Non-transplant Eligible Patients Research Articles

QoL during KTd or KRd induction followed by K maintenance or observation in transplant noneligible patients with newly diagnosed multiple myeloma: Longitudinal and cross‐sectional analysis of the randomized AGMT 02 study

AbstractUnderstanding the impact of induction and maintenance therapy on patients’ quality of life (QoL) is important for treatment selection. This study aims to compare patient‐reported QoL between patients treated with KTd or KRd induction therapy and K maintenance therapy or observation. QoL was assessed using the EORTC QOL‐C 30 and QOL‐MY20 questionnaires in the AGMT‐02 study, in which 123 patients with newly diagnosed transplant ineligible multiple myeloma were randomized to nine cycles of either KTd or KRd induction therapy, followed by 12 cycles of K maintenance therapy, or observation. Longitudinal assessments showed statistically significant improvements in global health‐related QoL, various disease symptoms and pain for both treatment regimens. KTd improved insomnia and fatigue, and KRd improved physical functioning. Cross‐sectional comparisons indicated a “slight” superiority of KTd over KRd in several scales, with the exception of higher neuropathy scores with KTd. During maintenance, longitudinal comparisons showed no statistically significant changes. Cross‐sectional comparisons revealed a “slight” improvement in cognitive functioning during carfilzomib therapy, but a worsening in most other QoL scales. Induction therapy led to improvements in most QoL items, while maintenance therapy with K maintenance was associated with “slight” or “moderate” impairments in several QoL scales compared with the observation group.

Functional cure and long-term survival in multiple myeloma: how to challenge the previously impossible.

Multiple myeloma (MM) is a heterogeneous disease with survival ranging from months to decades. The goal of 'cure' remains elusive for most patients, but has been shown to be possible, with durable remission and a transition to a plateau phase (analogous to monoclonal gammopathy of uncertain significance/smoldering Myeloma (MGUS/SMM)). Two representative cases set the stage to illustrate how this might be possible and what still needs to be determined to achieve functional disease control over a prolonged period. Several developments have emerged, such as improved diagnostics including the definitions and use of SLiM-CRAB criteria and MRD with whole genome- /single-cell-sequencing as well as other correlates to better understand disease biology. These advances enable earlier detection, more accurate risk stratification and improved personalized treatment strategies by facilitating analysis of genetic alterations and clonal heterogeneity. Whole genome sequencing may also identify driver mutations and modes of resistance to targets like immunotherapies (IOs) as well as other targeted therapies. Today, induction with a CD38 antibody (CD38mAb), proteasome inhibitor, immunomodulatory drug, and dexamethasone, potentially followed by ASCT and lenalidomide maintenance, can be considered standard of care for transplant-eligible (TE) newly diagnosed (NDMM) patients. Whether prolonged disease control and functional cure can be achieved in non-transplant eligible (NTE) patients is currently emerging as a distinct possibility: data from phase III trials that incorporate a CD38mAb into the treatment of NTE NDMM patients demonstrate impressive MRD negativity rates that appear sustained over several years. While the long-term durability of CAR-Ts, bi-specific antibodies and other IOs are evaluated, several clinical trials are now investigating their role in frontline treatment for TE and NTE patients. These will address whether CAR-Ts will replace ASCT and whether such IOs will represent a truly curative option. We conclude that whilst cure remains elusive, the concept of operational or functional cure provides a new benchmark to strive for and is an emerging area of active and potentially achievable clinical research for MM.

In-class transition from bortezomib-based therapy to IRd is an effective approach in newly diagnosed multiple myeloma.

Aim: To compare the effectiveness of in-class transitionto all-oral ixazomib-lenalidomide-dexamethasone (IRd) following parenteral bortezomib (V)-based induction versus continued V-based therapy in US oncology clinics. Patients & methods: Non-transplant eligible patients with newly diagnosed multiple myeloma (MM) receiving in-class transition to IRd (N=100; US MM-6), or V-based therapy (N=111; INSIGHT MM). Results: Following inverse probability of treatment weighting, overall response ratewas 73.2% with IRd versus 57.5% with V-based therapy (p<0.0001). Median duration of treatmentwas 10.8 versus 5.3months (p<0.0001). Overall, 18/24% of patients discontinued IRd/V-based therapy due to adverse events. Conclusion: IRd after V-based induction was associated with significantly improved overall response rate and duration of treatment than continued V-based combination therapy. Clinical Trial Registration: US MM-6: NCT03173092; INSIGHT MM: NCT02761187 (ClinicalTrials.gov).

The Impact of Epstein-Barr Virus Infection on Second Cancer Development in Newly Diagnosed Myeloma Patients Treated with Lenalidomide in the UK NCRI Myeloma XI Trial

