Newly Diagnosed Multiple Myeloma Pts Research Articles

Rapid reduction of free light chains and improvement in renal outcomes in patients with newly diagnosed multiple myeloma admitted with acute kidney injury with daratumumab-based therapy and without plasmapheresis.

7525 Background: Cast nephropathy is the most common cause of acute kidney injury (AKI) in patients with multiple myeloma (MM), where light chain accumulation in the distal nephron leads to obstruction and injury of the distal and collecting tubules. A prompt reversal of renal injury is paramount to improve outcomes. Daratumumab (dara), an anti-CD38 monoclonal antibody, has significant clinical efficacy in MM. We report the effects of early initiation of dara-based therapy on sFLC reduction and renal recovery in pts admitted with a new diagnosis of MM and AKI. Methods: Between April 2016 and Dec 2023, pts admitted with newly diagnosed MM (NDMM) with AKI (sCr ≥2 mg/dL and/or eGFR <30 mL/min/1.73 m2 by CKD-EPI) and involved sFLC ≥500 mg/L who started dara-based therapy were identified and retrospectively reviewed. We studied pts who started treatment ≤14 days of presentation. Outcomes included sFLC kinetics and renal outcomes per IMWG criteria at 3 months. Results: We identified 20 NDMM pts. Median age was 65 (range 44-87). Median peak sCr at admission was 6.5 mg/dL (range 3.1-17.8) with median eGFR of 8 mL/min/1.73 m2 (range 2-16). Nine pts started hemodialysis (HD). The median peak sFLC at diagnosis was 6603 mg/L (range 1839-26,023). Initial dara regimens included cyclophosphamide, bortezomib, and dexamethasone in 11 pts (55%) and with bortezomib and dexamethasone in 9 pts (45%). Median time between presentation and dara start was 3 days (range 0-10). No pts underwent plasmapheresis. Within 1 cycle of therapy, all 20 pts achieved sFLC reduction ≥50% at a median of 3 days (95% CI, 3-7 days). Median time to sFLC ≤500 mg/L was 13 days (95% CI, 9-33 days), and this was in 15 out of 16 pts (94%) assessable for response after 1 cycle of treatment. At 3 m, the overall renal response (≥minor response) was 85% (N=17), with complete, partial, and minor responses in 50% (N=10), 10% (N=2), and 25% (N=5), respectively. Twelve pts (60%) recovered renal function with eGFR ≥40 mL/min. Of 9 pts who required HD, 4 and 6 pts were free of HD at 3 m and 12 m, respectively. Two pts on HD died within 3 m (age 86, from aspiration pneumonia; age 87, from progressive disease); and 1 continued on HD at 12 months. Fourteen pts (70%) later added lenalidomide, and 3 pts (15%) underwent autologous stem cell transplant. The IMWG ORR was 100% with VGPR 90%. With a median follow up of 25 m, median PFS was 47 m (95% CI 12-not reached) and 2-year OS was 84% (95% CI 68-100%). Conclusions: This is the largest reported cohort of NDMM pts hospitalized with AKI treated with dara-based induction therapy. Treatment with dara combinations shows rapid and deep reductions in sFLC, improving renal recovery outcomes. These findings highlight the efficacy of early use of dara in pts with MM-induced AKI and provide an approach without plasmapheresis.

Real-world outcomes (RWO) with tandem transplantation in patients (pts) with newly diagnosed multiple myeloma (NDMM).

7564 Background: Stem cell transplant (SCT) followed by maintenance therapy (MT) is the standard of care for transplant eligible NDMM pts. Tandem transplantation has been found to have progression free (PFS) and overall survival (OS) benefit particularly for patients with high-risk cytogenetic abnormalities (HRCA). However, this modality remains under-utilized in clinical practice. We report RWO with tandem transplant (TT) in comparison with single SCT followed by MT (STM). Methods: We performed a multi-center, retrospective, observational study using the de-identified COTA real-world database derived from the EMRs of US centers. Pts with NDMM from 1/1/2012 to 1/1/23 were included in the study. Kaplan-Meier method was used to evaluate time to next treatment (TTNT), OS, follow-up time (reverse OS endpoint), and report log-rank test p-values. TTNT was defined in two ways: time from 1st SCT (2nd if TT) to the earliest of initiation of next line of therapy (LOT) or death (TTNT1) and the time from 2nd LOT post-SCT to the earliest of initiation of next LOT or death (TTNT2). A propensity score (PS) model was used to compare study cohorts, and hazard ratios (HRs) were estimated using the Cox proportional hazards method. HRCA were defined as pts with 17p(-), t(4;14), t(14;16), t(14;20) and 1q+. Results: 1117 pts met the study criteria. Median age at diagnosis was 60 yrs. 56.9% were male, 68.9% were White, and 32% had HRCA. 937 pts received STM and 180 pts received TT with median follow-up time of 68 months (mos) (95% CI: 65.4, 71.9) and 39 mos (95% CI: 31.9, 50.1), respectively. Median TTNT1 for TT vs STM was 52.7 vs 51 mos, (p=0.85), respectively. Median TTNT2 for TT vs STM was 33.9 vs 11.8 mos, (p<0.001). respectively. Median OS for TT vs STM was not reached (NR) vs 108.1 mos, (p<0.001), respectively. In the PS model, the TT group had significantly lower hazard of TTNT2 and OS events (HRs 0.49 and 0.47, p<0.001 and p=0.01, respectively) as compared to STM. Conclusions: Our study demonstrates significant improvement in unadjusted TTNT2 and OS RWO for TT pts, despite higher incidence of HRCA compared to STM pts. PS analysis demonstrated a similar effect with decreased HRs for TT. OS is an extremely difficult primary outcome to achieve in MM RCTs where survival may have to be collected for decades. Thus, our large study of RWO with long-term follow-up is valuable. [Table: see text]

Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ).

7500 Background: The first line of treatment (tx) is important for patients (pts) with newly diagnosed multiple myeloma (NDMM) as pts may not have a chance for subsequent therapy. VRd is currently a standard of care (SOC) in NDMM. Isa is an approved anti-CD38 monoclonal antibody (mAb) inducing myeloma cell death through multiple mechanisms. In the Phase 3 IMROZ study (NCT03319667), we investigate the efficacy and safety of Isa-VRd vs VRd in transplant-ineligible NDMM pts. Methods: IMROZ is a global, prospective, randomized, open-label study done at 102 study sites in 21 countries. Included pts had active, measurable NDMM not considered for transplant due to elderly age or comorbidities. Pts aged ≥80 were excluded. Pts were randomized 3:2 and stratified by age, R-ISS stage and China vs non-China, to receive Isa-VRd or VRd. Isa-VRd arm pts received Isa (10 mg/kg IV); both arms received V (1.3 mg/m2 SC), R (25 mg PO) and d (20 mg IV/PO). The primary endpoint was progression-free survival (PFS). Key secondary endpoints were complete response (CR), minimal residual disease negativity (MRD-) (10-5 by NGS) in pts with CR, very good partial response or better and overall survival. Adverse events (AEs) and laboratory parameters were graded with NCI CTCAE v4.03. Results: 446 pts (265 Isa-VRd, 181 VRd) were randomized; pt characteristics were well balanced. At data cutoff (26 Sep 2023), 125 (47.2%) and 44 (24.3%) pts in Isa-VRd and VRd arms were still on tx, respectively. Median (mdn) tx duration was 53.2 (Isa-VRd) vs 31.3 (VRd) mo; addition of Isa did not significantly affect relative dose intensity of VRd. At mdn follow-up of 59.7 mo, mdn PFS was not reached (Isa-VRd) vs 54.3 mo (VRd); HR 0.596 (98.5% CI 0.406–0.876), log-rank p=0.0005. From the current trend, projected Isa-VRd mdn PFS will reach ~90 mo. PFS benefit was consistent across subgroups and maintained through subsequent line of therapy (PFS2 HR 0.697; 95% CI: 0.51-0.952). Isa-VRd led to deep and sustained responses and was well-tolerated (Table). Exposure-adjusted Grade 5 TEAE rate was 0.03 (Isa-VRd) vs 0.02 (VRd). Conclusions: IMROZ is the first Phase 3 study of an anti-CD38 mAb with SOC VRd in this pt population to show a significantly reduced risk of progression or death by 40.4% vs VRd while providing deep and sustained responses. The safety profile was consistent with addition of Isa to VRd. Numerical differences in TEAEs are largely explained by longer exposure in the Isa-VRd arm. These results support Isa-VRd as a potential new SOC in pts not intended for transplant. Clinical trial information: NCT03319667 . [Table: see text]

Carfilzomib-Lenalidomide-Dexamethasone (KRd) Vs. Lenalidomide-Dexamethasone (Rd) in Newly Diagnosed Fit or Intermediate-Fit Multiple Myeloma Patients Not Eligible for Autologous Stem-Cell Transplantation (Phase III EMN20 Trial): Analysis of Sustained Undetectable Minimal Residual Disease (MRD)

