5-1.0), and the median relative dose intensity was 49.7% (range, 34.1%-73.5%). Regarding dose modifications, in group A, 40 of 151 planned doses (26.5%) were held, all due to OAEs. In group B, 23 of 136 planned doses (16.9%) were held due to VRA results. No drug administration enabled by a total of 121 VRA assessments was withheld by ophthalmologists due to presence of grade ≥3 OAEs. In the 1.9 mg/kg cohort (n = 42; n = 12 and n = 30 in parts 1 and 2, respectively), time to reinfusion varied significantly among patients (every 8-19 weeks), with 32 of 42 patients presenting a coefficient of variation of >20%. The variation in time to reinfusion after 12 months was numerically lower, with 21 of 28 patients presenting a coefficient of variation of <20%.

Efficacy end points

The ORR was 96.7% (29/30) in both groups. One patient achieved a minimal response at the time of data analysis. Overall, in both groups, 13 patients (43.3%) showed a stringent CR, 3 patients (10.0%) showed a CR, 10 patients (33.3%) showed a very good partial response, and 1 patient (3.3%) showed a partial response. No significant differences were noted between the 2 groups ( Figure 2 ). Fifteen patients (50.0%) achieved MRD negativity. Interestingly, MRD negativity was achieved in 33 of 66 patients (50.0%) in both parts of the BelaRd study, whereas 14 of these patients (42.4%) had sustained MRD negativity for at least 12 months at the time of this analysis. The median time to first response was 1.1 months (range, 1.0-4.0), and the median time to best response was 10 months (range, 1.1-26; Table 2 ). The median PFS and OS have not been reached yet ( Figure 3 ). The 18-month PFS rate was 86.7% (95% CI, 56.4-96.5) for group A and 71.4% (95% CI, 40.6-88.2) for group B.

Overall, the 18-month PFS and TTP rates for the 42 patients receiving belamaf at 1.9 mg/kg in both parts of the study were 82.9% (95% CI, 67.5-91.5) and 97.2% (95% CI, 81.9-99.6), respectively. CR was achieved in 76.2% (16 of 21) and 28.6% (6 of 21) of the patients with a belamaf dose intensity below and above median (0.605 mg/kg every 4 weeks), respectively; 2 events of progressive disease occurred, both in the group with a belamaf dose above the median. At a median follow-up of 28.8 months, 24-month PFS rates were 89.3% (95% CI, 63.2-97.2) and 64.6% (95% CI, 39.7-81.34) for patients with a belamaf dose intensity below and above median, respectively.

Safety and OAEs

The safety profile in part 2 was consistent with that observed in part 1 ( supplemental Table 1 ). At the data cutoff date, 24 (80.0%) patients were alive, and 6 (20.0%) had died. In group A, 13 of 15 patients (86.7%) were alive, and 2 of 15 patients (13.3%) had died, whereas in group B, 11 of 15 patients (73.3%) were alive, and 4 of 15 patients (26.7%) had died. All 6 deaths were attributed to AEs (n = 1 from cardiac failure, n = 2 from sudden cardiac death, n = 1 from asphyxia accident, n = 1 from bacterial pneumonia, and n = 1 from viral pneumonia). Both patients who died due to infections were categorized as intermediate fit from a frailty perspective. There were no reported deaths due to progressive disease.

In part 2, hypogammaglobulinemia (IgG <400 mg/dL) was observed in 24 of 30 patients (80.0%), with severe hypogammaglobulinemia (IgG <200 mg/dL) occurring in 10 patients (33.3%). Nineteen patients among those with hypogammaglobulinemia (79.2%) received subcutaneous immunoglobulins or intravenous immunoglobulins. Infections were reported as treatment-emergent AEs in 19 patients (63.3%) overall; among these, COVID-19 was reported in 11 patients (36.7%), and lower respiratory tract infection was reported in 3 patients (10.0%). Importantly, severe infections of grade 3 or higher were reported in only 4 patients (13.3%).

