Transplant-eligible Patients Research Articles

Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study

AbstractDuring the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

Clinical Outcomes and Evolution of Clonal Hematopoiesis in Patients with Newly Diagnosed Multiple Myeloma.

Using our algorithm to differentiate tumor and germline mutations from CH mutations, we detected CH in approximately 10% of patients with newly diagnosed myeloma, including both transplant eligible and ineligible patients. Receiving IMiDs improved outcomes irrespective of CH status, but the prevalence of CH significantly rose throughout myeloma-directed therapy.

Clinical impacts of severe thrombocytopenia in the first cycle of azacitidine monotherapy and cytogenetics in patients with myelodysplastic syndrome: The Kyoto Conditional Survival Scoring System.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma

BackgroundDaratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed.MethodsIn this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)–negative status.ResultsAt a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P=0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group.ConclusionsThe addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.)

Predictors of unsustained measurable residual disease negativity in transplant-eligible patients with multiple myeloma

AbstractThe role of measurable residual disease (MRD) negativity as a biomarker to stop treatment is being investigated in transplant-eligible patients with multiple myeloma (MM). Thus, it is important to identify risk factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them. Here, we studied 267 newly diagnosed transplant-eligible patients with MM enrolled in the GEM2012MENOS65 and GEM2014MAIN clinical trials who achieved MRD negativity by next-generation flow cytometry. After a median follow-up of 73 months since the first MRD negative assessment, 111 of the 267 (42%) patients showed MRD resurgence and/or PD. The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International Staging System (ISS) 3 and the presence of ≥0.01% circulating tumor cells (CTCs). Failure to achieve MRD negativity after induction also predicted higher risk of MRD resurgence and/or PD. Patients having 0 vs 1 vs ≥2 risk factors (ISS 3, ≥0.01% CTCs, and late MRD negativity) showed 5-year rates of MRD resurgence and/or PD of 16%, 33%, and 57%, respectively (P < .001). Thus, these easily measurable risk factors could help refine the selection of patients for whom treatment cessation after MRD negativity is being investigated in clinical trials. This trial was registered at www.clinicaltrials.gov as NCT01916252 and NCT02406144.

Predictors of early morbidity and mortality in newly diagnosed multiple myeloma: data from five randomized, controlled, phase III trials in 3700 patients

Early morbidity and mortality affect patient outcomes in multiple myeloma. Thus, we dissected the incidence and causes of morbidity/mortality during induction therapy (IT) for newly diagnosed multiple myeloma (NDMM), and developed/validated a predictive risk score. We evaluated 3700 transplant-eligible NDMM patients treated in 2005–2020 with novel agent-based triplet/quadruplet IT. Primary endpoints were severe infections, death, or a combination of both. Patients were divided in a training (n = 1333) and three validation cohorts (n = 2367). During IT, 11.8%, 1.8%, and 12.5% of patients in the training cohort experienced severe infections, death, or both, respectively. Four major, baseline risk factors for severe infection/death were identified: low platelet count (<150/nL), ISS III, higher WHO performance status (>1), and age (>60 years). A risk score (1 risk factor=1 point) stratified patients in low (39.5%; 0 points), intermediate (41.9%; 1 point), and high (18.6%; ≥2 points) risk. The risk for severe infection/death increased from 7.7% vs. 11.5% vs. 23.3% in the low- vs. intermediate- vs. high-risk groups (p < 0.001). The risk score was independently validated in three trials incorporating quadruplet IT with an anti-CD38 antibody. Our analyses established a robust and easy-to-use score to identify NDMM patients at risk of severe infection/death, covering the latest quadruplet induction therapies. Trial registrations: HOVON-65/GMMG-HD4: EudraCT No. 2004-000944-26. GMMG-MM5: EudraCT No. 2010-019173-16. GMMG-HD6: NCT02495922. EMN02/HOVON-95: NCT01208766. GMMG-HD7: NCT03617731.

Upfront or Deferred Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Triplet and Quadruplet Induction and Minimal Residual Disease/Risk-Adapted Therapy.

The standards of care for the initial treatment of patients with newly diagnosed multiple myeloma (NDMM) who are eligible for high-dose melphalan and autologous stem cell transplantation (HDM-ASCT) include highly active triplet and quadruplet regimens based on proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. These regimens are resulting in improved outcomes and increasingly high rates of minimal residual disease (MRD)-negative responses without HDM-ASCT as part of the upfront therapy. Furthermore, recent randomized studies have shown that, while transplant-based approaches as a frontline therapy result in significantly longer progression-free survival compared to non-transplant approaches, this has not translated into an overall survival benefit. Given these developments, and in the context of the treatment burden of undergoing HDM-ASCT, in addition to the acute toxicities and long-term sequelae of HDM, which are associated with the genotoxicity of melphalan, there is an increasing rationale for considering deferring upfront HDM-ASCT in select transplant-eligible patients and saving it as a treatment option for later salvage therapy. Here, we review the latest clinical trial data on upfront or deferred HDM-ASCT and on the activity of quadruplet induction regimens, including rates of MRD-negative responses, and summarize emerging treatment approaches in the upfront setting such as the use of MRD-directed therapy and alternatives to HDM-ASCT.

Daratumumab, Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) Alone in Transplant-Ineligible Asian Patients with Newly Diagnosed Multiple Myeloma: Final Analysis of the Phase 3 Octans Study