Background. Before the recent introduction of daratumumab (Dara) in the frontline setting, lenalidomide-dexamethasone (Rd) has represented a standard of care for transplant-ineligible (NTE), patients (pts) with newly diagnosed multiple myeloma (NDMM). Nonetheless, minimal residual disease negativity (MRD Neg) rate and median progression-free survival (PFS) with Rd were still relatively limited, as compared with 3/4-drug regimens, also including carfilzomib (K). The EMN20 trial (NCT04096066) is a randomized, multicenter study designed to compare weekly K in addition to Rd (KRd) with Rd in fit or intermediate-fit NTE NDMM pts, with the objective of attaining improved rates of PFS and 2-year MRD Neg through a triplet regimen. Methods. Fit or intermediate-fit NTE NDMM pts (according to the International Myeloma Working Group frailty score) were randomly assigned to receive KRd (28-day cycles, once-weekly K 56 mg/m² on days [dd] 1,8,15 for 12 cycles and on dd 1,15 from cycle 13 onwards for 5 years (yr), R 25 mg orally on dd 1-21 continuously and d 40 mg on dd 1,8,15,22 continuously) or continuous Rd (28-day cycles, R 25 mg on dd 1-21, d 40 mg on dd 1,8,15,22). Pts were stratified based on International Staging System (ISS) stage and fitness status, using a web-based procedure completely concealed from study participants. Patients in the KRd arm sustaining MRD Neg after 2 yr of treatment will discontinue carfilzomib early (at 2 yr) and continue Rd alone. The primary endpoints were MRD Neg after 2 yr of treatment and PFS. For MRD assessment, the clonoSEQ™ assay was used at the sensitivity of ≥10⁻⁵. The MRD Neg rate was the proportion of MRD-Neg pts (sensitivity ≥10⁻⁵) at 2 treatment yr. Key secondary endpoints included response rates, overall survival (OS) and safety. The protocol was prematurely stopped on Nov 23, 2021, after the introduction of frontline Dara-Rd. Results. A total of 101 pts were enrolled and 82 were randomized (KRd 42 vs Rd 40); 19 pts were not randomized due to screening failure (17) and withdrawal of consent (2). Pt characteristics were well balanced between the KRd and Rd arms: median age was 73 (IQR 70-76) and 74 yr (IQR 72-76), 60% vs 58% of pts were fit, 33% vs 30% had ISS III and 22% vs 22% had high-risk cytogenetics, respectively. In the KRd vs Rd arms, 33/42 (78.6%) vs 18/40 (45.0%) pts are still under treatment; reasons for discontinuation were medical decision (1 vs 4), death (2 vs 5), adverse events (AEs; 2 vs 1), progressive disease (3 vs 10), lost to follow-up (1 vs 0) and consent withdrawal (0 vs 2). After a median follow-up of 24.9 months (IQR 20-29), 79% of KRd pts and 50% of Rd pts were alive and progression-free. In the ITT population, MRD Neg rates (at 10⁻⁵) were observed in 21/42 (50%) KRd pts vs. 0 Rd pts at 1 yr of treatment (p<0.0001) and in 23/42 (55%) KRd pts and 0 Rd pts at 2 yr (p<0.0001). 16/42 (38%) KRd pts and 0 Rd pts sustained MRD Neg at 2 yr (p<0.0001; Figure panel a). At the time of abstract submission, the assessment of MRD at 2 yr of treatment was still pending for 6 KRd pts and 10 Rd pts. Median PFS was not reached with KRd vs 20.9 months with Rd (HR 0.29, 95% CI 0.13-0.64, p=0.002; Figure panel b). In multivariable analysis, no significant effect modification was observed in terms of ISS or frailty status. 2-yr OS was 89% with KRd vs 74% with Rd (HR 0.36, 95% CI 0.11-1.17, p=0.09). The most frequent grade 3-4 AEs with KRd were neutropenia (22%), thrombocytopenia (10%), cardiac AEs (7%), infection (7%) and hypertension (5%), while with Rd they were neutropenia (12%) and dermatologic AEs (10%). Second primary malignancy was observed in 1 pt (3%) in the Rd arm. Eighty-five percent of pts in the KRd and 70% in the Rd arms had ≥1 dose reductions of any drug. Conclusions. To our knowledge, these results demonstrate for the first time an unexpected high rate of MRD Neg in NTE NDMM pts. Half of pts treated with KRd achieved MRD Neg, improving over time with therapy (50% at 1 yr and 55% at 2 yr), and 38% of KRd patients sustained MRD Neg at 2 yr. This higher rate of MRD Neg was associated with prolonged PFS. Toxicities were predictable and manageable. Updated results will be presented at the meeting.

Deletion 1p at Time of Diagnosis of Multiple Myeloma Portends Inferior Outcomes

Background: Multiple myeloma (MM) is associated with several cytogenetic abnormalities (CA) that influence the disease course, response to treatment and survival. Trisomies and immunoglobulin H chain translocations are primary CA while del(17p), gain(1q), del(1p) and others are secondary CA. Gain (3 copies) and amplification (>3 copies) 1q have been recognized as adverse prognostic markers and incorporated into the second revision of the International Staging System (R2-ISS). However, the role of del(1p) is less well defined, especially in the era of modern myeloma therapeutics. We aimed to analyze the outcomes of newly diagnosed MM (NDMM) patients (pts) with chromosome 1 abnormalities, mainly del 1p, treated with autologous hematopoietic cell transplant (AHCT) consolidation at The Ohio State University. Methods: We identified and reviewed the medical records of all NDMM pts who were treated with AHCT from 1/1/2015-2/13/2019 (n=511). High-risk cytogenetics (HRC) was defined by the presence of del(17p), t(4;14), or t(14;16) similar to R-ISS; standard-risk cytogenetics (SRC) were defined as the absence of HRC. Modified HR cytogenetics (mHRC) included gain/amp 1q and/or t(14;20) in addition to HRC, while ultra high-risk (uHRC) included 2 or more mHRC risk factors. Results: The baseline pt characteristics are presented in Table 1. Of 511 pts transplanted, 453 had cytogenetic data from diagnosis. SRC were seen in 353 pts (77.9%), while 100 (22.1%) had HRC, 156 (34.4%) had mHRC, and 43 (9.5%) had uHRC. Thirty-two (7.1%) pts had del(1p) while 105 (23.2%) had gain 1q and 30 (6.6%) had amp 1q. As expected, compared to SRC pts, pts with HRC, mHRC and uHRC had higher risk of relapse or death. Patients with gain and amp 1q had inferior outcomes in terms of PFS (HR 1.35; 95% CI 1.06-1.73, p=0.016), TTNT (HR 1.84; 95% CI 1.40-2.42, p<0.001) and OS (HR 1.47; 95% CI 1.06-2.02, p=0.02), consistent with published literature. The median PFS, TTNT and OS from AHCT in pts with gain/amp 1q was 3.17 years (y), 3.95y and 7.13y, respectively, compared to 4.01y, 7.60y and 8.21y in pts without gain/amp 1q. Pts with del(1p) had inferior PFS (median 2.43y versus 3.98y; HR 1.75; 95% CI 1.16-2.64, p=0.008), TTNT (median 2.72y versus 6.17y; HR 1.96; 95% CI 1.22-3.14, p=0.005) and OS (median 4.11y versus 8.38y; HR 2.19; 95% CI 1.34-3.58, p=0.002) from AHCT compared to those without del(1p). (Figure 1). Conclusions: In this cohort of NDMM pts that underwent AHCT, del(1p) at diagnosis was an independent predictor of shorter PFS, TTNT and OS. Despite advances in induction regimens, AHCT consolidation and maintenance therapy, del(1p) continues to portend inferior outcomes. Larger analyses are needed to validate the prognostic value of del(1p) and investigate its role in predicting outcomes in MM.

An Updated Analysis of Ocular Adverse Events and Vision-Related Functioning in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Belantamab Mafodotin, Lenalidomide, and Dexamethasone in the Phase 1/2 Belard Trial

Introduction Belantamab mafodotin (belamaf; GSK2857916) is a B-cell maturation antigen-binding antibody-drug conjugate approved as a monotherapy in pretreated patients (pts) with relapsed/refractory multiple myeloma. Ocular adverse events (OAEs), manifesting as visual acuity changes, ocular symptoms, and corneal findings, are common with belamaf and the main reason for dose modifications (dose reduction, dose holds) or treatment discontinuation. In this descriptive analysis, we evaluate the OAEs and their impact on daily functioning in transplant ineligible (TI) pts with newly diagnosed multiple myeloma (NDMM), treated with an extended dosing schedule of belamaf in combination with lenalidomide and dexamethasone (Rd) in the phase 1/2 BelaRd study. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. The study is comprised of 2 Parts: Part 1 evaluates the safety/clinical activity of three different belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd and establishes the recommended phase 2 dose (RP2D). Part 2 further investigates the safety/efficacy of RP2D in two Groups and evaluates two different sets of guidelines for the management of OAEs. In Part 1, belamaf is initially administered q8w and, depending on toxicity, dosing may be adjusted to q12w. Ocular assessments include best corrected visual acuity (BCVA), using Snellen chart and manifest refraction, and corneal exam using slit lamp microscopy. Ocular symptoms are classified by Common Terminology Criteria for Adverse Events v5.0, while dry eye disease severity and vision-related functioning is assessed with the patient-reported questionnaire Ocular Surface Disease Index (OSDI). In Part 1 of the study, severity of corneal events is assessed with the Keratopathy Visual Acuity scale. This descriptive analysis presents the OAEs in all Part 1 pts over an extensive follow-up period (data cut-off: 05 June 2023). Results Thirty-six pts were included in this analysis, who were followed up for a median of 20.3 months (range 3.2-26.8). At baseline, all pts had ocular comorbidities. Among 216/244/201 BCVA assessments in cohorts 2.5/1.9/1.4 mg/kg, a meaningful BCVA decline (BCVA <20/50) with at least 3 lines drop in the better seeing eye, was observed in 21 (10%)/24 (10%)/17 (8%) of the assessments, while BCVA ≤20/200 with at least 3 lines drop in the better seeing eye was noted in only 2 (1%)/3 (1%)/8 (4%), with a median time to resolution of 1 month. The most frequently reported ≥Gr 3 ocular symptom was decreased vision, observed in 11 (5%)/ 8 (3%)/ 7 (3%) of the assessments, while ≥Gr3 keratopathy was noted in < 2% of assessments across all cohorts. Regarding OSDI, from 202/234/196 responses received, the number of “all/most” of the time worst responses in the ocular symptoms category were 6 (3%)/6 (3%)/8 (4%), while the respective proportions in the Activities of Daily Living category (ADL) were 6 (3%)/4 (2%)/3 (2%). In terms of missed doses due to OAEs, among 129/138/119 planned belamaf infusions, the number of skipped doses were 53 (41%)/48 (35%)/32 (27%). The overall response rate was 100%, no disease progression was observed over a median follow-up of 20.3 months, and 30 (83%) patients achieved at least VGPR while 19 (53%) achieved at least CR, with a median time to first response of 1 month. Conclusions Over a prolonged follow-up period, the belamaf-Rd triplet, with the extended dosing schedule for belamaf, had a minimal impact in vision-related functioning, as the ‘all/most’ of the time worst answers in the ADL category of OSDI was ≤3% across all cohorts. Furthermore, the frequency of clinically relevant impairment in vision was low, as a meaningful BCVA decline was observed in <10% of assessments, with a rapid time to resolution. Finally, the treatment combination induced rapid, deep and durable responses across all dose levels, with no PD observed. In conclusion, this novel extended belamaf schedule nearly eradicates the risk for clinically relevant ocular toxicity and impact on ADL, without any compromise in clinical activity, suggesting it may be a valid option in the upfront treatment of this frail, elderly and difficult-to-treat pt population.