Background Several factors have been linked to second primary malignancy (SPM) development in myeloma patients, including advanced age, immunocompromise and therapy, such as melphalan and lenalidomide (len). The impact of infection, including EBV is yet to be elucidated. Here we address this in the context of the UK NCRI Myeloma XI Trial for newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) patients. Methods Myeloma XI was a phase III, randomised, multi-centre, parallel group design, open-label trial comparing cyclophosphamide, thalidomide, len, carfilzomib and bortezomib induction combinations and len maintenance treatment in TE and TNE patients. TE patients received high dose melphalan supported by autologous stem cell transplantation (ASCT). Patients in both pathways were randomised to maintenance with len or observation. In total, 4358 patients entered. Planned SPM analysis was conducted in May 2019, with 318 patients developing an SPM prior to that point. Median follow-up from trial entry was 60 months (IQ range 47-76). A nested cohort analysis was performed to determine EBV infection and immunity status in 170 SPM patients for which serum samples were available. Forty-two trial patients who did not develop an SPM were used as a control group. EBV assessment time-points included pre-induction, post induction, 4 months post ASCT (TE only) and 1 year post induction. Peripheral blood serum samples were tested for EBV EBNA IgG Antibody/index (LIAISON®), EBV VCA IgM Antibody/Index (LIAISON®) and EBV positivity was determined using the artus® EBV RG PCR Kit from Qiagen. Active or recent EBV infection was evidenced by a positive EBV IgM antibody and/or EBV PCR. Results Of the 170 patients, 208 SPM were noted with 147 patients developing 1 SPM and 23 patients developing ≥2. One hundred and five patients developed an SPM following maintenance randomisation, with 76 receiving len and 29 being observed. The remaining 65 patients developed an SPM prior to maintenance. Eighty-four SPMs were diagnosed in 68 TE patients and 124 SPMs in 102 TNE patients. Of the 170 SPM patients, 8 had evidence of recent or active infection at the time of testing, evidenced by either IgM EBV antibodies (n=5), positive EBV PCR (n=2) or both (n=1). The median EBV DNA copies/ml was 353 (range 337-428). The median IgM antibody titre was 71.5U/ml (26 - &amp;gt;160). No patients in the control group had evidence of recent EBV infection (p=0.36). Of the 8 patients with evidence of EBV infection, 6 developed &amp;gt;1 SPM, Table 1. Five had been treated in the TE pathway, with all developing post maintenance randomisation, and 4 of the 5 receiving len maintenance. None of the 3 TNE patients received len maintenance, with 2 developing an SPM prior to maintenance randomisation. The median time from EBV testing to SPM diagnosis was 17·9 months (0.5-51.7). Two of the EBV positive patients developed a haematological SPM: myelodysplastic syndrome and Hodgkin lymphoma. Four patients developed a solid malignancy: lung, breast, ovary, and colon. The remaining cases were non-melanoma skin cancers, Table 1. Immune status (EBV IgG) was also determined. In TE patients, the median EBV IgG titre was 65.3U/ml at diagnosis (&amp;lt;3 - 600, n=48), falling to 28.1U/ml following induction (&amp;lt;3 - 326, n=41) and recovering to 44.2U/ml one year post ASCT (&amp;lt;3 - 600, n=22). In TNE patients, the median IgG titre at diagnosis was 39.1U/ml (&amp;lt;3 to 517, n=72), falling to 31.2U/ml 4 months post induction (&amp;lt;3 - 287, n=42) and recovering to 51.3U/ml after 1 year (&amp;lt;3 - 554, n=41). In the SPM patients the IgG EBV titres were noted to be &amp;lt;20U/ml in 5 of the 8 patients. Three of the eight patients had no detectable EBV IgG level (&amp;lt;3U/ml) Conclusions These data suggest that EBV infection is unlikely to be a risk factor for SPM development in myeloma patients. This is supported by the finding that EBV IgG titres were consistent with immunity in most patients (&amp;gt;20U/ml) and even in the patients with possible EBV infection, EBV DNA was only identified in 3 patients, and at a low level. In addition, the SPM developed are not classically associated with EBV infection or reactivation. It is noted that EBV infection status was not always determined at the time of SPM development. Despite this, the data does show that EBV immunity recovers following therapy, even in the post ASCT setting. EBV monitoring is therefore not supported by this work, although in patients who develop ≥2 SPM, further clarification is required.

Real World Data of Axicabtagene Ciloleucel As Second Line Therapy for Patients with Large B Cell Lymphoma: First Results of a Lysa Study from the French Descar-T Registry

Background and Significance: Axicabtagene ciloleucel (axi-cel) has demonstrated superior efficacy as second-line therapy (2L) over standard of care chemo-immunotherapy in transplant-eligible patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). In ZUMA-7 trial, 180 patients were randomized to receive axi-cel in 2L, achieving an estimated 4-year overall survival of 54% after a median follow-up of 47 months. In the ALYCANTE phase II study, 62 transplant-ineligible patients with R/R LBCL were treated with axi-cel as 2L, resulting in a 3-month complete metabolic response rate of 71% with a median progression free survival of 11.8 months. Here, we report the first real-world data of axi-cel as 2L for patients with early R/R LBCL treated in French centers. Study Design and Methods: DESCAR-T is a French nationwide registry collecting real-life data of all patients treated with approved CAR T-cell therapies (NCT04328298). All patients were informed before inclusion in the registry. The goal of the present analysis was to describe patients' characteristics, treatment course, and outcomes of all patients consecutively included in DESCART registry since July 2022, and infused with axi-cel according to the early access program supported by French authorities for patients with LBCL in early relapse (&amp;lt; 1 year) or refractory after a first line treatment. Results: Between July 2022 and March 2023, axi-cel was ordered and leukapheresis was performed for 85 patients. The first axi-cel infusion was performed in September 2022 and enrollment increased rapidly with 51 new patients waiting for a leukapheresis at the time of data cut-off in March 2023. No manufacturing failures occurred, at the data cut-off, 78 patients were infused with axi-cel in 22 centers, and 7 patients died before axi-cel infusion (5 because of progression, 2 from other cause). Among the 78 patients infused, 48 (61.5%) were male, median age was 60 years (range: 23-79), 35% were over 65 years old and 5% over 70 years old. Most patients had primary refractory disease (n = 58, 74.3%), a good performance status (n = 62, 79.5% ECOG 0-1), stage III-IV disease (n = 59, 75.6%) and elevated LDH (n = 48, 61.5%). The median time between leukapheresis and axi-cel infusion was 36 days, and 65 patients (83%) received bridging therapy, primarily immuno-chemotherapy (n = 57, 73%). At the time of lymphodepletion, patients had progressive (n = 35, 54%) or stable disease (n = 6, 9%), with only 23 patients (29%) responding to bridging therapy. The median follow-up since CAR-T-cells infusion was 1.1 month (range: 0-6). Safety information was reported for 65 patients: CRS occurred in 95% of patients, however only 3 patients (&amp;lt;5%) had a grade 3 or higher CRS. Neurotoxicity occurred in 43% of the cases, with 6 patients (9%) presenting grade 3 or higher toxicity. Furthermore, 13 patients (21%) were transferred to intensive care unit. Four patients (5%) died, 3 from lymphoma progression (missing data for the remaining patient). Among the 52 patients with at least 1 month of follow-up: the overall response and complete response rates at 1 month were 76.9% and 57.7% respectively (Figure 1). Conclusion: These preliminary results demonstrated that axi-cel in 2L for R/R LBCL is feasible and safe in real-life for transplant and non-transplant eligible patients. Although follow-up of our population remains short, early assessments of response are in line with those described in ZUMA-7 study. Inclusion in DESCART registry is on-going and updated results with at least 3 months of follow-up since infusion will be presented at the meeting.