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action and has shown clinical efficacy for the treatment of multiple myeloma (MM). In an updated analysis of the global phase 3 ALCYONE study, D-VMP demonstrated a significant progression-free survival (PFS) benefit compared to VMP in transplant-ineligible patients with newly diagnosed MM (NDMM). A prior analysis of the phase 3 OCTANS study (median follow-up, 12.3 months) also showed a favorable clinical benefit/risk profile for D-VMP versus VMP in transplant-ineligible Asian patients with NDMM. Here, we report results from the final analysis of OCTANS, with a median follow-up of &amp;gt;3 years. Methods: The randomized, phase 3 OCTANS study (NCT03217812) enrolled Asian patients with NDMM who were ineligible for autologous stem-cell transplant due to age or presence of comorbidities. Patients were randomized 1:2 (VMP:D-VMP) to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 weeks in Cycles 2-9, and every 4 weeks thereafter until disease progression). Per a protocol amendment, patients receiving daratumumab IV were permitted to switch to daratumumab SC 1,800 mg (same schedule as IV) on Day 1 of any cycle. The primary endpoint was achievement of a very good partial response (VGPR) or better. Results: A total of 220 patients were randomized to D-VMP (n = 146) or VMP (n = 74). At the time of the final analysis, with a median follow-up of 41.2 months, the rate of VGPR or better was significantly higher with D-VMP versus VMP (80.1% vs 47.3%; P &amp;lt;0.0001; Table). The rate of measurable residual disease negativity (10 -5) was also higher with D-VMP versus VMP (40.4% vs 10.8%; P &amp;lt;0.0001). D-VMP continued to show a significant improvement in PFS versus VMP (median, 38.7 vs 19.2 months; HR, 0.35; 95% CI, 0.23-0.52; P &amp;lt;0.0001; Table, Figure), as well as a longer time to subsequent antimyeloma therapy (median, 46.8 vs 20.6 months; HR, 0.31; 95% CI, 0.20-0.47; P &amp;lt;0.0001). However, median overall survival was not yet reached for either group. The overall safety profile of D-VMP was consistent with that observed for the primary analysis. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported for 133 (92.4%) patients who received D-VMP and 60 (84.5%) patients who received VMP and were primarily hematologic events; nonhematologic grade 3/4 TEAEs in ≥10% of patients included pneumonia (D-VMP, 31.3% vs VMP, 18.3%), hypokalemia (15.3% vs 4.2%), and hypertension (13.2% vs 8.5%). Grade 3/4 infection TEAEs were reported for 67 (46.5%) and 22 (31.0%) patients who received D-VMP or VMP, respectively. Serious TEAEs were reported for 75 (52.1%) and 28 (39.4%) patients in the D-VMP and VMP groups, respectively, and TEAEs led to treatment discontinuation in 6 (4.2%) and 4 (5.6%) patients, respectively. The incidence of infusion-related reaction TEAEs in the D-VMP group was 33.3%, which is consistent with that previously reported for daratumumab; most events were of grade 1 or 2 severity. The risk of immunogenicity to daratumumab was low, with 1 of 130 evaluable patients testing positive for daratumumab antibodies. Within the D-VMP group, 76 patients switched from daratumumab IV to SC administration. Among these patients, 64 (84.2%) patients preferred SC administration, 7 (9.2%) preferred IV administration, and 15 (19.7%) had no preference on ≥1 of 2 surveys. Of the 64 patients who preferred SC administration, primary reasons included treatment administration time (84.4%), more comfortable administration process (57.8%), less caregiver burden (31.2%), and fewer administration-related reactions (26.6%). Conclusions: With a median follow-up of &amp;gt;3 years, this final analysis of OCTANS demonstrated a continued clinical benefit with D-VMP versus VMP in Asian patients, with PFS improvement comparable to that observed in the global ALCYONE study (HR, 0.35 vs 0.42, respectively). No new safety concerns were identified for D-VMP with extended follow-up. In addition, daratumumab SC administration was preferred by the majority of patients who switched from daratumumab IV. These results further support the use of daratumumab IV or SC in combination with VMP in transplant-ineligible Asian patients with NDMM.

A Randomized Phase II Study of Daratumumab, Ixazomib, and Dexamethasone (DId, Arm A) Vs Daratumumab, Bortezomib and Dexamethasone (DVd) Followed By Daratumumab, Did (Arm B) in Newly Diagnosed Multiple Myeloma (DeRIVE) Study

Introduction: The safety and efficacy established by daratumumab (a CD38 monoclonal antibody)-based induction therapies for both transplant-eligible myeloma patients (based on CASSIOPEIA, and GRIFFIN trials) and transplant-ineligible patients (based on MAIA trial) have gained an accelerated momentum for adoption into regular clinical practice. In this context, to find the most optimal non-IMID based daratumumab-combination therapy as induction, we conducted a randomized phase 2 study to evaluate the safety and efficacy for in-class transition from bortezomib to ixazomib, stratified by transplant-eligibility and R-ISS. Methods: Patients were randomized to receive Arm A [daratumumab, ixazomib and dexamethsone (DId) X 8 cycles)] or Arm B [(daratumumab, bortezomib and dexamethsone (DVd) x 3) followed by (DId x 5 cycles)] for the primary endpoint of ≥ very good partial response rate (VGPR) rate post-induction cycle 8. Several other secondary endpoints were evaluated including safety, overall repsonse rate (ORR), progression free survival (PFS) and overall survival (OS). Standard dosing schedule was used [DId: daratumumab IV 16 mg/kg on days 1, 8, 15, 22 every 28 days x 2 cycles; then on days 1, 15 every 28 days x 6 cycles and every 28 days during maintenance (or 1800 mg SC at the same schedule), ixazomib - 4 mg PO on Days 1, 8, and 15 every 28 days and dexamethasone - 40 mg PO on days 1, 8, 15 and 22 every 28 days; DVd: daratumumab IV 16 mg/kg on days 1, 8, 15, 22 every 28 days x 2 cycles; then on days 1, 15 every 28 days x 6 cycles and every 28 days during maintenance (or 1800 mg SC at the same schedule), bortezomib - 1.3 mg/m2 SC on days 1, 4, 8 and 11 every 21 day and dexamethasone - 40 mg PO on days 1, 8, 15 and 22 every 28 days]. Transplant eligible patients may receive stem cell collection and transplant after cycle 8. During the maintenance phase, patients receive DId as maintennace therapy for a total of 32 cycles. 52 subjects were enrolled at Winship Cancer Institute of Emory University between 07/2019 and 05/2022. Results: The median age was 64 years for the 48 evaluable subjects [25 (52%) in arm A, 68 (48-87) and 23 (48%) in arm B, 61 (37-80), p&amp;lt;0.25]. 56% of the cohort was male (64 vs 48%, p=0.20), 48% were black (40% vs 56.5%, p=0.245). 20.8% had t(11;14), 29.2% had 1q abnormalities, 70.8% had hyperdiploidy, 25% had complex karyotype and 10.4% were high-risk [defined as presence of del17p, t(4;14) or t(14;16)]. 38 (81%) patients underwent an autologous stem cell transplant (72% in Arm A and 90.9% in Arm B, p=1.00). The primary endpoint favored arm B (Arm A vs Arm B ≥VGPR rate: 28% vs 56.5%, p&amp;lt;0.043). Similarly, the ORR favored arm B as well (Arm A vs Arm B ORR: 76% vs 95.7%, p&amp;lt;0.062). Post transplant ≥VGPR rates and ORR were 88.9% vs 95%, p=0.458 and 100% vs 100%, p=NS, respectively. At a median follow up of 35.2 months, 80% of the patients remain progression free as shown in figure 1. The adverse event profile was similar across both cohorts (grade 3/4 events occurred in 6 (24%) vs 7 (30%) for Arm A and B, respectively, p=0.27). There was no grade 3/4 peripheral neuropathy (PN), though grade 1/2 PN were higher in Arm B. There were two secondary primary malignancy reported in Arm B (prostate adenocarcinoma, esophageal adenocarcinoma). All together the safety signals were comparable between both arms. Conclusion: This is one of the first studies showing the safety and efficacy of non-IMID based dara-combination induction therapies with in-class transition of bortezomib to ixazomib yielding higher response rates post-induction and post-transplant without compromising on the safety. 3-year PFS rate of close to 80% across both arms is for daratumumab and proteasome inhibitor combination therapy are highly encouraging and may be an alternative regimen for patients that may not tolerate IMIDs or that have a contraindication to receive IMIDs.