Evaluation of a Novel Method for the Assessment of Ocular Adverse Events and Associated Functional Impact in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Belantamab Mafodotin, Lenalidomide, and Dexamethasone in the Phase 1/2 Belard Trial

Introduction Belantamab mafodotin (belamaf; GSK2857916), an antibody-drug conjugate targeting B-cell maturation antigen, has shown promising efficacy and a favorable tolerability profile in the treatment of multiple myeloma. Ocular adverse events (OAEs), manifesting as visual acuity changes, ocular symptoms, and corneal findings, are common with belamaf and the main reason for dose modifications (dose reduction, dose holds) or treatment discontinuation. Keratopathy and Visual Acuity (KVA) scale was used in most belamaf trials, including the pivotal DREAMM-2, to guide belamaf dose modifications. KVA grading is dependent on an ophthalmologist consultation prior to belamaf administration. Herein, we evaluate a novel approach to guide belamaf dosing in transplant ineligible (TI) patients (pts) with newly diagnosed multiple myeloma (NDMM), treated with an extended dosing schedule of belamaf in combination with lenalidomide and dexamethasone (Rd) in the phase 1/2 BelaRd study. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. Part 1 evaluated the safety/tolerability of three belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd in 36 pts and established that the recommended phase 2 dose (RP2D) is 1.9 mg/kg, initially administered q8w and, depending on toxicity, adjusted to q12w. Part 2 investigates the safety/efficacy of RP2D in Groups A and B, comprised of 15 pts each, and evaluates two different sets of guidelines for the management of OAEs. In Group A, belamaf dosing is guided by the KVA scale; in Group B, dose modifications are determined by the pts' responses on ocular symptoms and their impact on activities of daily living (ADL), captured by the Vision Related Anamnestic (VRA) tool, and by the presence of ≥Grade (Gr) 3 KVA events (BCVA reduced/corneal findings). VRA is a novel, 9-item physician administered questionnaire designed to assess the frequency of ocular symptoms and their impact on vision-related activities. Ocular exams include Snellen best corrected visual acuity (BCVA) and slit lamp corneal evaluation, while ocular symptoms are classified by CTCAE v5.0. Herein, we present the OAEs and the clinical activity of the treatment combination for both Groups of Part 2 (cut-off date 05/06/2023). Results By the cut-off date, twenty-four pts [median age: 75.5 years; male: 16 (66.7%)] had received ≥ 1 belamaf dose in Part 2 and were still on treatment. At baseline, most pts had ocular comorbidities. The median belamaf administrations and number of cycles reached were 3.0/2.0 and 6.5/5.5, for Groups A and B, respectively. A meaningful BCVA decline (BCVA <20/50) with at least 3 lines drop in the better seeing eye, was noted in 5/52 (9.6%) and 5/45 (11.1%) assessments, while BCVA ≤20/200 with at least 3 lines drop was noted in 1/59 (1.7%) and 2/51 (3.9%), respectively. Overall, no ≥Gr 3 ocular symptoms were observed, while the most frequent ≥Gr 2 ocular symptom was dry eye (57/110, 51.8%); also, no ≥Gr3 keratopathies were recorded. Among 66/59 VRA assessments, ocular symptoms and ADL impairment, manifesting for >50% of the time (substantial time) in the last 24 hours prior to belamaf administration, were noted in 2 (3.0%)/9 (15.3%) and 2 (3.0%)/7 (11.9%), respectively. Importantly, numerically similar proportions of KVA events and skipped belamaf doses were noted in both Groups (Table 1). Furthermore, although the sample size of the present analysis does not allow conclusions for the VRA test characteristics, it is notable that in all assessments where eyesight difficulties were reported for substantial time, ≥Gr2 KVA events were also recorded, suggesting a potential association between VRA responses and KVA events, that warrants further investigation. Finally, in terms of clinical activity, for the 19 response-evaluable pts (≥2 efficacy assessments), at a median follow-up of 7.4 months the ORR was 90%/100% in Groups A and B (PR/VGPR: 30%/60%; 66.7%/33.3%) with no disease progression observed. Conclusions In this preliminary descriptive analysis, the VRA tool was safe and effective in informing belamaf dose adjustments in the extended dosing schedule. Recruitment in Part 2 is ongoing and, as data accumulates, future analyses will provide further insight on the potential association of the VRA tool with KVA events, which may eliminate the need for an ophthalmic exam prior to belamaf dosing.

Response and Safety of Selinexor with VRD Regimen in Newly Diagnosed Multiple Myeloma (NDMM) with Extramedullary Disease (EMD): A Prospective, Open-Label, Multicenter, Phase 2 Study

INTRODUCTION: Extramedullary disease (EMD) is a rare but increasingly recognized complication in newly diagnosed multiple myeloma (NDMM) patients, associated with a poorer prognosis and drug resistance. However, data on treatment outcomes for EMD are primarily based on retrospective studies, necessitating prospective studies with well-defined EMD to assess treatment efficacy and safety accurately. In this context, we present the preliminary findings from a prospective phase 2 study evaluating the safety and efficacy of selinexor in combination with VRd as a first-line treatment for NDMM patients with EMD(NCT05900882). METHODS: The study enrolled NDMM patients under the age of 75 who had measurable extramedullary disease (defined as paraosseous or extramedullary plasmacytoma ≥2cm. Patients received selinexor (60 mg QW) in combination with VRd (SVRD) regimen as induction therapy for 4 cycles (28 days of each cycle). Following the induction phase, patients underwent two cycles of VRd consolidation therapy after autologous stem cell transplantation (ASCT), while those who did not undergo ASCT received another 4 cycles of SVRD consolidation therapy. All pts received bortezomib plus lenalidomide for maintenance for at least 24 months. The primary endpoint of the study was the best response rate during induction therapy, and secondary endpoints included complete response (CR) rate, duration of response (DOR), safety, and survival outcomes. RESULTS: Between Oct 17, 2022 and May 12, 2023, a total of 10 NDMM pts with EMD were enrolled and received treatment at The First Affiliated Hospital of Nanjing Medical University. The median age was 62 years (range 48-70). Among them, 7 patients (70%) had RISS stage II/III disease, 7 patients (70%) were classified as high risk based on the mSMART stratification, and 3 patients (30%) had extra-osseous extramedullary plasmacytomas (EMP) as per Table 1. By the data cut-off date of July 15, 2023, at a median follow-up of 5.5 months (range 2.2-9.3 months), 5 pts completed 4 cycles of SVRd inductive treatment, 2 pts underwent ASCT, 1 pts discontinued the clinical trial due to progressive disease, and 3 pts were now receiving consolidation therapy ( Figure 1). Among the 10 evaluable pts for best serological response, 4 pts (40%) achieved serological CR/sCR, and 6 pts (60%) achieved VGPR. The depth of remission improved with the continuous treatment. Extramedullary disease evaluation in 9 patients showed complete disappearance of extramedullary lesions in 3 patients (30%), partial response in 5 patients (50%), and stable disease in 1 patient (10%). 8 (80%) pts experienced any grade AE. Grade 3 or 4 AEs were reported in 2 pts (9 events in total), with the most common being leukopenia (3), neutropenia (3) and thrombocytopenia (3). Non-hematological AEs were mainly grade 1-2, except for 1 pt with grade 3 anorexia. No pts required dose reductions or discontinuations due to AEs. CONCLUSIONS: The combination of selinexor with VRd regimen demonstrated early, deep, and durable responses in NDMM patients with extramedullary disease, both in serological and extramedullary responses, with a manageable safety profile. These results suggest that this therapeutic intervention holds promise as an effective and well-tolerated treatment option for multiple myeloma patients with EMD. Further studies are warranted to validate these findings and establish the long-term benefits of this combination therapy.