Outcomes in Acute Lymphoid Leukemia Patients with Incomplete Hyper-CVAD Cycles

Introduction: Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone) is a commonly used regimen in acute lymphoblastic leukemia (ALL) for a total of 4 A/B intensive courses. This regimen is often limited due to multiple complications including organ dysfunction and medication toxicities along with high rates of relapse or disease progression. Prior studies have indicated five-year overall survival (OS) of 39% with severe prolonged myelosuppression being a common complication. In one study 6% of patients died during induction therapy. Here we provide clinical outcomes of non-transplanted patients with ALL receiving hyper-CVAD regimen in our tertiary referral center. We assessed overall survival, mortality rates, and complications during induction therapy with hyper-CVAD in our cohort of adult patients. Methods: We conducted a comprehensive, retrospective study at our center, evaluating outcomes of non-transplant eligible ALL patients treated from February 2003 to October 2022. We excluded patients without all available diagnostic information, and those who underwent allogeneic stem cell transplantation (SCT). We classified the patient based on their BCR - ABL1 gene status. Groups were subcategorized by highest cycle of Hyper-CVAD completion, with reason for cessation (medication toxicity/organ dysfunction, lost to follow up, progressive disease/relapse) elicited for those who did not complete all treatment cycles. Overall survival was analyzed using T-Test, ANOVA and Bartlett's test. Statistics are descriptive and our institutional review board approved this retrospective study. Results: We report outcomes of 43 ALL patients who did not undergo SCT. Median age at diagnosis was 52 years (range of 18-71 years). 33/43 (76.7%) patients received Hyper-CVAD regimen. 2/33 (6.1%) completed the entire course through 4B. 12 (36.3%) out of 33 patients received less than cycle 3b; 21/33 (63.6%) received at least cycle 3b. 2/6 (33.3%) completed up to cycle 1B, 2/11 (18.2%) completed up to cycle 2B, 13/25 (52%) completed up to cycle 3B, and 2/33 (6.1%) completed up to cycle 4B. 12/33 (36.4%) of patients were not able to complete more than cycle 3A due to organ dysfunction and intolerance, being lost to follow up, progressive disease or relapse, or participation in a trial. For the patients who received less than cycle 3b, the reasons for early discontinuation were: organ dysfunction 6/12 (50%), progressive disease or relapse 3/12 (25%), lost to follow up 2/12 (16.7%), or participation in a trial 1/12 (8.3%). Median overall survival (OS) for patients who received up to cycle 3A was 640 days compared to a median of 711 days for those who received at least cycle 3B. Median OS for patients who received up to cycle 3A in the Ph-negative group was 21.0 months and 23.1 months in the Ph-positive group. Median OS for patients who received at least 3B in the Ph-negative group was 20.9 months and 23.9 months in the Ph-positive group. Conclusion: Hyper-CVAD is the mainstay of ALL treatment. Induction chemotherapy in ALL is commonly associated with myelosuppression and documented infections (sepsis, pneumonia, port infection). Other significant side effects include neurotoxicity, liver and kidney failure. Induction chemotherapy in some patients was a limiting factor in completing therapy. We report the different reasons for terminating the treatment course to be: organ dysfunction or intolerance such as liver injury, neutropenic fever, septicemia, subarachnoid hemorrhage, renal failure, congestive heart failure, respiratory failure requiring intubation, port infection, cytokine release syndrome, and neurotoxicity. Median OS was longer in the Ph positive subgroup but the mortality rates for this subtype was not different between the patients who received up to cycle 3A verses those that received at least cycle 3B. In this study, our descriptive analysis did not show a clinically meaningful difference in survival in patients who did not finish the total induction course. A limitation of this study was not analyzing intrathecal prophylaxis as involvement of the central nervous system is a major clinical concern. Herein, we suggest a personalized approach in treating ALL patients considering infection risk, disease cytogenetic risk and depth of response to help adjusting the number of induction cycles based on the mentioned risk factors.