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 &amp;lt;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 &amp;gt;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.

Comparison of Time to Next Treatment or Death between Front-Line Daratumumab, Lenalidomide, and Dexamethasone (DRd) and Bortezomib, Lenalidomide, and Dexamethasone (VRd) in Transplant Ineligible Patients with Multiple Myeloma

Introduction: Daratumumab, lenalidomide, and dexamethasone (DRd) and bortezomib, lenalidomide, and dexamethasone (VRd) are the only two regimens that are considered as preferred per the National Comprehensive Care Network for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). While there are no head-to-head studies comparing clinical outcomes of DRd and VRd in this population, an indirect comparison (PEGASUS study [Durie et al., 2020]) has shown that DRd was associated with significantly lower risk of disease progression or death compared with VRd and Rd. This study aims at supplementing this information by comparing real-world time-to-next-treatment (TTNT) or death between NDMM TIE patients treated with front-line (FL) DRd or VRd. Methods: A retrospective cohort study was conducted for patients with NDMM who initiated FL DRd or VRd in Acentrus (1/1/2018 - 5/31/2023), an electronic medical record (EMR) database from academic and non-teaching hospitals in the United States. Patients were included if they had ≥2 records with an ICD-10-CM diagnosis code for MM, ≥6 months of data availability prior to first record with MM diagnosis (without use of antineoplastic agent), initiated FL treatment (initiation of DRd or VRd; index date) within 12 months of first record of MM diagnosis, and ≥90 days of data availability post-index. Patients with pre-index diagnosis of amyloidosis or other cancers and those who participated in a clinical trial before or during FL treatment were excluded. To limit the analysis to the TIE population, patients who had a record of a stem-cell transplant (SCT) before or during FL treatment and those who were &amp;lt;65 years old (used as proxy to SCT eligibility) were excluded. Patient characteristics were evaluated up to 12-months pre-index (baseline period). Patients were followed from the index date until earliest of date of initiation of a next line of treatment, death, or end of data availability. Medications received within 60 days from the date of the first MM antineoplastic agent were considered as FL therapy regimen. Next line of treatment was identified as initiation of a new antineoplastic agent (excluding corticosteroids) outside of FL therapy or re-treatment of FL after &amp;gt;90-day gap. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics between study cohorts, with variables with standardized differences &amp;lt;10% considered balanced. Weighted Kaplan-Meier (KM) curves and a doubly-robust Cox proportional hazards model adjusting for baseline variables remaining imbalanced after IPTW were used compare TTNT or death between study cohorts. Results: Overall, 149 and 494 patients were identified in the DRd and VRd cohorts, respectively. After weighting (N DRd weighted = 302, N VRd weighted = 341), most baseline characteristics in both cohorts were similar, including mean age (DRd: 75.3, VRd: 74.5), female sex (DRd: 48.9%, VRd: 45.8%), white race (DRd: 55.8%, VRd: 58.7%), black race (DRd: 8.8%, VRd: 11.3%), Medicare insurance coverage (DRd: 62.7%, VRd: 65.9%), and mean Quan-Charlson comorbidity index (DRd: 3.8, VRd: 3.6; Table 1). Some imbalances remained for mean age, race, ethnicity, and index year, thus they were additionally adjusted for in doubly-robust Cox model. The median duration of follow-up was 20.2 months and 21.5 months among DRd and VRd patients, respectively. A total of 98 (32.4%) DRd patients and 175 (51.2%) VRd patients received a subsequent line of therapy or died, with the median TTNT or death being 37.8 and 18.7 months in the DRd and VRd cohorts, respectively (hazard ratio: 0.58, 95% CI: 0.35, 0.81; p&amp;lt;0.001; Figure 1). KM estimates for patients remaining on FL therapy were significantly higher for DRd than VRd at 6 months (93.0% vs. 80.1%), 12 months (80.0% vs. 61.0%), 18 months (64.9% vs. 51.3%), and 24 months (60.2% vs. 42.9%). Conclusion: In this retrospective cohort study using EMR data, TIE NDMM patients who initiated DRd had a significantly longer time to next treatment or death than patients who initiated VRd. Results from this real-world study fills an unmet data gap by providing information on the comparative effectiveness evidence for DRd versus VRd among TIE NDMM patients. These findings support the use of DRd as an effective treatment option in the TIE NDMM patient population.

Outcomes of Transplant-Eligible and Transplant-Ineligible Patients with Mantle Cell Lymphoma in Ontario, Canada