OAEs were reported in 100% of patients in part 2 ( Table 3 ). However, no patient discontinued treatment due to OAEs. In group A, ocular symptoms were graded as follows: grade 2 in 8 patients (53.3%), grade 3 in 6 patients (40.0%), and grade 4 in 1 patient (6.7%). In 26 of 280 assessments (9.3%), a clinically meaningful decline in BCVA worse than 20 of 50 and at least a 3-line drop in the better-seeing eye was evident. In group B, ocular symptoms were documented as follows: grade 1 in 1 patient (6.7%), grade 2 in 11 patients (73.3%), grade 3 in 2 patients (13.3%), and grade 4 in 1 patient (6.7%). A clinically meaningful decline in BCVA was observed in 12 of 212 evaluations (5.7%). The median time to resolution of keratopathy and BCVA ocular events of grade 2 or higher was 1.8 months (range, 0.9-9) for both groups, 1.9 months (range, 0.9-9.0) for group A, and 1.2 months (range, 0.9-3.7) for group B. In part 2, patients with less severe OAEs tended to report that their ocular symptoms were present for a minimal period or no time through the VRA tool. More specifically, of 513 assessments reported as “minimal/no time” (<50% of the time), only 12 (2.3%) showed grade 3/4 decline in BCVA or keratopathy. Conversely, 10 of 38 assessments (26.3%) exhibited a grade 3/4 decline in BCVA or keratopathy among those reported as “substantial time.” In the same context, grade ≥3 OAEs without VRA-reported “substantial time” (>50% of the time) were detected in 10 of 300 ophthalmologist assessments (3.3%) in group A and 2 of 251 ophthalmologist assessments (0.8%) in group B. Cessation of driving and reading due to eyesight issues in both groups was reported in 1 and 2 of the 558 monthly assessments, respectively.

Discussion

This phase 1/2 study demonstrated the promising efficacy and tolerability of BelaRd in TI patients with NDMM who were of intermediate fit and frail. The median time to first response was 1 month, ORR was 97.6% to 100%, and MRD negativity was reported in 50% of the patients, supporting the high efficacy of the combination. The 18-month TTP and PFS rates suggest sustained disease control. The depth, speed, and durability of the response are at least comparable to triplet and quadruplet regimens commonly used in the nontransplant setting. 13 , 14 , 15 , 16 , 17 , 18 Responses and PFS were not adversely affected by dose holds. Interestingly, the RP2D subgroup with dose intensity below the median of 0.605 mg/kg every 4 weeks exhibited numerically deeper responses and better PFS rates than the group with dose intensity above the median. We must note, however, that only 8% (5 of 66) of our patients were categorized as frail in both parts of the study and, thus, formal subgroup analyses between intermediate-fit and frail patients were not applicable.

Our findings expand upon the favorable outcomes of belamaf studies for the relapsed/refractory setting. 2 , 4 , 19 Unlike studies with dosing every 3 or 4 weeks, we used a deintensified schedule every 8 or 12 weeks. This approach led to a more favorable ocular toxicity profile as compared to that in the DREAMM-7 and DREAMM-8 studies, in which a clinically meaningful decline in visual acuity was reported in 34% of patients. 20 This schedule may have led to reduced OAE frequency and severity, being consistent with ongoing studies evaluating belamaf with VRd (bortezomib, lenalidomide, dexamethasone) in the up-front setting with a reported ORR >80%. 21 , 22 The impact of this schedule on quality of life as depicted through daily activities appears to be limited. Given the variability in belamaf reinfusion times after OAEs, which appears to decrease after a minimum follow-up of 12 months, further evaluation of optimizing belamaf dosing schedules on a patient-by-patient basis is justified.

The implementation of the VRA tool enabled a patient-centered approach to toxicity management and led to fewer dose holds. 23 Differentiation between clinically significant and asymptomatic ocular toxicity to inform belamaf dosing is essential. Patients exhibiting milder OAEs reported brief or absent symptoms. The VRA patient-reported burden of ocular toxicity correlated with the objective severity of OAEs assessed by an ophthalmologist as no drug administration enabled by VRA assessments was withheld by ophthalmologists for grade ≥3 OAEs. The VRA is a clinical tool supplemental to the ophthalmologic examination; after a baseline ophthalmologic examination, the VRA tool could be implemented before each patient visit or when symptoms are reported and inform referral to an ophthalmologist and belamaf administration.