Long-Term Safety and Efficacy Results of Belantamab Mafodotin Plus Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: An Updated Part 1 Analysis from the Phase 1/2 Belard Trial

Introduction The preferred upfront treatment of transplant ineligible (TI) patients (pts) with newly diagnosed multiple myeloma (NDMM) consists of the combination of lenalidomide and dexamethasone (Rd) with a third antimyeloma agent of a different mechanism of action (e.g., proteasome inhibitors or anti-CD38 monoclonal antibodies). Belantamab mafodotin (belamaf; GSK2857916), an antibody-drug conjugate targeting BCMA, has shown efficacy in pretreated MM pts, while preclinical data demonstrate synergy between belamaf and lenalidomide, with no overlapping toxicities. Thus, there is a strong rationale for investigating the belamaf-Rd triplet in TI NDMM pts. Methods BelaRd (NCT04808037) is an open-label, phase 1/2 study conducted in Greece, aiming to enroll 66 TI NDMM pts. Eligible are adult pts with ECOG PS 0-2 and adequate organ function. Part 1 evaluates the safety/tolerability of three belamaf doses (2.5/1.9/1.4 mg/kg) plus Rd in 36 pts and establishes the recommended phase 2 dose (RP2D). In this part, belamaf is initially administered q8w and, depending on toxicity, dosing may be adjusted to q12w. Ocular exams include Snellen best corrected visual acuity (BCVA) and slit lamp corneal evaluation. Ocular symptoms are classified by CTCAE v5.0, while the Ocular Surface Disease Index (OSDI) captures dry eye disease and activities of daily living (ADL).Herein, we present updated safety and efficacy results of all Part 1 pts with an extended follow-up time (cut-off date 05/06/2023). Results Of the 36 pts [median age: 72.5 years; male: 19 (53%)] in Part 1, 29 (81%) are still on treatment, while 7 (19%) have discontinued [6 pts due to belamaf-unrelated fatal events: (COVID-19: 1/1/2; Pneumonia: 1/1/0, for cohorts 2.5/1.9/1.4 respectively); 1 pt withdrew consent]. The median belamaf administrations and number of cycles reached were 6/7/7 and 20.0/22.5/20.0, for the respective cohorts. The most common (≥10% of pts) non-ocular ≥ Gr3 treatment-emergent adverse events were fatigue (21 pts, 58%; [7 (58%)/7 (58%)/7 (58%)]), diarrhoea (8 pts, 22%; 2 (17%)/3 (25%)/3 (25%)]), rash (6 pts, 17%; [2 (17%)/2 (17%)/2 (17%)]), COVID-19 (5 pts, 14%; [2 (17%)/1 (8%)/2 (17%)]) and insomnia (4 pts, 11%; 0/4 (33%)/0]) , while no ≥Gr3 thrombocytopenias and infusion-related reactions were reported. Regarding ≥Gr3 infections other than COVID-19, pneumonia was reported for 3 (8%) pts [1/1/1 (8%)] and lower respiratory tract infection for 1 (3%) pt [0/0/1(8%)]. Regarding ocular adverse events (OAEs), among 216/244/201 BCVA assessments in cohorts 2.5/1.9/1.4, a meaningful BCVA decline (BCVA <20/50) with at least 3 lines drop in the better seeing eye, was observed in 21 (10%)/24 (10%)/17 (8%), while BCVA ≤20/200 with at least 3 lines drop in the better seeing eye was noted in only 2 (1%)/3 (1%)/8 (4%), with a median time to resolution of 1 month. Across all cohorts, the most frequently reported ≥Gr 3 ocular symptom was decreased vision (26/665, 4%), while ≥Gr3 keratopathy was noted in <2% of assessments. Regarding OSDI, from 202/234/196 responses received, the number of “all/most” of the time worst responses in the ocular symptoms category were 6 (3%)/6 (3%)/8 (4%), while the respective proportions in the ADL category were 6 (3%)/4 (2%)/3 (2%). The overall response rate was 100% across all cohorts: More specifically CR or better was achieved by 7 (58%)/6 (50%)/6 (50%), VGPR by 3 (25%)/5 (42%)/3 (25%) and PR by 2 (17%)/1 (8%)/3 (25%) pts in cohorts 2.5/1.9/1.4, with a median time to first response of 1 month. Finally, at a median follow-up of 20.3 months, no disease progression was observed, median PFS and median time to progression were not reached ( Figure 1) and responses continue to deepen across all cohorts. Conclusions Over an extended follow-up period, the belamaf-Rd triplet has proven a safe and effective combination for the upfront treatment of TI NDMM pts, with no long-term safety signals. Furthermore, the extended dosing schedule for belamaf had a minimal impact in vision-related functioning, as very low rates of meaningful BCVA decline and “most/all” OSDI responses were noted across all cohorts, with a rapid time to resolution. Meanwhile, a very promising clinical activity is observed, with rapid, deep and durable responses across all dose levels. Consequently, after validation with bigger pt numbers, this novel combination may well be a very attractive frontline option for this vulnerable and difficult-to-treat pt population.

Results of the Phase III Randomized Iskia Trial: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone Vs Carfilzomib-Lenalidomide-Dexamethasone As Pre-Transplant Induction and Post-Transplant Consolidation in Newly Diagnosed Multiple Myeloma Patients

Background. The current standard treatment for transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM) consists of quadruplet induction with proteasome inhibitors, immunomodulatory agents, dexamethasone and anti-CD38 monoclonal antibody followed by high-dose melphalan and autologous stem-cell transplant (MEL200-ASCT), with subsequent consolidation. The phase III IsKia trial assessed efficacy and safety of isatuximab-carfilzomib-lenalidomide-dexamethasone (IsaKRd) as pre-ASCT induction and post-ASCT consolidation vs KRd. Methods. TE NDMM pts aged <70 years were enrolled and randomized. IsaKRd pts received 4 28-day cycles of Isa: 10 mg/kg IV days 1, 8, 15, 22 cycle 1, followed by 10 mg/kg days 1, 15 cycles 2-4; K: 20 mg/m 2 IV day 1 cycle 1, followed by 56 mg/m 2 IV days 8, 15 cycle 1 and days 1, 8, 15 cycles 2-4; R: 25 mg PO daily days 1-21; d: 40 mg PO days 1, 8, 15, 22; MEL200-ASCT and 4 consolidation cycles with IsaKRd at the same schedule. KRd pts received 4 KRd induction cycles; MEL200-ASCT and 4 KRd consolidation cycles (K, R and d at the same schedule as in the IsaKRd arm). The primary endpoint was the rate of minimal residual disease (MRD) negativity by next-generation sequencing (NGS; 10 -5) after consolidation in the intention-to-treat (ITT) population. MRD was tested in all pts who achieved at least a very good partial response (≥VGPR). Key secondary endpoints were the rate of NGS MRD negativity (10 -5) after induction and PFS. MRD rates were evaluated in an ITT analysis (pts with missing MRD data or who achieved ≤PR were considered as MRD positive). The data cut-off for the analysis was May 22, 2023. Results. 302 pts were enrolled and randomized (151 in both the IsaKRd and KRd arms). Pt characteristics were well balanced between the two arms: median age was 61 vs 60 years, respectively; 18% vs 19% of pts had high-risk (HiR) cytogenetic abnormalities (CA) [del(17p) and/or t(4;14) and/or t(14;16)]; 9% vs 8% had ≥2 HiR CA [double hit; including del(17p), t(4;14), t(14;16) and gain/amp(1q)]. In ITT analysis, the rates of MRD negativity at the 10 -5 cut-off after consolidation (primary endpoint) were 77% vs 67% (OR 1.67; p=0.049) with IsaKRd vs KRd; the respective rates of MRD negativity at the 10 -6 cut-off were 67% vs 48% (OR 2.29; p<0.001); consistent MRD results were detected by next-generation flow. ≥VGPR after consolidation was 94% in both arms; ≥CR 74% vs 72% and sCR 64% vs 67% in the IsaKRd vs KRd arms. The MRD negativity advantage, both at 10 -5 and 10 -6, was retained in all subgroups analyzed ( Figure), with similar benefit in pts with standard-risk (SR) and HiR features. In particular, the 10 -5 MRD negativity rates with IsaKRd were 76% in HiR and 77% in double-hit pts, comparable to the one in SR pts (79%). In the KRd arm, the 10 -5 MRD negativity rates were 58% in HiR and 53% in double-hit pts, inferior to the one in SR pts (70%). The 10 -6 MRD negativity rates with IsaKRd were 72% in HiR, 77% in double-hit pts and 67% in SR pts. The MRD negativity rate after induction (first key secondary endpoint) was also significantly higher with IsaKRd vs KRd (10 -5: 45% vs 26%, OR 2.34, p<0.001; 10 -6: 27% vs 14%, OR 2.36, p=0.004), with a consistent benefit in all subgroups. After induction, the MRD negativity rates in HiR and double-hit pts treated with IsaKRd were: 10 -5, HiR 60%, double-hit 54%; 10 -6, HiR 40%, double-hit 31%. The MRD negativity rates after ASCT were also significantly better with IsaKRd vs KRd (10 -5: 64% vs 49%, OR 1.93, p=0.006; 10 -6: 52% vs 27%, OR 3.01, p<0.001), with a consistent advantage in all subgroups. At the current follow-up (median, 20 months, IQR 18-23), there was no difference in PFS (95% at 1 year in both arms). 55% of pts had ≥1 hematologic adverse events (AEs) with IsaKRd vs 43% with KRd; main grade 3-4 hematologic AEs in IsaKRd vs KRd were neutropenia (37% vs 22%) and thrombocytopenia (15% vs 17%). 41% of pts had ≥1 non-hematologic AEs with IsaKRd vs 37% with KRd, including infections (16% vs 12%), gastrointestinal (7% vs 5%), vascular (2% vs 7%) and cardiac events (1% vs 4%). Discontinuation for toxicity was 6% in IsaKRd vs 5% in KRd arms; treatment-related deaths were 4 with IsaKRd (2 COVID, 1 pneumonia, 1 pulmonary embolism) and 1 with KRd (septic shock). Conclusion. In TE NDMM pts, the addition of isatuximab to KRd induction and consolidation significantly increased MRD negativity rates in every treatment phase as compared to KRd, with no new safety concerns. This benefit was retained in HiR pts.