Background The frontline treatment of patients with symptomatic mantle cell lymphoma (MCL) requiring treatment varies in practice. In Ontario, Canada, transplant-eligible (TE) patients have been treated with chemoimmunotherapy followed by autologous stem cell transplant (ASCT). In 2013, R-CHOP alternating with R-DHAP prior to ASCT replaced R-CHOP alone as standard of care based on the European MCL Younger trial (Hermine JCO 2022). Although this regimen improves progression-free survival, there remains concern about its toxicity. For transplant-ineligible (TI) patients, the standard of care has evolved over time. Evidence in support of bendamustine-rituximab (BR) efficacy in indolent lymphoma resulted in its increased use in TI patients with MCL over the last decade. However, real-world data are lacking on toxicities of this regimen compared to other chemoimmunotherapy. We aimed to characterize survival and healthcare utilization outcomes of patients with MCL using current treatment approaches. Methods We conducted a retrospective population-based study of patients with MCL using healthcare administrative databases from Ontario, Canada, from 2005 to 2020. Patients were defined as TE if they were less than 70 years old at the time of treatment initiation, and received either R-CHOP or R-CHOP/R-DHAP. Patients were defined as TI if they were 70 years or greater at the time of treatment initiation, and treated with BR or other forms of chemoimmunotherapy. The primary outcome was 5-year overall survival (OS), from the time of first treatment to death or end of the study period. Secondary outcomes were toxicities of treatment and healthcare utilization. Cox regression analyses were used to assess the impact of demographic and treatment variables on OS. Results A total of 918 patients with MCL were included in this study; 426 were TE and 492 TI. For TE patients, 254 were treated with R-CHOP, and 172 with R-CHOP/R-DHAP. The median age of patients in both groups was 60 years (range 36-70 years, p=0.37). Patients treated with R-CHOP alone were followed for a mean of 6.01 years, and patients treated with R-CHOP/R-DHAP for a mean of 3.38 years. Maintenance rituximab (MR) was used in 70.5% of patients treated with R-CHOP and 77.3% of patients treated with R-CHOP/R-DHAP (p=0.12). ASCT was received by 53.5% of patients treated with R-CHOP and 83.7% of patients treated with R-CHOP/R-DHAP (p&amp;lt;0.01). 5-year OS of patients treated with R-CHOP/R-DHAP was 70.5% vs 62.0% for patients treated with R-CHOP regardless of transplant status ( Figure 1A hazard ratio [HR] 0.75, 95% CI 0.51-1.10). Of the 270 patients who received ASCT within 1 year of treatment initiation, survival was not impacted by prior receipt of R-CHOP alone or R-CHOP/R-DHAP (HR for R-CHOP/R-DHAP vs. R-CHOP 0.76, 95% CI 0.42-1.39). A higher proportion of patients treated with R-CHOP/R-DHAP required hospital admissions for fever, infection, neutropenia, and renal toxicity, compared to R-CHOP alone ( Table 1). There was no difference between regimens in the number of patients requiring emergency department (ED) visits between regimens (p=0.39). 492 TI patients were included; 303 treated with BR and 189 treated with other regimens, most commonly R-CHOP (n=62) or R-CVP (n=108). The median age of patients in both groups was 77 years (range 71-94 years, p=0.17), and there was no significant difference in comorbidities (p=0.23). MR was more commonly used after BR compared to historical regimens (72.6% vs. 54.5%, p&amp;lt;0.01). 5-year unadjusted OS of patients treated with BR was 40.3% and 27.5% for patients treated with R-CHOP/R-CVP ( Figure 1B), with significantly lower mortality with the use of BR (HR 0.68, 95% CI 0.51-0.89). After adjusting for age, sex, comorbidities, and MR, this was no longer significant (HR 0.86, 95% CI 0.65-1.14). MR use was associated with significantly lower mortality (HR 0.33, 95% CI 0.24-0.44). More patients treated with BR had hospital admissions for neutropenia and febrile neutropenia ( Table 1). Conclusion In this large population-based study of patients with MCL, R-CHOP/R-DHAP prior to ASCT showed a trend toward improved 5-year OS, though not significant. For TI patients, BR resulted in superior OS compared to other regimens with similar rates of toxicities, however this was not significant after adjusting for use of MR, suggesting other regimens followed by MR may be a reasonable alternatives.

Incidence of Pneumonia, Sepsis and Febrile Neutropenia in Transplant-Ineligible Patients with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Based Combination Therapy: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction Prognosis remains dismal for older patients with acute myeloid leukemia (AML) even after hypomethylation agent or low dose cytarabine. Venetoclax is a highly selective oral BCL-2 inhibitor which induces apoptosis in BCL-2 dependent leukemic cells. In recent years, phase III RCTs have shown that the addition of venetoclax to standard treatment in older patients with newly diagnosed AML (ND AML) significantly improved efficacy with notable toxicities. We conducted a combined analysis of randomized controlled trials (RCT) to determine the risks of pneumonia, sepsis and febrile neutropenia in transplant-ineligible patients with ND AML treated with venetoclax based combination therapy. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing venetoclax in transplant-ineligible patients with ND AML that mention febrile neutropenia, sepsis and pneumonia as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results A total of 637 transplant-ineligible patients with ND AML from 2 phase III RCTs (VIALE-A and VIALE-V) were eligible. VIALE-A and VIALE-V compared azacitidine + venetoclax vs azacitidine + placebo, and venetoclax + low dose cytarabine vs placebo + low dose cytarabine respectively. The randomization ratio was 2:1 in both studies. The incidence of any-grade pneumonia was 22.1% in study group vs 23.6% in control group (RR, 0.94; 95% CI: 0.70 - 1.27; P=0.69). High-grade pneumonia rate was nearly 2.9% lower in the study arm compared to control arm, but RR was not statistically significant at 0.86 (95% CI: 0.62 - 1.21; P = 0.39). High-grade sepsis was reported in the study arm (5.6%) versus 7.5% in control arm with RR of 0.75 (95% CI: 0.41- 1.38; P = 0.35). High-grade febrile neutropenia as hematologic adverse events was noted in 163 (38.4%) of patients in study group compared to 47 (22.2%) in control group with RR of 1.73 (95% CI: 1.31- 2.29; P = 0.0001). Febrile neutropenia as serious adverse events was reported in 107 (25.1%%) of patients in study group compared to 27 (12.7%) in control group with RR of 1.98 (95% CI: 1.34- 2.93; P = 0.0006). Conclusions Our meta-analysis showed that venetoclax based anti-leukemic therapy contributed to higher incidence of high-grade febrile neutropenia as hematologic and serious adverse events in transplant-ineligible patients with ND AML, with RR of 1.73 and 1.98. However, the risks of high-grade sepsis and pneumonia were found to be statistically not significant between the two groups. Timely intervention with proper supportive care is required.