Dynamic Frailty Status Enables Better Prediction of Survival Probability - Results of the HOVON 143 Study

Introduction The clinical outcome of non-transplant eligible patients with newly diagnosed Multiple Myeloma (NDMM) is heterogeneous, largely depending on frailty level. Clinical scores such as the International Myeloma Working Group frailty index (IMWG-FI) classify patients in categories ‘fit’, ‘intermediate-fit’ or ‘frail’. As disease and treatment burden can change over time, frailty can improve but also deteriorate during treatment. However, data are scarce and the effects on clinical outcome are largely unknown. To address this, we prospectively investigated the dynamics of frailty scores and impact on clinical outcome of non-transplant eligible patients with NDMM (NTE-NDMM) included in the HOVON 143 study. Methods The HOVON 143 study included NTE-NDMM classified as intermediate-fit (score 1) or frail (score ≥2) by the IMWG-FI (score ranging from 0 to 5, fit being defined as 0). Patients were treated with nine 28 days-cycles of ixazomib (4mg on days 1, 4, 15), daratumumab (16mg/kg iv; cycles 1-2: days 1, 8, 15, 22; cycles 3-6: days 1, 15; cycles 7-9: day 1) and low dose dexamethasone (cycle 1-2: 20mg; subsequent cycles 10mg, co-administered with daratumumab). The IMWG-FI was calculated at baseline, after 3 and 9 cycles. A joint model was employed to model survival outcomes and longitudinal frailty score data. For this purpose, a cox model was used to model survival outcome and a mixed-effects model to model longitudinal frailty score data (R statistical program, package JM). Results Of the 130 included patients, 65 were intermediate-fit at baseline and 65 patients were frail (49% score 2, 28% score 3, 22 % score 4, 1% score 5). After nine cycles, 82 patients were still on protocol of whom frailty level over time was known in 74 patients (39 intermediate-fit, 35 frail). Six/35 frail patients could not improve in frailty score as well as category, as they were classified as ‘frail’ due to age &amp;gt;80 years without any impairments or comorbidities. Of the 29 frail patients that could improve, 14 (48%) improved in frailty score. Of those, 5 patients became intermediate-fit, 1 became fit and 8 remained frail because of still having a score of ≥2. Reasons for improvement were becoming less iADL dependent (11/14), less ADL dependent (10/14), or both (8/14). Improvement in Charlson Comorbidity Index (CCI) occurred in 4/14. Six out of 34 (18%) who could deteriorate in frailty score (excluding the patient with frailty score of 5), did so. Two frail patients became ADL dependent, 2 became iADL dependent and 2 deteriorated in score solely due to age (turning 81 years old during treatment). Out of the 39 intermediate-fit patients that could improve in frailty score, 6 (15%) improved and consequently became fit (frailty score from 1 to 0). Reasons for improvement were becoming less ADL dependent (3/6) and improved CCI (3/6). Five intermediate-fit patients (13%) deteriorated. One intermediate-fit patient became iADL dependent (1/5), 1 patient acquired a comorbidity (1/5) and 3 deteriorated in score solely due to age (turning 76 old during treatment). Median duration of follow up of all 130 patients was 46 months. Including frailty score as a time varying covariate in survival analysis by a joint model indicated that the frailty score improved over course of treatment, and that improvement of frailty score was associated with higher survival probabilities (HR 0.58 (95%CI 0.42 - 0.79), p&amp;lt;0.001) ( Figure 1). Conclusion This is the first study to report the dynamics in IMWG frailty assessment of non-transplant eligible patients with NDMM during a clinical trial. The frailty score improved in nearly half of frail patients and 15% of the intermediate fit patients during MM treatment. This led to reclassification to intermediate-fit or fit in a substantial number of patients. Improvement of the frailty score was associated with prolonged survival. Future studies are needed to investigate whether dynamic frailty status is a better predictor for clinical outcome than frailty status at baseline.

Selinexor-Based Triplet Regimens in Patients With Multiple Myeloma Previously Treated With Anti-CD38 Monoclonal Antibodies

BackgroundThe increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options. Patients and methodsWe analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs. ResultsSixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications. ConclusionSelinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients.

The Burden of a Multiple Myeloma Diagnosis on Patients and Caregivers in the First Year: Western European Findings.

This research aimed to quantify the burden of illness (BoI) in transplant eligible (TE) and transplant non-eligible (TNE) newly diagnosed multiple myeloma (NDMM) patients and their caregivers, in the first year after diagnosis: at months 0, 3, and 12. Prospective, cross-sectional, observational NDMM study of TE and TNE patients and their caregivers from France, Germany, Italy, and Spain was conducted between May 2019 and January 2021. A structured, online questionnaire measuring disease burden, direct and costs, out-of-pocket expenses, and health-related quality of life (HRQoL) was used. Descriptive statistics were performed. A total of 164, 160, and 190 NDMM patients [>65 years; self-described healthy; not working; living with caregiver] answered at months 0, 3, and 12. Patients lost independence to perform daily activities; mean pain intensity rose and opioid utilization increased, more significantly among TNE patients. Overall health status and HRQoL remained stable. Median 3-month direct medical costs peaked at month 3. Specialist consultations and hospital admissions were the greatest cost amongst TE and TNE patients. Home adaptations increased out-of-pocket expenditures amongst TNE patients. Patients describing themselves as working spent a median 0 hours in the office at all time points. A total of 131, 122, and 124 caregivers answered at months 0, 3, and 12. Mean self-rated burden score rose. By month 12, half of caregivers developed stress, anxiety or depression. Most employed caregivers continued working. Productivity was low at month 0 with a trend of recovering at month 12. Caregivers of TNE compared to TE patients reported greater time burden. Caregivers' HRQoL was stable over time. NDMM is burdensome for patients and caregivers in the first year after diagnosis. TNE patients are more dependent on caregivers and incur higher care costs than TE patients. Despite the financial, physical, and emotional burden, HRQoL remains stable possibly indicating resilience and illness adjustment amongst patients and caregivers.