Autologous STEM Cell Collection after Daratumumab, Bortezomib, Thalidomide and Dexamethasone Versus Bortezomib, Thalidomide and Dexamethasone in NEWLY Diagnosed Multiple Myeloma: A Real-Life Monocentric Italian Experience

Introduction In newly diagnosed multiple myeloma (NDMM) patients (pts), induction followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) remains the standard of care. The addition of an anti-CD38 antibody, daratumumab, to an established frontline protocol based on bortezomib, thalidomide and dexamethasone (D-VTd), improves efficacy but could hamper peripheral blood stem cell collection (PBCS). Methods The aim of our study is to evaluate the possible impact of the addition of daratumumab to induction therapy prior to ASCT on PBCS and hospitalization parameters a real-world population with NDMM. We hereby, retrospectively analyzed 28 NDMM pts who received 6 cycles of D-VTd as induction therapy before ASCT and compared them with a consecutive series of 32 VTD-treated NDMM pts who were matched for cytogenetic abnormalities and age, managed at the Hematology Department of Sapienza University in Rome. Results Patient baseline characteristics were equally distributed among both groups, as summarized in Table 1. After induction therapy, a combination of cyclophosphamide (CTX) with granulocyte colony stimulating factor (G-CSF) at standard dose of 10 mg/sqm/day was used as the first mobilizing regimen attempt in both groups. The median time between the last day of induction therapy and the first day of mobilization therapy was 30 days for D-VTd groups and 22 days for VTD groups (p=0.041). Overall, 94% of pts treated with VTd met the desired collection goal after first mobilization therapy, compared to 68% of pts treated with D-VTd (p=0.01). In the VTd arm, 1 pts required a second mobilization attempt, and 1 pts required a further one. In the D-VTd arm, 5 pts required a second mobilization attempt, and 4 pts also required a further one. Overall, 3 pts in the D-VTd arm did not meet the collection goal. In pts with impaired mobilization, plerixafor was used in 4/32 pts in the VTd arm (13%), compared to 29% of pts treated with D-VTd (p=0.195). In the D-VTd arm, 12/28 pts (43%) had received a higher dose of CTX as mobilization therapy (3 g/m 2) compared to the standard dose of 2.4 g/m 2 in 16/28 pts (57%). Nevertheless, no difference was observed in the rate of PBSC collection at the first attempt (p=0.7). No baseline clinical or disease characteristics were observed to have negative impact on the PBSC at first mobilization attempt, including treatment response at the end of induction therapy. Nevertheless, a significantly lower pre-mobilization level of platelet was detected in the group of D-VTd treated pts (173.000/mm 3 vs 210.000/mm 3, p=0.012) that did not meet the desired collection goal after first mobilization therapy. The median PBSC collection was 9.1x10 6 CD34+ cells/Kg in the whole cohort, with no significant difference in the two groups. A lower pre-mobilization level of neutrophils (p=0.028) and platelets (p=0.004) was observed in the D-VTd arm compared to the VTd arm, possibly reflecting prolonged daratumumab-related hematological toxicity. No significant difference was observed in the leucocyte (WBC) azimuth value in the two arms. However, the two groups reached this value on two different days. In the VTd arm the median day was 8, and in the D-VTd arm it was 11 (p=0.034). The use of G-CSF for more days did not result in an increase in CD34+ and the median azimuth value of CD34 was significantly lower in the D-VTd group than in the VTD group (p<0.001). The median collection volume from apheresis devices was significantly higher in the D-VTd group (372 ml) compared to VTd arm (301 ml) (p=0.05), possibly related to a higher WBC azimuth in D-VTd arm, resulting in a prolonged apheresis procedure. Pts receiving D-VTd had slightly delayed hematopoietic neutrophil (11 vs 14 days, p=0.030) and platelet (15 vs 14 days, p=0.018) engraftment, but no requiring a higher number of red cell (p=0.6) and platelet (p=0.3) transfusions and a longer hospitalization (20 vs 17 days, p=0.2) after the first ASCT, compared to pts treated with VTd. No difference in the two groups regarding rate of febrile neutropenia (65% vs 45%, p=0.2) and use of antibiotics (53% vs 57%, p=0.8) were observed. Conclusions In conclusion, frontline induction daratumumab-based therapy is likely to affect PBSC collection after first mobilization attempt, even if not clinically relevant, and potentially mitigated with higher use of plerixafor. Furthermore, the inclusion of daratumumab in pretransplant therapy regimens did not impair ASCT.

Updated Results of a Phase I Open-Label Single-Arm Study of Dual Targeting BCMA and CD19 Fastcar-T Cells (GC012F) As First-Line Therapy for Transplant-Eligible Newly Diagnosed High-Risk Multiple Myeloma

Background High-risk (HR) newly-diagnosed multiple myeloma (NDMM) has poor outcomes with standard first-line therapies, even in transplant-eligible (TE) patients (pts). A CAR-T therapy with high efficacy and manageable safety profile would be a potential solution to this significant unmet need. GC012F is an autologous B cell maturation antigen (BCMA) and CD19 dual-targeting CAR-T cells therapy developed on the novel FasTCAR-T enabling next-day manufacturing platform [J Clin Oncol 41, 2023 (suppl; abstr 8005)]. The phase I single-arm study has been conducted in frontline setting for TE high-risk NDMM pts to characterize the safety and feasibility of GC012F CAR-T cell therapy (NCT04935580). The data was presented at ASH 2022 for initial 13 pts (Blood (2022) 140 (Supplement 1): 889-890.). Here we present updated data with longer follow up and 9 additional pts treated (total N=22) in this study. Methods This is a single arm, open-label phase I investigator-initiated study (NCT04935580). TE NDMM pts, aged between 18-70, and with one or more of the following features were considered eligible for the study: R-ISS-II or-III; del17p, t (4;14), t (14;16), or 1q21amp ≥ 4 copies; extramedullary disease (EM); IgD or IgE subtype; LDH > the upper limit of normal; or any of the high-risk definition of mSMART3.0. As of the data cutoff date, 22 evaluable pts (median age 59, range 43-69) are reported here. The median time from diagnosis to infusion was 100 days (range 63-152). All patients had one or more high-risk features including 91% R-ISS stage II or III, 55% with EM, 32% 1q21≥4 copies, and 9% IgD type. Of the 22 pts, 21 pts received 2 cycles induction therapy of bortezomib, lenalidomide and dexamethasone (VRd), and one patient received 1 cycle bortezomib, epirubicin, and dexamethasone (PAD) and 1 cycle VRd prior to the infusion. GC012F was administered as a single infusion at 3 doses levels (DL) of 1x10 5/kg (n=1), 2x10 5/kg (n=4), or 3x10 5/kg (n=17), after a standard 3-day lymphodepletion consisting of cyclophosphamide and fludarabine . Results As of June 9 th, 2023 data cutoff, 22 patients were enrolled and evaluable for safety and efficacy. Median follow-up was 13.6 months (range 2.1-23.9 months). Overall response rate (ORR) was 100% and stringent complete response (sCR) rate was 95.5%. All treated pts (100%) across all dose levels achieved minimal residual disease (MRD) negativity assessed by Euroflow (sensitivity of 10 -6). All evaluable pts achieved MRD negativity at Month 1, and maintained MRD- at landmark analysis of Month 6 and Month 12. Median duration of response (DOR) and progression-free survival (PFS) were not reached. Only 6 pts (27%) experience low-grade cytokine release syndrome (CRS), including 23% grade 1 (n=5) and 4% grade 2 (n=1). No treatment-related grade ≥3 CRS, nor ICANS of any grade, and nor deaths occurred in the study. Robust CAR T-cell expansion was observed in all pts; the median peak expansion (Cmax) was 62,131 (range: 8,754-331,159) copies /μg DNA with a median Tmax of 10 days (range 9-14 d). Conclusion Consistent with the previous RRMM cohort treated with GC012F, initial data from this phase I study demonstrated that BCMA-CD19 dual-targeting FasTCAR-T GC012F resulted in deep and durable response in transplant-eligible newly-diagnosed high-risk pts with a very favorable safety profile. All three dose groups achieved 100% MRD negativity and 100% ORR and sCR. The promising preliminary results achieved with GC012F demonstrate potential of CAR-T therapy in newly-diagnosed MM pts. Further research with larger patient population and longer follow-up shall bring the hope to this unmet medical need.

Real-World Outcomes of Newly Diagnosed Multiple Myeloma (NDMM) Patients Treated before the Anti-CD38 Antibodies Era in France, the Emmy Cohort 2017 to 2020

Background In randomized clinical trials (RCTs), patients (pts) with comorbidities or a very aggressive presentation of myeloma may be excluded. The results of RCTs may not be generalizable to pts in the real-world setting. Therefore, RCT data need to be backed up by results from real-world studies. Methods EMMY is a non-interventional, prospective study conducted in 73 IFM (Intergroupe Francophone du Myélome) sponsor sites in France. Any patient initiating treatment for multiple myeloma (MM) over a 3-month (mo) period, from October to December, is included, since 2017. It is a dynamic cohort with 900 pts on average, enrolled each year. Here, we present the results of NDMM pts for the first 4 years of inclusion (2017 to 2020). Pts with NDMM who receive front-line therapy with an autologous stem cell transplant (ASCT group) are described separately from non-transplant eligible pts (NTE group). Results 1597 pts with NDMM were included in EMMY over the 2017-2020 period. Of these, 1036 were in the NTE group (64.9%) and 561 in the ASCT group (35.1%). Data are presented with a median follow-up of 23.7 mo (IQR 12.3 - 39.0). ASCT group These pts had a median age of 60.6 years (range 23.4 - 78.5). 5.2 % were older than 70 years at ASCT. In routine practice, cytogenetic tests were carried out for 75.7% of pts, 19.6% of them harboured high-risk (HR) anomalies of t(4;14) or del(17p). The period 2017-2020 was marked by a shift in induction treatment from Velcade Thalidomide dexamethasone (VTd) (n = 163, 29.1% of pts who received ASCT) to Velcade Revlimid dexamethasone (VRd) (n = 309, 55.1%). Fifty-three (9.5%) pts received a double transplantation which was stable over time. 22.8 % of pts with HR anomalies received a double transplant. NTE group The 1036 NTE pts had a median age of 74.9 years (range 33.8 - 97.8), and more than 30.4% (n = 315) were aged ≥ 80 years. Among these pts, 65.9% were considered frail, with 33.6% having an Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≥ 2 and almost half (47.1%) had comorbidities. Significant renal impairment (glomerular filtration rate [GFR] < 30 mL/min) was observed in 118 (13%) pts at treatment initiation. A subgroup of 126 younger pts (age < 65 years) was considered ineligible for transplantation. Regarding cytogenetics 56.4% of the pts were tested in regular practice (mean age 73.3 years). NTE pts mostly received three main combinations: VRd (28.4% of pts, n = 294), Velcade Melphalan prednisone (VMp) (21.9% of pts, n = 21.9%) and Revlimid dexamethansone (Rd) (21.1%, n = 219). During the study period, VMp use decreased from 36.9% to 6.5% of pts, VRd use increased from 10.6% to 48.5% and Rd use remained constant, at around 20%. Other bortezomib-based regimens, including Velcade dexamethasone (Vd) and Velcade Cyclophosphamide dexamethasone (VCd), were used steadily, in approximately 12% and 7% of pts, respectively, over the period. Survival data Median progression-free survival (mPFS) was 25.8 mo (95% CI: 23.5-29.1) in the overall NDMM population, 46.5 mo (95% CI: 37.8-50.6) in pts who received ASCT and 18.7 mo (95% CI: 16.3-20.8) in NTE pts ( P < 0.0001). (Figure 1). The median PFS2 (mPFS2) was estimated at 50.6 mo (95% CI: 47.6-NA) in all pts with NDMM. mPFS2 was 36.4 mo (95% CI: 34.7-39.9) in NTE pts; it was not reached in the ASCT group. The median overall survival (OS) had not yet been reached. The estimated OS rate was 72.9% (95% CI: 69.8-75.9) at 48 mo for the total NDMM population. (Figure 2). AE leading to discontinuation. 139 pts experienced an adverse event (AE) leading to treatment discontinuation (6.8 % of ASCT pts and 14.5% in the NTE group). This occurred at a median of 4.3 mo after treatment initiation and was mainly reported with the most used agents (lenalidomide, bortezomib or melphalan). The most frequently reported AEs were neuropathy (n = 14; 10.1%), digestive disorders (n = 13; 9.4%), rash (n = 12; 8.6%), deterioration of general condition (n = 12; 8.6%), cardiovascular AEs (n = 10; 7.2%) and acute renal failure (n = 10; 7.2%). Conclusion The 2017-2020 period for pts with NDMM in France was marked by the expansion of the use of lenalidomide in first line for the majority of pts. A major difference in PFS and OS is still observed between ASCT and NTE pts. A shorter PFS than in IFM2009 trial (PFS 50 mo) was observed in EMMY ASCT pts.