MASS-4 Is More Suitable Than MASS-3 for Prognostic Stratification in Transplant-Eligible Patients Withnewly Diagnosed Multiple Myeloma

Introduction: In 2022, Mayo Clinic proposed the Mayo Additive Staging System (MASS), a new staging system for patients with newly diagnosed multiple myeloma (NDMM). Based on the number of risk factors (International Staging System III, elevated lactate dehydrogenase, 1q gain/ amplification, high-risk IgH translocations, chromosome 17 abnormalities), they were divided into the 3-tier MASS (MASS-3) (no, 1, ≥2 high-risk factors for stage I, II, III, respectively) and 4-tier MASS (MASS-4) (no, 1, 2, ≥3 high-risk factors for stage I, II, III, IV, respectively). Real-world studies have shown that MASS-3 and MASS-4 are suitable for prognostic stratification in Chinese patients with NDMM, but there is no clear evidence of their utility in transplant-eligible patients with NDMM. Methods: A retrospective analysis of the clinical data of 215 NDMM patients who received “induction therapy-autologous hematopoietic stem cell transplantation (ASCT)” in our center was performed. The prognostic stratification value of the two stages was analyzed and compared in patients overall, with different transplant times, with different ages, and with different induction regimens. Results: 72 (33.5%), 66 (30.7%), and 77 (35.8%) patients were classified as MASS-3 I, II, and III, respectively. The median progression-free survival (PFS) was 77.7, 87.7, and 50.5 months, respectively(P=0.011), and the median overall survival (OS) was not reached, 109.6, and 69.7 months, respectively(P=0.003). The PFS and OS of patients with MASS-3 III were significantly shorter than those of stage I (P&amp;lt;0.05). 72 (33.5%), 66 (30.7%), 54 (25.1%) and 23 (10.7%) patients were classified as MASS-4 I, II, III, and IV, respectively. The median PFS was 77.7, 87.7, 52.6, and 34.5 months, respectively (P=0.004), and the median OS was not reached, 109.6, 106.0, and 40.6 months, respectively (P&amp;lt;0.001). The PFS and OS of patients with MASS-4 III were significantly shorter than those of stage I (P&amp;lt;0.05). The PFS of patients with MASS-4 IV was significantly shorter than that of stage I, II, or III (P&amp;lt;0.001). The OS of stage IV was significantly shorter than that of stage I or II (P&amp;lt;0.01), and tended to be shorter than that of III (P =0.06). Among 118 (64.1%) Revised International Staging System II patients, MASS-3 could not distinguish their prognosis (P&amp;gt;0.05), but MASS-4 could differentiate their prognosis (P&amp;lt;0.05), with MASS-4 IV patients having significantly shorter PFS and OS compared with stage I, II, or III (P&amp;lt;0.05). In patients with single ASCT, different ages, and different induction regimens, the prognostic stratification of MASS-4 was also better than that of MASS-3. However, there was no significant difference in PFS and OS between different MASS-3 or MASS-4 stages in patients with tandem ASCT. Conclusion: Among transplant-eligible patients with NDMM, the prognostic stratification value of MASS-4 was better than that of MASS-3, particularly distinguishing high-risk patients with poor prognosis. Compared with single ASCT, tandem ASCT may overcome the poor prognosis of high-risk MASS patients.

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 &amp;lt;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 &amp;lt; 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 &amp;lt;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.

Isatuximab Rescue for Inadequate Response to Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: Primary Analysis of the Phase II Iril Study of the Australian Myeloma Research Consortium (AMaRC 18-02)

Background: A significant proportion of transplant ineligible, treatment-naïve multiple myeloma (NDMM, TNE) patients (pts) do not proceed to second line anti-MM therapy. Given depth of response to initial therapy correlates with overall survival (OS), a deep remission should be the target for this often elderly and frail cohort of pts. Additionally, current risk-stratification models utilizing predictive biomarkers, cytogenetics, FISH, and molecular profile cannot reliably identify patients with functional high-risk MM who respond sub optimally [i.e., &amp;lt; partial response (PR)]to standard first line therapy. IRIL is a phase II, multicentre, response-adapted study examining treatment rescue/intensification with isatuximab (Isa), an anti-CD38 monoclonal antibody, for functional high-risk pts, defined as those not achieving pre-defined target responses to lenalidomide and dexamethasone (Rd). Method: TNE NDMM pts meeting IMWG criteria for treatment were eligible for enrolment. Pts commenced treatment with lenalidomide [R; 25mg D1-D21 of a 28-day cycle (c)] and dexamethasone [d; 40mg (20mg for those aged ³75 years) PO weekly]. Isa (10mg/kg IV weekly for c1, then fortnightly) was added for failure to achieve pre-defined target responses [³PR after 4c, ³VGPR after 6c, or ³CR after 9c of Rd] or progressive disease (PD) within the first 9c Rd and was continued until PD or consent withdrawal. The primary endpoint was the achievement of PR or better after an additional 6c of Isa-Rd in pts who progressed during the first 4c of Rd or did not achieve a PR after 4c of Rd (i.e., the functional high-risk subgroup). A dual-criteria, Bayesian Proof-of-Concept (PoC) design was implemented requiring an observed rate of PR (or better) after 6c Isa-Rd of ≥ 50% with a posterior probability that the true rate exceeds 37.7% of &amp;gt;95%. The protocol allowed the trial management committee (TMC) to halt accrual at the first demonstration of PoC. The secondary endpoints were achievement of VGPR or CR after an additional 6c Isa-Rd in pts failing to meet these milestones after 6 or 9c Rd, progression free survival (PFS), OS and safety. This is a report of a per-protocol specified interim analysis of the primary endpoint. Results: From June 2019 until April 2023, 68 pts [52% male, median age 78.2 years (range 65.5-91.9), R-ISS Stage I (n=11), Stage II (n=37), Stage III (n=10)] were enrolled (67 commenced treatment with Rd). At the first interim analysis, both Bayesian PoC criteria were met with the observed PR rate after up to 6 additional cycles of Isa-Rd of 73.3% with a posterior probability that the true rate exceeded 37.7%, greater than 95% (Table 1). Given PoC was demonstrated and the SARS-CoV-2 pandemic-related slower than expected accrual, the TMC terminated study recruitment. At the most recent sweep in June 2023 (Figure 1), 14/15 rescued pts have achieved a PR or better (9/15 VGPR or CR), 4 deaths have been reported (1 each of disease-related, cardiac event, trauma, cause unknown) while 8/15 pts remain on treatment. With an estimated median potential follow-up of 28 months, a preliminary estimate of PFS at 24-months is 73.3% (median PFS not reached). The safety profile for the combination Isa-Rd is similar to previously reported. 14/15 pts had any grade (Gr) adverse event (AE) reported, while 73% pts had at least 1 ³ Gr 3 AE (10 pts with Gr 3, 1 pt with Gr 4). The most common ³ Gr 3 AE were neutropenia (40%), fever (13.3%), back pain (13.3%) and mood disturbance (13.3%). Conclusion: A response-adapted approach to treatment of TNE NDMM pts with Isa rescue upon disease progression or failure to meet a target response to Rd is safe and effective. Isa rescue improves depth of response after 6 additional cycles of therapy in 73% of functionally high-risk patients. The study was closed to recruitment early due to demonstration of PoC of a response-adapted treatment strategy. There were no new safety signals observed from the Isa-Rd combination. Reports on secondary endpoints will be presented, 12 months following the last Isa rescued patient's 6 th cycle of IsaRd. This study is supported by BMS/Celgene (funding), Sanofi/Genzyme (provision of Isatuximab), The Victorian Cancer Agency (funding) and the Victorian Epigenetics Group (funding).