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (Isa-KRd) in Patients with High-Risk Newly Diagnosed Multiple Myeloma: Planned Interim Analysis of the GMMG-Concept Trial

Background: High-risk (HR) multiple myeloma (MM) patients (pts) have a significantly disadvantageous prognosis. Emerging data show that achievement of minimal residual disease (MRD) negativity is associated with better outcome in HR pts. Most recently, several clinical trials demonstrated that addition of monoclonal anti CD38 antibodies (i.e. isatuximab) significantly improve MRD negativity, response rate and survival when added to standard of care regimens. Carfilzomib (K), lenalidomide (R) and dexamethasone (d) is one of the most effective and tolerable regimens in newly diagnosed multiple myeloma (NDMM). The phase II CONCEPT trial (NCT03104842) investigates the quadruplet regimen isatuximab plus KRd (Isa-KRd) in HR NDMM in induction and consolidation including high-dose melphalan (HDM) for pts being transplant-eligible (TE). Here, we report for the first time the planned interim analysis (IA) of the primary endpoint MRD negativity after consolidation for TE-patients and the corresponding final analysis of transplant non-eligible (TNE) pts. Methods: 153 pts with HR NDMM were included into the open-label, academic, multicentre phase II clinical trial, an extension cohort of TE pts is currently recruiting. According to the trial design, 99 of 127 TE pts in study arm A (TE-ITT) were included in the intention-to-treat population (ITT) of the planned IA (TE-ITT-IA); results of the 26 TNE pts in study arm B (TNE-ITT) are finally reported. HR MM was defined by the presence of del17p or t(4;14) or t(14;16) or > 3 copies 1q21 in combination with ISS 2 or 3 stage disease. Pts could be included after a maximum of 1 cycle of MM treatment. Pts received 6 cycles of Isa-KRd induction, followed by HDM for TE pts or 2 Isa-KRd cycles for TNE pts, 4 cycles Isa-KRd consolidation and Isa-KR maintenance. Primary endpoint is MRD negativity at end of consolidation measured by next-generation flow at the minimum sensitivity threshold of 10-5 (H0: MRD-neg-rate ≤ 50% (TE) and ≤ 30% (TNE), tested by one-sided binomial test), this planned IA reports on. Secondary endpoint is progression-free survival (PFS), tertiary endpoints include overall response rate (ORR) and safety. Results: 125 pts (99 TE-ITT-IA, 26 TNE-ITT) were included from August 2017 to April 2020 in the IA population in 17 German Centres. No bias arose in the reduction of the TE-ITT population to the TE-ITT-IA population. Based on inclusion criteria, all pts had cytogenetic HR disease including del17p in 55 pts (44.0%), t(4;14) in 48 (38.4%), t(14;16) in 19 (15.2%) and > 3 copies 1q21 in 45 pts (36.0%). 38 pts (30.4%) had ≥ 2 HR aberrations. 66 pts (52.8%) had ISS 2 and 58 (46.4%) ISS 3 disease. Median age (range) was 58 (35-73) years in the TE-ITT-IA and 74 (64-87) years in the TNE-ITT. The design of the study provides for the MRD-analysis to be performed on 93 patients in the TE-ITT-IA and 24 patients in the TNE-IA. At the end of consolidation, in the TE-ITT-IA population 67.7% (n=63) of pts were MRD negative, 3.2% (n=3) MRD positive, 24.7% (n=23) timepoint not reached, 4.3% (n=4) missing (4 pts not assessable, 2 did not start). In the TNE-ITT population 54.2% (n=13) of pts were MRD negative, 0% MRD positive, 45.8% (n=11) timepoint not reached. The primary endpoint was significantly reached in both study arms (p = 0.0004 for TE-ITT-IA and p=0.012 for TNE-ITT). ORR (best response to treatment) in the TE-ITT-IA was 94.9% (n=94) with 72.7% showing complete remission (CR) or better (n=72), 18.2% (n=18) very good partial remission (VGPR), 4% (n=4) partial remission (PR), 1% (n=1) progressive disease (PD) and 4% (n=4) timepoint not reached. In the TNE-ITT, 57.7% (n=15) showed CR or better 30.8% (n=8) VGPR, 3.8% (n=1) were unknown and 7.7% (n=2) timepoint not reached. Updated PFS data will be shown. Safety-population consists of 122 pts. In total, 85.2% (n=104) developed ≥ grade 3 treatment-emergent adverse events (TEAEs). Serious TEAEs occurred in 64.8% (n=79) of pts. TEAEs leading to discontinuation of study treatment occurred in 5 pts. Conclusions: The CONCEPT trial is the first trial investigating Isa-KRd for HR NDMM in TE and TNE patients. Isa-KRd in induction and consolidation leads to high MRD negativity rates after consolidation in this difficult-to-treat population. Toxicity was consistent with expectations and no new safety signals occurred in this IA. In our view, our data underline the importance of optimized quadruplet treatment in NDMM, especially in HR disease.