In-Class Transition ( iCT) from Parenteral Bortezomib (V) to Oral Ixazomib Therapy in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) in the Community-Based US MM-6 Study: Subanalysis of Randomized Controlled Trial (RCT)-Ineligible and RCT-Eligible Pts

Introduction Up to 72% of real-world multiple myeloma (MM) pts are considered ineligible for RCTs due to criteria such as old age, frailty, and comorbidities, limiting the generalizability of findings to the wider MM population. The US MM-6 study (NCT03173092) aimed to increase the duration of proteasome inhibitor (PI)-based therapy and improve outcomes with a tolerable safety profile in a patient (pt) cohort representative of that in routine clinical practice. Results for the fully accrued dataset have been reported previously (N=141; Yimer IMS 2022). Here we report the results of a US MM-6 subanalysis describing pt characteristics and key efficacy and safety outcomes of two groups: RCT-ineligible (RCT-i) and RCT-eligible (RCT-e). Methods Transplant-ineligible/delayed-transplant (≥24 months) NDMM pts with ≥stable disease after 3 cycles of parenteral V-based induction were enrolled at US community sites to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd) for up to 39 cycles or until progression or toxicity (Manda CLML 2020). Pts were grouped based on whether any baseline characteristic met common RCT ineligibility criteria including but not limited to hematologic/organ dysfunction, ECOG PS >2, renal dysfunction, prior malignancies, cardiac dysfunction, and pulmonary disease. Two-year progression-free survival (PFS; primary endpoint), overall survival (OS), overall response rate (ORR), and safety were analyzed by RCT group. Results At final data cut-off (Oct 17, 2022) 140 pts were evaluable; 57 (40.7%) met ≥1 RCT ineligibility criteria and were included in the RCT-i group; 83 (59.3%) were included in the RCT-e group. The most common ineligibility criteria in the RCT-i group were cardiac arrhythmias (14.3%), chronic pulmonary disease (8.6%), and prior malignancy (7.9%) (Table). At enrollment, in the RCT-i vs RCT-e groups, median age was 73 years (range 48-90) vs 72 years (range 49-86), 54.4% vs 60.2% were male, 77.2% vs 69.9% were white. In RCT-i vs RCT-e, 24.6% vs 27.7%, 40.4% vs 42.2%, and 33.3% vs 30.1% had ISS stage I, II, and III, respectively. A total of 98.2% vs 90.4% of pts in the RCT-i vs RCT-e group had any comorbidity; 15.8% vs 10.8% had peripheral neuropathy (PN) as a comorbidity. At data cut-off, 84.2% of pts in the RCT-i group had discontinued treatment, commonly (>20% of pts) due to progressive disease (27.1%), adverse events (25.0%), and pt withdrawal (20.8%). In the RCT-e group, 75.9% had discontinued treatment, commonly due to pt withdrawal (25.4%) and adverse events (23.8%). In both RCT-i and RCT-e groups, pts received a median of 11 (range 1-39) IRd and ixazomib cycles; median duration of PI therapy was 13.6 months. After a median follow-up of 29.2 vs 24.6 months for RCT-i vs RCT-e groups, 2-year PFS rates were 68% (95% confidence interval [CI] 52-80) vs 73% (95% CI 60-82); 2-year OS rates were 90% (95% CI 78-96) vs 84% (95% CI 72-91). ORR increased from 61.4% vs 66.3% at the end of V-based induction to 80.7% vs 79.5% after iCT for RCT-i vs RCT-e groups. For the respective RCT-i and RCT-e groups, treatment-emergent adverse events (TEAEs) were observed in 98.2% and 97.6% of pts (treatment-related: 82.5% and 81.9%), and serious TEAEs in 43.9% and 44.6% (treatment-related: 12.3% and 13.3%) of pts; on-study deaths occurred in 3 pts and 1 pt. The most common any-grade TEAEs (>30% of pts in either arm) were diarrhea (RCT-i: 49.1%; RCT-e: 51.8%), fatigue (RCT-i: 38.6%; RCT-e: 30.1%), and PN (RCT-i: 31.6%; RCT-e: 25.3%). In the RCT-i and RCT-e groups, respectively, grade ≥3 TEAEs were observed in 73.7% and 65.1% of pts. The most common grade ≥3 TEAEs in RCT-i pts were pneumonia (8.8%), cellulitis, neutropenia, and hypokalemia (all 7.0%). Among RCT-e pts the most common grade ≥3 TEAEs were diarrhea (12.0%), pneumonia, anemia, and fatigue (all 4.8%). TEAEs led to dose modification/discontinuation of any of the three study drugs in the IRd regimen in 68.4%/21.1% of RCT-i pts and 65.1%/19.3% of RCT-e pts. Conclusions This subanalysis demonstrates the feasibility of utilizing iCT to obtain similar outcomes to RCTs in the community. Although 41% of US MM-6 pts would have been ineligible for RCTs, there were no notable differences in PFS, ORR, OS, and safety data between the two groups. These data show that iCT from V-based induction to IRd permits long-term, tolerable PI-based therapy translating into improved efficacy in community-treated pts with NDMM who are more representative of the wider MM population.

Real-world analysis of D-RVd v. RVd at induction for newly diagnosed transplant eligible multiple myeloma patients.

e20024 Background: Daratumumab with lenalidomide, bortezomib, and dexamethasone (D-RVd) induction chemotherapy (IC) has recently been shown to improve depth of treatment response for transplant-eligible newly diagnosed multiple myeloma (NDMM) patients (pts) compared to RVd alone. The aim of this real-world data (RWD) retrospective study is to assess the efficacy and depth of response of D-RVd IC compared to RVd in transplant-eligible pts with NDMM. Methods: HealthTree Cure Hub for Multiple Myeloma (PMID: 35271305) an online portal for pts with plasma cell dyscrasias, was used to analyze validated RWD of 59 pts who received D-RVd to 121 pts with similar clinical characteristics but who received RVd at IC. Of the total 180 pts, 84 had completed IC and were at the initiation of maintenance (MT) at the time of this analysis. Patients that progressed prior to reaching MT or whose treatment deviated from the line of therapy (D-RVd/RVd IC, autologous stem cell transplant [ASCT], and MT, with or without consolidation) were also excluded. Response during MT was assessed using IMWG criteria. Results: From the 180 pts reviewed, 98 were excluded, 5 D-RVd and 10 RVD pts progressed before reaching MT, 11 D-RVd and 31 RVd pts deviated from the line of therapy, and 41 pts had not reached the MT phase at the time of the analysis. The remaining 84 pts (18 D-RVd pts and 64 RVd pts) were analyzed. Demographics and clinical characteristics were well-balanced between groups. The median age of both groups was 65 (range, 42-81), and over half were female (51%). The majority of pts (87%) had R-ISS stage I or II, and 45 pts (25%) had high-risk genetics (by mSMART 3.0). The overall response rate (ORR) was significantly higher for the D-RVd group compared to the RVd group at the initiation of MT (100% vs 62%; odds ratio, 22.4; P = 0.03). As assessed prior to the start of MT the depth of response was more favorable with D-RVd, with the odds ratio of achieving a VGPR or better at MT being significantly higher than RVd (89% to 58%; odds ratio (OR), 5.8; P = 0.03), complete response (CR) (78% to 47%; OR, 3.97; P = 0.03), stringent CR (sCR) (22% to 16%; OR, 1.5; P = 0.51), and minimal residual disease (MRD) negativity (17% to 11%; OR, 1.6; P = 0.51). With a median follow-up of 17 months for the D-RVd group (n = 18) and 29 months for the RVd group (n = 64), 0 events of disease progression occurred in the D-RVd group compared to 23 events in the RVd group. Median PFS was not reached in the D-RVd group and a Kaplan-Meier probability indicated a median PFS of 41 months for the RVd group. Conclusions: These data document improved response rate in transplant-eligible NDMM pts who received daratumumab with RVd as an IC therapy. D-RVd also improved PFS with significant differences between the two groups seen at 12 and 18 months. These results add to the accumulating data that the addition of daratumumab with RVd may be the new standard of care for the aforementioned patient population.