CDKN2C Deletion on 1p32 Locus As Part of Irwazh Score, a New Risk Assessment Model for Venous Thromboembolism Occurring within 6-12 Months of Treatment Initiation in Newly Diagnosed Multiple Myeloma

Background Adequate risk-stratification of venous thromboembolism (VTE) in multiple myeloma (MM) is an unmet need. Methods This is a retrospective study of 320 newly diagnosed MM (NDMM) patients treated from 2011 to 2023. All gave their informed consent. Required minimal follow-up (FU) length was 12 months or lower if VTE or death occurred. We aimed to evaluate VTE incidence at 6 and 12 months of first line treatment (L1) initiation, identify risk predictors and assess VTE impact on overall survival (OS). Comorbidities, baseline demographic (excluding race), clinical, biological (including FISH) and imaging data, treatment exposures, response profile and OS were all analyzed. Total scores for 4 existing risk assessment models (RAM) (IMPEDE-VTE, SAVED, PRISM, IFM/DFCI-related) were also calculated from L1 start. VTE events (VTEe) were adjudicated to exclude superficial ones and restrict analysis to documented deep vein thrombosis (DVT) and pulmonary embolism (PE). Predictors validated by Cox model were weighted based on their hazard ratios (HR). Results The cohort comprised 147 (45.9%) women and 111 (34.7%) transplant-eligible patients. Overall median age was 70.1 (36.6-98.4) years and 205 (64.1%) subjects were &amp;gt;65. Two hundred and twenty-five (70.3%) received standard-of-care regimens containing immunomodulatory drugs (IMID) (Thalidomide in 98: 30.6%; Revlimid in 127: 39.7%), while 130 (40.6%) received high-dose (≥160 mg) Dexamethasone (HDD) per L1 cycle. VTE prophylaxis was omitted in 32 (10%) or consisted of NSAID in 97 (30.3%), prophylactic low molecular weight heparin (LMWHp) in 115 (36%) and direct oral anticoagulant (DOA) in 55 (17.2%), while 10 (3.1%), 9 (2.8%) and 2 (0.6%) were previously receiving curative LMWH (LMWHc), vitamin K antagonist (VKA) or a mixed regimen, respectively, for prior VTE or other indications. In 33 (10.3%) patients, 34 VTEe occurred (31 [91.2%] within the first 6 months): 4 (11.8%) as both PE and DVT; 3 (8.8%) as PE; 27 (79.4%) as isolated proximal (12 [35.3%]) or distal (15 [44.1%]) DVT of the upper (2 [5.9%]) or lower (25 [73.5%]) limbs, including 3 (8.8%) with both proximal and distal and 3 (8.8%) close to central venous catheter. Based on Cox univariate analysis, VTEe were not related to usual parameters such as past VTE history, IMID, HDD or EPO exposure, prophylaxis omission or modality or recent surgery. A 6-parameter RAM, named Irwazh score, was built from multivariate Cox model, including: age &amp;lt;55 years (HR 0.34; 95% confidence interval [CI]: 0.0-0.8; p=0.014), prior diabetes (HR 3.41; 95% CI: 1.48-7.85; p=0.004), creatinine clearance (Cr-Cl) using MDRD &amp;lt;40 ml/mn (HR 2.64; 95% CI: 1.26-5.51; p=0.009), CRP ≥10 mg/dl (HR 2.65; 95% CI: 1.27-5.48; p=0.009), ≥50% 1p32 deletion (HR 3.44; 95% CI: 1.17-10.09; p=0.024) and minimal response (MR) to L1 (HR 4.67; 95% CI: 1.71-12.73; p=0.003). Area under the curve (AUC) was 0.718 (95% CI: 0.624-0.811; p&amp;lt;0.0001) at 12 months and 0.731 (95% CI: 0.636-0.825; p&amp;lt;0.0001) at 6. In comparison, AUC was 0.649 (95% CI: 0.546-0.751; p=0.004) for IMPEDE-VTE, 0.597 (95% CI: 0.505-0.689; p=0.039) for PRISM, 0.584 (95% CI: 0.486-0.682: p=0.091) for IFM/DFCI-related and 0.580 (95% CI: 0.473-0.687; p=0.141) for SAVED (Figure 1). Based on points attributed to each parameter (age &amp;lt;55 years: 1; prior diabetes: 9; Cr-Cl&amp;lt;40 ml/mn: 6; CRP≥10 mg/dl: 6; ≥50% 1p32 deletion: 9; MR: 11), patients were stratified into low (&amp;lt;6 points), intermediate (6-15) and high risk (≥16), with 12-month cumulative VTE incidence of 4,51% (6/133), 10,45% (16/153) and 35,29% (12/34), respectively. Of low-risk patients, 2 were receiving NSAID and 4 LMWHp; of intermediate-risk ones, 2 had no prophylaxis, 9 were under NSAID and 5 LMWHp; of high-risk ones, 2 had no prophylaxis, 5 were receiving NSAID, 2 LMWHp, 1 VKA, 1 LMWHc and 1 DOA. Using Kaplan-Meier analysis for VTE-free survival, statistical difference was found significant between low- and intermediate-risk ( p=0.043), low- and high-risk ( p&amp;lt;0.0001) and intermediate- and high-risk groups ( p=0.000) (Figure 2). Median total FU was 33.2 (0.2-147) months; OS assessment using Cox model did not find a significant statistical impact of VTE neither at 6 ( p=0.491) and 12 ( p=0.199) months nor during the whole FU length ( p=0.438). Conclusion The Irwazh score, with an unprecedented FISH feature, a statistically significant risk-stratifying power and a better AUC than existing VTE RAMs is worth validating in a larger clinical study.