Randomized Comparison between Krd and Ktd Induction, Followed By K Maintenance or Control in Transplant Non-Eligible Patients with NDMM: Efficacy and Qol Data (AGMT-MM02 Trial)

Randomized Comparison between Krd and Ktd Induction, Followed By K Maintenance or Control in Transplant Non-Eligible Patients with NDMM: Efficacy and Qol Data (AGMT-MM02 Trial)

Stem Cell Mobilization Characteristics for Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) Treated with Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab (KRd-Dara)

Introduction: CD38 monoclonal antibody (mAb)-containing quadruplet regimens have been shown to improve depth and duration of response in patients with NDMM eligible for autologous stem cell transplant (ASCT). However, some studies have raised concerns about the detrimental effect of combined lenalidomide and CD38 mAbs on stem cell mobilization. As an exploratory endpoint, we evaluated the effect of KRd-Dara on stem cell mobilization and collection in the Levine Cancer Institute (LCI) KRd-Dara study (NCT04113018) that permits up to 8 cycles of induction with KRd-Dara followed by an MRD-directed treatment algorithm for transplant-eligible and transplant-noneligible patients (Bhutani et al, Blood 2020 Abstr 1388). We provide a table summarizing our results from stage 1, along with two other phase II studies, the MANHATTAN (Landgren et al, JAMA Oncol 2021) and the MASTER (Costa et al, JCO 2021) studies that used variable numbers of KRd-Dara induction cycles prior to stem cell apheresis. Patients and study design: Eligible patients had NDMM and an ECOG performance status score of 0-2. Induction treatment consisted of 28-day cycles of KRd-Dara with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); lenalidomide orally, 25 mg (days 1-21); dexamethasone weekly; daratumumab (subcutaneous) per standard approved dosing schedule. One pre-study cycle with non-protocol therapy was allowed. During stage I of the study, stem cell collection for transplant-eligible patients was performed after 8 cycles of induction. All patients were mobilized with granulocyte-colony stimulating factor (G-CSF, 10 µg/kg) daily for 5 days. Preemptive Plerixafor was administered in the evening of Day 4 if the blood CD34+ cell count was <50/µl. Collection was done over 2 days in some patients who failed to collect sufficient CD34+ cells during the first day. A second mobilization attempt after a few weeks of additional wash-out was allowed. Our center-specific minimum required collection target is 3 x 106 CD34+ cells/kg, below which the stem cell dose is considered inadequate to perform a single ASCT. Physicians requested collection for potentially 2 or 3 transplants per patient, with a collection goal of 8 -12 x 106 CD34+ cells/kg. Mobilization failure was defined as the proportion of patients with Day 4 CD34 count <1/µl or collection of <3 x 106 CD34+ cells/kg (considered inadequate for even one ASCT) during the first mobilization attempt. Results: Among the 22 mobilized patients during stage 1 analysis, the median age was 60 years (range, 34 to 72) and 32% were African Americans. Eighteen patients received plerixafor, 3 did not based on futility as their Day 4 blood CD34 count was zero, and only one patient met the threshold of not receiving Plerixafor. The median total CD34+ cells collected were 7.73 x 106/kg (range, 0.00-19.18). Six (27%) patients had mobilization failure after their first attempt. Four of these patients underwent a second attempt after a median of 56 days (range, 36-98 days), with only one patient collecting enough CD34+ cells for one ASCT. Of the 10 patients whose collection goal was 2 transplants (8 million CD34 cells/kg), 9 patients did not meet the goal. Of the 12 patients whose collection goal was 3 transplants (12 million CD34 cells/kg), 8 patients did not meet the goal. Conclusions: The stem cell mobilization failure rate was high in patients collecting after 7 or 8 cycles KRd-Dara. Second remobilization with G-CSF and plerixafor was successful in only 1 of the 4 patients. We have modified stage 2 of the protocol to allow stem cell collection after cycle 3 of KRd-Dara induction. We plan to do combined analyses of LCI, MANHATTAN and MASTER to determine predictive factors associated with poor stem cell mobilization after KRd-Dara induction. Based on our results, we recommend stem cell collection after 3-4 cycles of KRd-Dara regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved survival in myeloma patients-a nationwide registry study of 4,647 patients ≥75 years treated in Denmark and Sweden.

The prevalence of multiple myeloma (MM) is increasing in Nordic countries and the rest of the western world. Patients aged ≥75 years at diagnosis constitute an increasing proportion of all MM patients, but are underrepresented in randomized clinical trials. There is an urgent need for studies of the characteristics, treatment and outcome in this cohort. We present data from two nationwide population-based registries of all MM patients diagnosed in Denmark from January 1, 2005 until February 18, 2020, and in Sweden from January 1, 2008 until December 31, 2019, including treatment data for patients diagnosed until 2018 (Denmark) and 2019 (Sweden). In total 4,647 patients were ≥75 years at diagnosis, compared to 7,378 younger patients. Patients ≥75 years, accounting for approximately 40% of all MM patients, are a distinct cohort with more advanced disease at diagnosis, reflected by higher International Staging System (ISS) stage, and a higher proportion have renal failure and anemia. We found a more gradual introduction of modern medications in the older cohort than in the younger, despite simultaneous changes in guidelines. Compared to the cohorts in randomized controlled trials that guide the treatment of non-transplant eligible patients, we found a higher proportion of patients ≥75 years and presenting with ISS III in the real-world populations. Nevertheless, response rates and survival are increasing, indicating that modern treatment regimens are effective and well tolerated also in elderly MM patients in real-world populations.