Taking into consideration the relatively small sample size in each cohort in part 2, our findings regarding the ophthalmologic assessment can serve as a basis for future validation of the VRA tool in larger prospective studies.

Infections emerged as an important safety signal in this population. However, the BelaRd profile appears more favorable than bispecific antibodies, which report grade ≥3 infections in up to 46% of patients and infection-related mortality rates at 10% to 12%. 24 , 25 , 26 , 27 , 28 , 29 , 30 In comparison, the incidence of infections with anti-CD38–based combinations in patients with non–transplant-eligible NDMM was 45% with isatuximab, bortezomib, lenalidomide, and dexamethasone and 43% with daratumumab, lenalidomide, and dexamethasone in the IMROZ and MAIA studies, respectively. 13 , 16 Although B-cell depletion with belamaf-based regimens remains a concern, 31 , 32 the risk can be mitigated with preventive measures, including antibiotic prophylaxis, vaccination, and immunoglobulin replacement. 33

In conclusion, the BelaRd study demonstrated that a belamaf dose of 1.9 mg/kg every 8 weeks with lenalidomide and dexamethasone is highly active in TI patients with NDMM. Importantly, no drug administration enabled by the clinician using the VRA instrument was contraindicated by the ophthalmologic assessment, whereas the schedule of every 8 weeks had minimal impact on daily activities, including reading and driving. Therefore, we advocate for a clinician-based, VRA-driven belamaf administration supplemented by an ophthalmologic assessment only at baseline and when needed thereafter. Overall, these data warrant the evaluation of BelaRd in randomized controlled studies for TI patients with NDMM.

Conflict-of-interest disclosure: E.T. declares honoraria for advisory boards or lectures from Amgen, AstraZeneca, Bristol Myers Squibb, Eusa Pharma, GSK, Integris Pharma, Janssen, Pfizer, Sanofi, and Takeda; research support (to the institution) from Amgen, GSK, Janssen, Sanofi, and Takeda; and travel grants from Amgen, Eusa Pharma, and Takeda. M.G. declares honoraria from GSK, Janssen, Sanofi, AbbVie, Amgen, and Takeda. I.N.-S. and P.M. declare honoraria from Janssen. E.K. declares honoraria and research funding from Amgen, Janssen, GSK, and Pfizer. M.A.D. declares honoraria from AbbVie, Amgen, Bristol Myers Squibb, GSK, Janssen, Karyopharm, Pharmacyclics, Pfizer, Sanofi, and Takeda. G.P. is an employee of Veeda Lifesciences, Dublin, Ireland. The remaining authors declare no competing financial interests.

Acknowledgments

The authors thank the patients for participating in this study.

This study was supported, in part, by research funding from GSK.

Authorship

Contribution: E.T. and M.A.D. conceptualized the study and provided supervision; E.T., M.G., and I.N.-S. contributed to methodology; G.P. conducted the formal analysis; E.T., M.G., I.N.-S., P.M., D.F., M.M., F.T., V.S., N.K., E.S., E.E.-P., E.K., and M.A.D. performed the investigation; E.T. and M.G. wrote the original draft; I.N.-S., P.M., D.F., M.M., F.T., V.S., N.K., E.S., E.E.-P., G.P., E.K., and M.A.D. reviewed and edited the manuscript; and all authors read and agreed to the published version of the manuscript.

Footnotes

Primary data are available from the corresponding author, Evangelos Terpos ( eterpos@med.uoa.gr ), on reasonable request.

The online version of this article contains a data supplement.

There is a Blood Commentary on this article in this issue.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Supplementary Material

Supplemental Methods and Table

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Associated Data

Supplementary Materials

Supplemental Methods and Table