Second Line Treatment and Outcomes of Patients with Multiple Myeloma: A Real World Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Introduction: The treatment of multiple myeloma (MM) has evolved rapidly, with various combinations of immunomodulators (IMiDs), proteasome inhibitors (PIs), corticosteroids and autologous stem cell transplantation (ASCT) utilized in newly diagnosed (ND) patients; in some jurisdictions, monoclonal antibodies (MABs) are also incorporated in first-line treatment. Over the last decade, the standard of care in Canada for NDMM in fit younger patients has consistently been induction (CyBorD/more recently RVD) followed by ASCT and maintenance lenalidomide (len) until progression. In transplant-ineligible patients, bortezomib- or len-based treatments in doublets or triplets have been used frontline. At relapse, options have included re-induction followed by 2nd ASCT or doublet/triplet combinations until progression. Limited comparative data are available to support any one approach. The aim of this retrospective study was to assess the treatment patterns and outcomes of MM patients treated at 1st relapse in a real-world setting. This data may be useful to myeloma stakeholders when evaluating the potential impact of even newer novel immunotherapeutic agents in patients in who have had 1 prior line of treatment. Methods: We performed a retrospective observational study using the Canadian Myeloma Research Group Database (CMRG-DB), which is a prospectively maintained disease-specific database with ≥ 9000 patients enrolled from 16 academic sites across Canada. All MM patients who initiated second-line therapy between 01/12/2010 - 30/06/2022 were included and results were analyzed up to 23/05/2023. We aimed to evaluate the following outcomes for each second-line regimen: overall response rate (ORR), progression-free survival (PFS) and overall survival (OS), calculated from the start of second-line therapy. Survival was estimated using Kaplan-Meier methods and compared between groups using the log rank test. Results: A total of 3569 patients were identified: 1638 (45.9%) who had prior ASCT and 1931 (54.1%) non-ASCT patients. 2715 (76%) patients were bortezomib-exposed in first line, 1052 (30%) were lenalidomide-exposed; 22% had high-risk cytogenetics. The most commonly used second-line regimens were Rd in 1325 (37%) of patients, DRd in 346 (10%), CyBorD in 291 (8%), 2nd ASCT in 270 (8%), RVd in 201 (6%) and DVd in 167 (5%). Outcomes including ORR, ≥ VGPR rate, PFS and OS from second-line treatment for regimens with &amp;gt;50 patients are presented in Table 1. Among all patients, the highest ORRs were seen with DRd (90%), 2nd ASCT (89%), Kd/KCd (79%), RVd (78.1%) and KRd (74%); DRd had the highest ≥ VGPR rate (66%). In patients who had received bortezomib-based first line treatment, the second line ORRs were 96%, 98% and 95% for VRd, KRd and DRd, respectively, with a corresponding median PFS of 20 months (VRd), 19 months (KRd) and 28 months (DRd). For patients who had len-based first line treatment, the second line ORRs were 80% for Kd/KCd and 95% for DVd with a median PFS of 16 months (Kd/KCd) and 11 months (DVd), respectively. The median PFS was 41 months after 2 nd ASCT; of these patients, 68% were exposed to bortezomib in first line and 34% were len exposed in first line. The median PFS was 30 months in those who had len maintenance after their 1 st transplant compared to 60 months in those with no initial maintenance. Conclusion: In this real-world observational study we demonstrate that Canadian patients achieved results comparable those noted in prospective clinical trials leading to the approval of these agents in the second-line setting. Triplet combinations with an IMID backbone, including DRd, KRd and Ixa-Rd, had high response rates, with DRd offering the longest PFS. Patients undergoing 2 nd ASCT had ORRs and PFS comparable to DRd, although these results were likely influenced by selection of a population with a favorable response to 1st ASCT . Given the expanding use of IMID, PI and MAB combinations in first-line, our results highlight the need for better modalities at the time of 1 st relapse. Earlier integration of “novel” agents, including CAR-T therapy, bi-specifics, conjugated antibodies and CEL-MoDs-even in the second-line setting–is likely required to improve on these outcomes. The current analysis provides efficacy benchmarks to guide their implementation. Financial Support: CMRG received financial support from Janssen Inc. for the conduct of this study

Subgroup Analyses of Progression-Free Survival from the Phase 3 Octans and Alcyone Studies in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Bortezomib, Melphalan, and Prednisone with or without Daratumumab