Treatment of Mantle Cell Lymphoma in Transplant Non-Eligible Patients

MCL is a rare but usually aggressive non-Hodgkin lymphoma that most commonly affects the elder population. It is now recognized as a heterogeneous disease with variable biologic and clinical behavior. MCL is considered incurable with current therapies and has historically been associated with a poor prognosis. . Large gains were made in the first decade of the new century when clinical trials established the importance of high-dose therapy and autologous stem-cell rescue and high-dose cytarabine in younger patients and the benefits of maintenance rituximab and bendamustine in older patients. Patients with mantle cell lymphoma (MCL) usually respond to initial combination chemotherapy, but the disease inevitably relapses and often follows an aggressive course. Treatment paradigms have evolved along two lines. Younger, fit mantle cell lymphoma (MCL) patients are generally treated with intensive strategies and older less fit patients with non-intensive strategies. Management of patients with newly diagnosed mantle cell lymphoma (MCL) depends on the age and fitness of the patient. For younger patients, the commonly accepted standard of care is a high-dose cytarabine-based induction chemotherapy followed by autologous stem cell transplantation (ASCT). In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT, the standard-of-care has generally been R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by rituximab, maintenance. In recent years, bendamustine-based therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients. Traditionally, the treatment of MCL has been determined by patients being deemed “transplant-eligible” or “transplant-ineligible”. In particular, greater depth of understanding of the molecular pathophysiology of MCL has resulted in an explosion of specifically targeted new efficacious agents. In particular, agents recently approved by the Food and Drug Administration include the proteasome inhibitor bortezomib, immunomodulator lenalidomide, and Bruton's tyrosine kinase inhibitor ibrutinib. Newer data suggest more tolerable front-line therapy, including regimens incorporating novel agents, may produce similar outcomes to intensive historical induction regimens. This may in turn preclude fewer patients from autologous stem cell transplant and produce better long-term outcomes in transplant-ineligible patients. In the relapsed/refractory setting, novel agents and combination regimens are improving outcomes and changing the landscape of treatment. New therapies with distinct mechanisms of action, including novel immunotherapeutics, antibody-drug conjugates, and non-covalent BTK inhibitors, have demonstrated great potential for improving outcomes post–BTK inhibitor failure in relapsed/refractory mantle cell lymphoma. Although cBTK inhibitor has transformed the treatment landscape in B-cell malignancies, the majority of patients will eventually experience disease progression or treatment intolerance. There are 2 oral BTK inhibitors approved for use in relapsed MCL: ibrutinib and acalabrutinib. Acalabrutinib, originally referred to as ACP-196, is a novel, irreversible BTK inhibitor that was designed to be more kinase-selective than ibrutinib. Orelabrutinib is an orally administered, potent, irreversible and highly selective BTK-inhibitor being developed the treatment of B cell malignancies and autoimmune diseases. Tirabrutinib irreversibly and covalently binds to BTK in B cells and inhibits aberrant B cell receptor signalling in B cell-related cancers and autoimmune diseases. Zanubrutinib received accelerated approval in the USA on 14 November 2019 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, based on overall response rate (ORR) seen in phase II and I/II clinical trials. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. Zilovertamab vedotin is an antibodydrug conjugate, which binds specifically to receptor tyrosine kinase-like orphan receptor-1 (ROR-1), an oncoprotein that is pathologically expressed in mantle cell lymphoma and other malignancies. The development of anti-CD19 CAR T-cell therapy represents a major advance in the treatment of patients with chemorefractory B-cell malignancies.

Impact of Comorbidities on Health-related Quality of Life in Nontransplant Eligible Patients With Newly Diagnosed Multiple Myeloma.

Impact of Comorbidities on Health-related Quality of Life in Nontransplant Eligible Patients With Newly Diagnosed Multiple Myeloma.

Abstract 498: TARE and PVE as pre-operative strategies in highly selected patients with primary and metastatic hepatic malignancies

Abstract Background: The treatment of malignancies confined to the liver (hepatocellular carcinoma [HCC], intrahepatic cholangiocarcinoma [ICC], metastatic neuroendocrine tumors [NET] and colorectal hepatic metastases [CRHM]) is challenging. Liver resection leading to post-operative liver failure is a devastating complication that can be mitigated by pre-resection embolization techniques to increase the future liver remnant, such as portal vein embolization (PVE) and transarterial radioembolization (TARE). The purpose of this study was to understand the natural history of this treatment algorithm in disparate patient populations. Methods: This was a retrospective case-control study from 2008 to 2018. The population consisted of non-transplant eligible patients that had various malignancies without extra-hepatic disease who underwent TARE, PVE, or resection at our institution; they were propensity matched based on co-morbidities, etiology of liver disease, Child-Pugh Score, and ECOG performance status. Statistical analyses were performed with chi-square. Results: We identified 196 patients with an average age of 57.8±12.6 years and 119 patients were male (60.7%). There were 137 Caucasian patients (CC, 70%) and 59 African American patients (AA, 30%). The tumor histologies were 61 HCC, 31 ICC, 65 CRHM, 12 NET, and 28 other. 148 of these patients underwent liver resection. HCC patients were more likely to undergo TARE (36.4%) compared to ICC (20%), CRHM (23.6%), or NET (9.1%, P= 0.043). While AA patients were more likely to undergo any embolization procedure compared to CC patients (47% vs 31%, P=0.03), they were less likely to undergo PVE (P=0.018). 126 patients (64%) did not undergo any pre-resection embolization procedures. Of patients requiring pre-resection embolization, CRHM patients were more likely to undergo PVE (80%) than other patients (P=0.029). TARE was a bridge to resection for 9 patients. Conclusions: AA patients underwent more embolization procedures compared to CC patients. It is not clear whether this was because that population required more interventions to optimize FLR or had limited access to care. Citation Format: Julia Pedo Freitas, Pradeep Podila, Daniel K. Powell, Wes Angel, Jeremiah L. Deneve, Paxton V. Dickson, Evan S. Glazer. TARE and PVE as pre-operative strategies in highly selected patients with primary and metastatic hepatic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 498.

Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): a study protocol for a randomised phase III trial

IntroductionMultiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population.Over the last 10 years, patient outcomes have improved. However, this...

TARE and PVE as pre-operative strategies in highly selected patients with primary and metastatic hepatic malignancies

Introduction The treatment of hepatic malignancies (hepatocellular carcinoma [HCC], intrahepatic cholangiocarcinoma [ICC], metastatic neuroendocrine tumors [NET] and colorectal hepatic metastases [CRHM]) is challenging. Post-operative liver failure can be mitigated by pre-resection embolization techniques, such as portal vein embolization (PVE) and transarterial radioembolization (TARE). The purpose of this study was to understand the natural history of this treatment algorithm in disparate patient populations. Methods This was a retrospective case-control study from 2008-2018. Population consisted of non-transplant eligible patients who underwent TARE, PVE, or resection; patients were propensity matched based on co-morbidities, diagnosis, Child-Pugh Score, and ECOG score. Analyses were performed with chi-square. Results We identified 196 patients with an average age of 57.8±12.6 years, 119 of which were male (60.7%). 137 patients were Caucasian (CC, 70%) and 59 were African American (AA, 30%). HCC patients were more likely to undergo TARE (36.4%) than all other patients (P= 0.043). AA patients were more likely to undergo any embolization procedure (47% vs 31%, P=0.03), but less likely to undergo PVE (P=0.018). CRHM patients were more likely to undergo pre-resection PVE (80%, P=0.029). TARE was a bridge to resection for 9 patients. Conclusions In select cases, TARE is an option to bridge patients to resection. AA patients underwent more embolization procedures than CC patients.

Lenalidomide Compared to Ixazomib Maintenance in Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

BackgroundMaintenance therapy is considered a standard of care in transplant eligible (TE) and non transplant eligible (NTE) patients with newly diagnosed multiple myeloma (NDMM). While immunomodulators (IMID) and proteasome inhibitors (PI) have been proposed as maintenance therapy options, there are no randomised trials (RCTs) directly comparing these agents in the maintenance setting. The IMID lenalidomide (Len) and the PI ixazomib (Ixa) have been compared against placebo as maintenance strategies in NDMM. We present a network meta-analysis (NMA) of RCTs comparing the efficacy and safety of Len and Ixa maintenance therapies in NDMM.MethodsWe searched various biomedical databases for eligible studies evaluating Len or Ixa against placebo/ observation as maintenance therapy in patients with NDMM from date of inception through November 2020. The primary outcome was progression-free survival (PFS). Secondary outcomes include overall survival (OS) and adverse events (AE). The Cochrane risk of bias tool version 2.0 was used to assess trial quality. A Bayesian NMA model was used to assess the relative effects of competing treatments on PFS and OS outcomes. Adverse events were assessed using the synthesis without meta-analysis (SWIM) approach due to variability in the toxicity scoring criteria. The GRADE approach was used to rate the certainty of the evidence. This study is registered with PROSPERO, CRD42021226157.ResultsWe identified eight studies including 3229 transplant eligible (TE) and 1689 non transplant eligible (NTE) patients. All studies were judged to have low risk of bias. Len but not Ixa was associated with statistically significant improvement in PFS when compared to placebo in TE (Len: Hazard Ratio (HR) 0.46, 95% Credible Interval (CrI) 0.35-0.56, high certainty; Ixa: HR 0.72, 95% CrI 0.46-1.13, moderate certainty) and NTE (Len: HR 0.46, 95% CrI 0.29-0.75, high certainty; Ixa: HR 0.69, 95% CrI 0.43-1.18, moderate certainty). Bayesian modelling demonstrated a 97% and 93% probability that Len resulted in superior PFS compared to Ixa in TE and NTE patients respectively. Both Len and Ixa were not associated with statistically significant improvement in OS compared to placebo in TE and NTE patients. There was no significant effect modification on the effect of Len vs placebo and Ixa vs placebo by cytogenetics status, use of proteasome inhibitors for induction or duration of maintenance therapies for PFS and/or OS outcomes. Len were judged to have a higher incidence of second malignancies and grade 3 or 4 neutropenia than Ixa while Ixa was judged to have a higher incidence of thrombocytopenia than Len.ConclusionsMaintenance therapy with Len may provide a larger PFS benefit than Ixa regardless of type of induction therapy and cytogenetic risk in patients with NDDM. The differing toxicity profile of these agents is also an important consideration for treatment decisions. RCTs directly comparing these maintenance strategies are warranted. [Display omitted] DisclosuresOoi: Jansen: Honoraria; Teva Pharmaceuticals: Honoraria; GSK: Honoraria; Abbvie: Honoraria; Amgen: Honoraria. Chng: Sanofi: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Amgen: Honoraria; BMS/Celgene: Honoraria, Research Funding; Johnson and Johnson: Honoraria, Research Funding; Pfizer: Honoraria.

Enrolment and Outcomes of Ethnic Minorities with Multiple Myeloma Treated in UK Myeloma Research Alliance (UK-MRA) Clinical Trials over 18 Years

Enrolment and Outcomes of Ethnic Minorities with Multiple Myeloma Treated in UK Myeloma Research Alliance (UK-MRA) Clinical Trials over 18 Years