Global Treatment Standard in Multiple Myeloma Remains Elusive: Updated Results from the INSIGHT MM Global, Prospective, Observational Study

Introduction INSIGHT MM (NCT02761187) is the largest global, prospective, observational multiple myeloma (MM) study to date, with 4188 newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM) patients (pts) included in this cross-sectional analysis. The study aims to describe contemporary, real-world patterns of pt & disease characteristics, treatment patterns, & outcomes. An interim analysis of the first 1000 pts enrolled to INSIGHT MM suggested considerable regional variation in treatment patterns (Boccadoro et al, EHA 2018). The aim of the current analysis is to characterize treatment patterns by world regions & line of therapy (LOT) in the overall INSIGHT MM study population. Methods Pts were enrolled at academic & community treatment facilities in 15 countries between July 2016 & July 2021. Data on prior & current treatments were collected at baseline & every 3 months. Full study methods have been reported previously (Costello 2019). We report a cross-sectional analysis of treatment regimens used in NDMM & RRMM pts at a data cut-off of Sept 30, 2021. A subset of pts with no protocol deviations (pts meeting all inclusion criteria who started index regimen <90 days before enrollment & enrolled at centers where data quality checks could be conducted) were included in an analysis of treatment shift patterns from first to second & subsequent LOTs. Results Among the 4188 pts, there were 2338 (55.8%) NDMM & 1850 (44.2%) RRMM cases at enrollment. This includes 2046 pts from Europe (EUR; Belgium, France, Germany, Greece, Italy, Spain, Turkey, United Kingdom; also includes Israel); 1317 pts from the United States (US); 470 pts from Latin America (LA; Brazil, Columbia, Mexico); & 355 pts from Asia (China, Taiwan). Median follow-up was 27.9 months. In NDMM pts, triplet therapy was the most common frontline approach across all regions (71.1% of pts overall); only 12.0% of pts received frontline doublet therapy. Triplet therapy typically included a proteasome inhibitor (PI) & dexamethasone (d; 62.5%). The most commonly used regimen was bortezomib (V), lenalidomide (R), & d (VRd; 23.5%); V-based triplet therapy with d & an IMiD was prescribed to 34.7% of NDMM pts overall. V-based triplets were the most widely used regimens across all regions. The US was the only region where carfilzomib (K) was included in one of the three most frequently used regimens (KRd in 8.3% of pts). Choice of IMiD varied regionally: R was most commonly used in the US, & thalidomide in EUR, LA, & Asia. In EUR & LA, cyclophosphamide (alkylating agent) was more commonly used than IMiDs. Vd (4.1%) & Rd (4.0%) doublets were the fourth & fifth most common regimens overall. Among RRMM pts, 49.6% received triplets & 33.7% received doublets. Triplet therapy was the most common approach across all LOTs & all regions except Asia; in Asia, doublets were more widely used than triplets (48.9% vs 42.4%). Rd was the most common regimen overall (15.4% across all regions & LOTs), & ixazomib-Rd (IRd) was the most common triplet (7.9% in all regions & LOTs; KRd was the second most common triplet overall [5.2%]). Unlike NDMM pts, RRMM pts were more likely to receive alternative PIs to V in ≥2nd LOT (IRd 6.8%; KRd 6.7%; VRd 2.7%), & daratumumab (D) was used instead of or alongside PIs in some triplets (DRd 4.9%; VDd 4.5%). Overall, 20.8% of pts received D as part of single-agent, doublet, triplet, or >triplet therapy. D was more widely used in the US (33.5%) than other regions (14.4-16.2%). Treatment shift patterns were examined in 3263 pts for whom robust data were available (1236 who underwent stem cell transplantation [SCT] in first line of therapy & 2027 who did not [NSCT]). A shift from predominantly PI- or PI/IMiD-based frontline therapy in both SCT & NSCT pts to more varied second-line regimens, including monoclonal antibody (mAb) therapy, was observed (Figure). Treatment shift patterns in later LOTs & across regions will be presented. Conclusions V-based triplets were the most common frontline treatment in NDMM pts in all regions. Regimens used in later LOTs in RRMM pts were more varied across regions, & generally included greater use of doublets, PIs other than V, & mAbs such as D. Acknowledging that treatment use is dependent on approval status & availability, this analysis shows that, while global frontline standard of care (SOC) is broadly established, there remains no consistent SOC in later LOTs; adoption of newer therapies, such as mAbs, varies across regions worldwide. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune Biomarkers of Survival and Severe Infection in Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) Treated with the Backbone Regimen Lenalidomide and Dexamethasone (Rd)

Introduction: Rd is a backbone of treatment in MM. The strong immunomodulatory effects of this regimen would suggest that immune profiling might complement conventional prognostic factors. However, immune signatures predictive of survival were not well defined in the past, and nowadays it is challenging to detach the effect of Rd from other backbone drugs in triplets or quadruplets, as well from high dose therapy in transplant eligible patients. Aim: Identify immune biomarkers in elderly NDMM pts treated with Rd. Methods: The GEM-CLARIDEX trial randomized transplant ineligible NDMM pts to Rd +/- clarithromycin until disease progression. Because clarithromycin had no effect in survival, the trial design yielded a unique opportunity to identify immune biomarkers in elderly MM pts treated with Rd. Immune profiling was performed in bone marrow (BM) at baseline in 186 pts, using multidimensional and computational flow cytometry together with lasso penalized Cox regression and 10-fold cross validation, for a holistic and unbiased definition of prognostic immune signatures. 38 cell populations were identified, including seven myeloid/erythroid and 29 lymphoid subsets plus normal and clonal plasma cells (PC). Single cell RNA sequencing (scRNAseq, 10x Genomics) was performed on BM immune cells sorted from healthy adults, MGUS, smoldering and active MM pts (n = 17). Results: An immune signature associated with inferior survival was defined based on increased frequency of cytotoxic CD314+ NK and CD4+ central memory (CM) CD127+ PD1+ T cells, and decreased percentages of CD4+ CM CD127+ PD1- and CD8+ CD127low PD1+ terminally differentiated T cells, as well as of B cell precursors. Median progression-free survival (PFS) of NDMM pts with high risk immune score (106/186 [57%]) was 18 months vs not reached in those with low risk (80/186 [43%]) (p=.0008, Fig 1A). The respective median overall survival (OS) rates at three years were 50% and 80% (p = .0021, Fig 1B). In multivariate analyses including age, ISS, LDH and cytogenetic risk, immune profiling showed independent prognostic value for PFS (HR: 2.6, p = .001) and OS (HR: 2.9, p = .003). Increased frequency of cytotoxic CD314+ NK cells was the immune biomarker with the highest negative impact in the survival predictive model. In an attempt to better understand this finding, we analyzed scRNAseq data of 61,637 NK cells from normal and tumor BM. Up to 47 NK-cell clusters were identified, and the one showing the highest expression of CD314 also displayed upregulation of granzymes K, H and B, perforin, CD16, CD38, CD69 and IFNγ, and therefore appeared to be associated with cytolytic activity and inflammation. Interestingly, there was a progressive expansion of this cluster within the NK cell compartment of normal vs pre-malignant vs neoplastic BM samples. Similarly, in genetically engineered BIcγ1 mice that develop active MM preceded by precursor states, there was a progressive expansion of CD314+ NK cells in normal vs benign vs malignant BM (p = .001). Being infection an important cause of morbidity and mortality in elderly MM pts as those included in this study, we next investigated if immune profiling at diagnosis could help predicting severe infection (≥ grade 3 CTCAE v4.0, n=43/186). The combination of five clinical features - age ≥ 75y, low hemoglobin and albumin, high β2m and LDH - plus seven immune biomarkers - increased percentages of eosinophils, together with decreased frequencies of CD4+ CM CD127+ PD1-, CD8+ naïve and CD127low PD1+ and PD1- terminally differentiated T cells, B cell precursors and normal PC - resulted in the most effective model to predict severe infection. B cell precursors and eosinophils, which are easily identified using flow cytometry at diagnosis, showed the strongest association. The area under the curve (AUC) of the model was 0.90 with a 4-fold cross validation showing a mean AUC = 0.86 ± 0.06. Conclusions: This study shows the clinical value of immune profiling at diagnosis and defined immune cell types, including a previously unidentified subset of CD314+ cytotoxic NK cells, which were predictive of survival in transplant ineligible NDMM pts treated with the backbone regimen Rd. Furthermore, this study uncovered immune biomarkers complementary to clinical features for predicting severe infection in elderly MM pts, which could be used to intensify prophylactic measures in specific subgroups that are more susceptible to severe infection. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bortezomib-Melphalan-Prednisone (VMP) Vs. Lenalidomide-Dexamethasone (Rd) in Transplant-Ineligible Real-Life Multiple Myeloma Patients: Updated Results of the Randomized Phase IV Real MM Trial