Introduction:Daratumumab, a human IgGκ monoclonal antibody targeting CD38, has shown clinical efficacy in combination with standard-of-care regimens in patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved clinical outcomes vs bortezomib, melphalan, and prednisone (VMP) in phase 3 studies in Asian patients (OCTANS) and a global population (ALCYONE) with transplant-ineligible (TIE) NDMM. Here, we present subgroup analyses of progression-free survival (PFS) by measurable residual disease (MRD) and cytogenetic risk status from OCTANS and ALCYONE. Methods: Eligible patients from OCTANS (NCT03217812) and ALCYONE (NCT02195479) had a diagnosis of NDMM and were TIE due to age or comorbidities. Patients were randomized to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 wk in Cycles 2-9, and every 4 wk thereafter until disease progression or unacceptable toxicity). MRD negativity (10 -5) was assessed by multi-parameter flow cytometry in OCTANS and next-generation sequencing in ALCYONE. Cytogenetic risk was assessed by FISH or karyotype testing. Results:A total of 220 Asian patients were randomized (D-VMP, n = 146; VMP, n = 74) in OCTANS, and 706 global patients were randomized (D-VMP, n = 350; VMP, n = 356) in ALCYONE. With a median follow-up of 41.2 mo (range, 0.0-59.9) in OCTANS, the median PFS was 38.7 mo with D-VMP and 19.2 mo with VMP (HR, 0.35; 95% CI, 0.23-0.52; P &amp;lt;0.0001). With a median follow-up of 40.1 mo (range, 0.0-52.1) in ALCYONE, the median PFS was 36.4 mo with D-VMP and 19.3 mo with VMP (HR, 0.42; 95% CI, 0.34-0.51; P &amp;lt;0.0001). The rates of overall and sustained MRD negativity were higher with D-VMP vs VMP. In OCTANS, the MRD-negativity rate was 40.4% with D-VMP vs 10.8% with VMP ( P &amp;lt;0.0001), and more patients in the D-VMP group had sustained MRD negativity lasting ≥12 mo (24.7% vs 1.4%; P &amp;lt;0.0001) and ≥18 mo (15.1% vs 1.4%; P = 0.0008). Similarly, in ALCYONE, the MRD-negativity rate was 28.3% with D-VMP vs 7.0% with VMP ( P &amp;lt;0.0001), with more patients in the D-VMP group having sustained MRD negativity lasting ≥12 mo (14.0% vs 2.8%; P &amp;lt;0.0001) and ≥18 mo (8.9% vs 1.7%: P &amp;lt;0.0001). In both studies, longer PFS was observed for patients who achieved MRD negativity vs those who did not within each treatment group; however, the PFS benefit observed for D-VMP vs VMP was maintained irrespective of MRD status ( Figure). In multivariate analyses, achievement of sustained MRD negativity lasting ≥12 mo was associated with longer PFS vs MRD negativity &amp;lt;12 mo in both OCTANS (HR, 0.23; 95% CI, 0.09-0.62; P = 0.004) and ALCYONE (HR, 0.13; 95% CI, 0.06-0.32; P &amp;lt;0.0001). No other factors showed a significant association with PFS in the multivariate analysis for OCTANS; other factors associated with longer PFS in ALCYONE included age &amp;lt;75 vs ≥75 y (HR, 0.38; 95% CI, 0.20-0.75; P = 0.005) and ISS disease stage I vs II (HR, 0.20; 95% CI, 0.05-0.86; P = 0.03). Data from OCTANS and ALCYONE were pooled for an analysis of PFS by cytogenetic risk subgroup (D-VMP, n = 496; VMP, n = 430). D-VMP prolonged median PFS vs VMP in patients with standard cytogenetic risk (not estimable vs 18.9 mo; HR, 0.33; 95% CI, 0.26-0.42) and high cytogenetic risk (25.6 vs 18.9 mo; HR, 0.54; 95% CI, 0.41-0.71), defined by the presence of t(4;14), t(14;16), del(17p), t(14;20), gain(1q21), and/or amp(1q21). Median PFS was also longer with D-VMP vs VMP for patients with gain and/or amp(1q21) (31.9 vs 18.9 mo; HR, 0.45; 95% CI, 0.32-0.63), 1 high-risk cytogenetic abnormality (HRCA; 24.4 vs 19.3 mo; HR, 0.62; 95% CI, 0.44-0.86), and ≥2 HRCA (28.2 vs 17.5 mo; HR, 0.36; 95% CI, 0.20-0.63). Conclusions:In this subgroup analysis of OCTANS and ALCYONE, the prolonged PFS observed with D-VMP vs VMP in the overall study populations was maintained irrespective of the achievement of MRD negativity or the presence of high cytogenetic risk. In addition, the rates of MRD negativity and sustained MRD negativity were higher with D-VMP vs VMP, and achievement of these deep responses translated into longer PFS, consistent with a prior pooled analysis of the MAIA and ALCYONE studies. These results further support the use of daratumumab in combination with VMP in both Asian and global patients with TIE NDMM.

Checkpoint Immunotherapy Is Associated with Preferential Activation of Tumor-Antigen Specific CD4 + T Cells in MDS

Background: Patients with intermediate and higher-risk MDS are generally treated with the DNA hypomethylating agents (HMAs) azacytidine and decitabine. These agents improve survival and cytopenias in ~50% of those treated; but only responders derive clinical benefit, and no pre-treatment response prediction has proven efficacy. There is thus an urgent need to develop new approaches to complement or enhance the response to standard-of-care HMA therapies. Studies suggest that HMAs might act in part via activation of anti-tumor immune mechanisms. Based upon this hypothesis a series of early phase trials combining immune checkpoint inhibitors (ICI: both anti-PD1/PDL1 and CTLA4) with azacitidine in MDS/AML patients were undertaken but clinical and immunological efficacy have proven disappointing. In these studies, the lack of antigen specificity made systematic assessment of the anti-MDS immune response and milieu challenging. Antigen specific assessments are particularly important in MDS patients treated with ICIs because distinct from solid tumors, myeloid stem cell cancers involve the populations of antigen presenting cells that modify the capacity for T-cell response, such as dendritic cells. Our group has shown that MDS/AML patients treated with decitabine show increased expression of NY-ESO-1, a well-characterized tumor antigen whose expression is normally suppressed through dense promoter hypermethylation. In our prior Phase I study, MDS patients received vaccination against NY-ESO-1 in combination with standard decitabine. This combination was not only safe, but it also induced NY-ESO-1 specific CD4 + and CD8 + T cell responses in most patients. We hypothesized that combining anti-NY-ESO-1 vaccination (an antigen specific approach) with decitabine and an ICI would allow us to understand the immune synapse in patients with MDS. Methods: We developed an investigator-initiated Phase 1 trial in transplant-ineligible patients with MDS/low blast count AML adding an anti-PD-1 ICI to our established combination of decitabine + NY-ESO-1 vaccination (#NCT 0335871). This open-label, non-randomized single center Phase 1 study used an HLA unrestricted NY-ESO-1 vaccine (CDX-1401 (1 mg) + poly-ICLC (1.8 mg)) in combination with standard dose decitabine (20mg/m2/d x 5 days) and nivolumab (3 mg/kg every 2 weeks), 4 cycles of combination therapy were planned on study; patients deriving clinical benefit could continue treatment at the discretion of the treating physician. The study was conducted in accordance with the Declaration of Helsinki and approved by the Roswell Park Cancer Institute (RPCI) Internal Review Board. Six patients were enrolled, treated, and completed &amp;gt; 4 cycles of decitabine; serial bone marrow and peripheral blood samples were collected for analysis. The combination was safe. Results: Two patients developed CR and the remainder had stable disease as the best response to therapy (Table 1). The majority of patients mounted NY-ESO-1 specific CD4 + T cell responses associated with up-regulation of anti-PD-1 immunotherapy gene signatures in the CD4 + memory T cell compartment. No responses in CD8 + T cells were seen. In seeking explanation for the disparate findings in CD4 + and CD8 + T-cell compartments, we examined conventional dendritic cell populations associated with activation of CD8 + T cells and identified that our patients had markedly reduced numbers of conventional dendritic cells marked by high expression of CD141 (cDC1). This population is critical for a successful response to immunotherapy. cDC1 from MDS patients also showed reduced expression of genes that are key for optimal T-cell activation and expansion. Conclusions: These results suggest that the use of immunotherapy to induce effective, cytotoxic anti-tumor T cell responses depends upon the myeloid immunologic milieu in MDS patients. The critical importance of cDC1 function has recently been described and appreciated in the context of solid tumor immunotherapy. The observation of both numerical and functional defects of this cell population in patients with myeloid neoplasia provides a possible explanation for the disappointing efficacy of immunotherapies in this disease state. Approaches to augment the number and function of specific cDC1 populations in myeloid disease might overcome this defect and thereby enhance the efficacy of immunotherapy for patients with MDS.