BACKGROUND. Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) have represented standards of care for transplant-ineligible (NTE) newly diagnosed multiple myeloma (NDMM) patients (pts) until the recent introduction of daratumumab (Dara) in the frontline setting. However, no prospective randomized trial has directly compared VMP with Rd. Moreover, real-life older NTE pts are underrepresented in clinical trials, and only few data on safety and efficacy in this population are available. AIMS. We conducted a randomized multicenter phase IV trial (NCT03829371; funded by the Italian Medicine Agency AIFA - Independent Research) to compare safety and efficacy of the two standard regimens, VMP vs Rd, in an unselected real-life population of NTE NDMM pts. METHODS. NDMM pts ineligible for transplant due to age ≥65 years or comorbidities were randomized 1:1 to: 9 VMP cycles (42-day cycles, V: 1.3 mg/m2, days (dd) 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1-4 and dd 1, 8, 22, and 29, cycles 5-9; M: 9 mg/m2, dd 1-4; P: 60 mg/m2, dd 1-4) vs continuous Rd (28-day cycles, R: 25 mg, dd 1-21; d: 40 mg, dd 1, 8, 15, and 22) according to standard practice. Pts gave written informed consent and were enrolled regardless of performance status, comorbidities, renal function, or baseline laboratory values. Pts were stratified according to the International Myeloma Working Group (IMWG) frailty score and cytogenetic risk by fluorescence in situ hybridization [high risk if positive for 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 response rates, overall survival (OS), and safety. RESULTS. At the data cut-off (July 4, 2022), 231 pts were randomly allocated to receive VMP (n=114) or Rd (n=117). Baseline characteristics were evenly balanced between the two arms: median age was 77 (IQR 73-80) and 76 years (IQR 73-79); 49% vs 50% of pts were frail; 17% vs 19% pts had high-risk cytogenetics, respectively. After a median follow-up of 19 months, the median PFS in the ITT population was 29.6 vs 26.2 months with VMP vs Rd (hazard ratio [HR] 0.82, 95% CI 0.51-1.31, P=0.41; Figure - panel A). However, the HR was not constant over time: from 0.65 (95% CI 0.36-1.19, P=0.16) during the first year of treatment (suggesting a slight benefit of VMP vs Rd) to 1.37 (95% CI 0.65-2.86, P=0.40) after the first year of treatment (suggesting a slight benefit of continuous Rd therapy). The subgroup analysis according to cytogenetic risk showed a significant effect modification of the comparison VMP vs Rd in terms of PFS, with an HR=0.21 (95% CI 0.04-0.99) in the high-risk group vs an HR=1.24 (95% CI 0.70-2.18) in the standard-risk group (interaction P=0.036). No significant effect modification was observed in terms of age or frailty status. In the ITT population, the 2-year OS was 89% with VMP vs 75% with Rd (HR 0.53, 95% CI 0.26-1.07, P=0.08; Figure - panel B). No safety concerns were reported. The most frequent grade (G)3-4 adverse events (AEs) with VMP were thrombocytopenia (15%) and neuropathy (7%), while neutropenia (23%), infections (12%), and dermatologic toxicities (9%) were the most frequent G3-4 AEs observed in the Rd arm. Sixty-six percent of pts in the VMP and 59% in the Rd arms had ≥1 dose reductions of any drug, including 35% of pts in the VMP arm switching to once-weekly V before cycle 5. CONCLUSION. We confirmed the efficacy of VMP and Rd in an older real-life population of NTE NDMM pts including ~50% of frail pts. VMP and Rd were equally effective in standard-risk pts and in all frailty subgroups in terms of PFS. However, high-risk pts benefited more from VMP (HR 0.21), suggesting that the doublet Rd is suboptimal in this subgroup. Safety data were consistent with those previously reported. Of note, only one third of real-life pts were able to receive full-dose VMP or Rd therapy according to their schedule. Despite the limited follow-up, the difference in terms of OS between the two arms may be explained by the poor outcomes of patients failing lenalidomide-based treatments. Importantly, following a recent amendment, as of July 2022, enrolled pts will be randomized to Dara-VMP vs Dara-Rd. Decision-making and treatment selection will be further supported by a future analysis of this addition of Dara, based on patient and disease characteristics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase I Open-Label Single-Arm Study of BCMA/CD19 Dual-Targeting FasTCAR-T Cells (GC012F) As First-Line Therapy for Transplant-Eligible Newly Diagnosed High-Risk Multiple Myeloma

Background High-risk (HR) newly diagnosed multiple myeloma (NDMM) has poor outcomes with standard first-line therapy, even in transplant-eligible (TE) patients (pts). A CAR-T therapy with high efficacy and manageable safety profile would be a potential solution to this significant unmet need. In a phase 1 multicenter single-arm study GC012F, an autologous B cell maturation antigen (BCMA) and CD19 dual-targeting CAR-T cells therapy developed on the novel FasTCAR-T enabling next-day manufacturing platform [J Clin Oncol 40, 2022 (suppl; abstr 8005) and HemaSphere, 2022;6:(S3):180], showed deep and durable responses with a favorable safety profile in heavily pretreated pts with relapsed or refractory multiple myeloma (RRMM). Based on these promising results, we assessed the safety and feasibility of GC012F CAR-T cell therapy in frontline setting for TE high-risk NDMM pts in a single arm, open-label phase 1 investigator-initiated study (NCT04935580). Methods TE high-risk NDMM pts were considered eligible for the study if they had one or more of the following features: R-ISS-2 or-3; del17p, t (4;14), t (14;16), or 1q21amp ≥ 4 copies; extramedullary disease (EM); IgD or IgE subtype; LDH > the upper limit of normal; or any of the high-risk definition of mSMART3.0. Results of the first 13 pts (median age 59, range 43-65) who received GC012F infusion are reported here, of which the median time from diagnosis to infusion was 4.5 (range 3.2-5.4) months. 100% of the patients had one or more high-risk features including 92.3% R-ISS stage II or III, 69.2% with EM, 33.3% 1q21≥4 copies, and 15.4% IgD type. Twelve pts received 2 cycles induction therapy of bortezomib, lenalidomide and dexamethasone (VRd), and one patient received 1 cycle bortezomib, epirubicin, and dexamethasone (PAD) and 1 cycle VRd prior to the infusion. GC012F was administered as a single infusion at 3 doses levels (DL) of 1x105/kg, 2x105/kg, or 3x105/kg, after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine.Results As of July 25th 2022 data cutoff (the median follow-up 5.3 months, range 2.3-12.5 months), efficacy-evaluable pts (n= 13) was met, with 100% overall response rate (ORR) [95% confidence interval (CI), 72-100)]; 100% of pts (95% CI, 72-100) achieved very good partial response (VGPR) or better, with 69% (95% CI, 39-90) stringent complete response (sCR, Figure 1). 100% (4/4) of pts in DL 2 and 50% (4/8) of pts in DL3 achieved MRD negative-sCR after infusion, which might be the patients in DL2 group carried fewer HR factors than patients in DL3 group. All pts (100%) achieved minimal residual disease (MRD) negativity. There was no difference observed in dose levels. MRD assessment with Euroflow for landmark analysis at 1 month 1 and month 6 post infusion, 100% of evaluable pts were MRD negative at both timepoints. Cytokine release syndrome (CRS) occurred only in three pts (23%) with 15% grade 1 (n=2) and 8% grade 2 (n=1), respectively. There was no treatment-related grade ≥3 CRS and ICANS events. Robust CAR T-cell expansion occurred in all pts with a median time to Tmax of 10 days (range 9-14 d), and peak copy number (Cmax) of 63086 (20097-331159) copies /μg DNA. Conclusion In this phase I study for transplant-eligible newly diagnosed high-risk MM, BCMA-CD19 dual FasTCAR-T GC012F showed a very favorable safety profile, high efficacy with 100% ORR and 100% MRD negativity. The promising preliminary results warrants further assessment of GC012F for TE NDMM with more patients and longer follow-up. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Humoral Immune Reconstitution Following Therapy with Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd), Autologous Hematopoietic Cell Transplantation (AHCT) and MRD-Response-Adapted Treatment Cessation

Introduction Quadruplet induction, AHCT, and measurable residual disease (MRD) response-adapted consolidation yields unprecedented depth of response in newly diagnosed multiple myeloma (NDMM). Immune reconstitution (IR) in patients (pts) receiving limited duration intensive therapy has not been well described. Methods NDMM pts treated on MASTER (NCT03224507) received induction with daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd; 4 cycles), followed by AHCT and 0, 4 or 8 cycles of Dara-KRd consolidation guided by serial assessments of bone marrow MRD by next-generation sequencing (NGS, ClonoSEQ®). Pts with two consecutive MRD <10-5 ceased therapy and entered active surveillance for MRD resurgence (MRD-SURE). The primary objective of this study is to evaluate humoral IR of MRD-SURE pts by characterizing quantitative changes in the repertoire of immunoglobulin (Ig) genes (IgH, IgK and IgL) by NGS and serum gamma globulin levels. Results After induction, the IgH repertoire was small and lacked diversity (median unique sequences (mus) 11,330/106, IQR 5,711-23,143). Of 63 evaluable pts who received AHCT and >=4 cycles of consolidation, a substantial expansion of the IgH repertoire was seen 90 days after AHCT (75,375 mus/106, IQR 49,361-113,305, P< 0.001) with a contraction after consolidation (15,795 mus/106, IQR 5,571-33,732, P< 0.001). Pts who received post-AHCT consolidation (N=27) had a smaller IgH repertoire at MRD-SURE entry compared to pts entering MRD-SURE after AHCT (N=28) (15,082 v 76,266 mus/106, p< 0.001), with near but incomplete recovery after 6 months (mo) of treatment cessation (83,954 v 107,715 mus/106, p=0.037) and no difference at 18 mo (109,989 v 115,246 mus/106, P=0.72) (Figure 1). Similar findings were seen for IgK and IgL. The serum protein gamma fraction was depressed (median 0.3 g/dL, IQR 0.23-0.41) in pts entering MRD-SURE post-AHCT, but rose off therapy reaching plateau after 12 months. Gamma globulin recovery was delayed in patients receiving consolidation (Figure 2). Risk of grade≥3 infection while on Dara-KRd was 3.8/100*patient*month during induction, and 2.2/100*patient*month during post-AHCT consolidation (overall 2.9/100*patient*month). Risk of grade≥3 infection reduced substantially to 0.22/100*patient*month during the first 6 months and 0.12/100*patient*month during subsequent 12 months of MRD-SURE (overall 0.15/100*patient*month). Conclusions Quadruplet, anti-CD38 mAb-containing therapy leads to profound hypogammaglobulinemia and reduction in the Ig gene repertoire. Pts who received post-AHCT consolidation had delayed IR as compared to those who did not, however the Ig repertoire steadily recovered, with no statistically significant difference 18 mo after treatment cessation. Grade ≥3 infection risk is very low after treatment cessation, as the Ig gene repertoire expands prior to recovery of immunoglobulin levels. Further evaluation of IR after MRD-adapted therapy is warranted as new immunotherapeutic agents are incorporated in therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal