Eligible Multiple Myeloma Patients Research Articles

Steady-State Versus Chemotherapy-Based Stem Cell Mobilization in Multiple Myeloma: A Single-Center Study to Analyze Efficacy and Safety.

High-dose chemotherapy followed by autologous hematopoietic stem cell support is recommended in the treatment of eligible multiple myeloma (MM) patients. The aim of this study was to compare the efficacy and safety of steady-state versus chemotherapy-based stem cell mobilization in our Hungarian patient population. The subjects were 210 MM patients who underwent stem cell mobilization procedure between 2018 and 2022. Solo granulocyte colony-stimulating factor (G-CSF) was administered in 104 cases, while 106 patients received chemotherapy which was followed by G-CSF administration. We evaluated the ratio of successful mobilizations, the amount of collected stem cells, the incidence of infections and cost-effectivity in the two groups. In the steady-state group, there was a significantly higher need for plerixafor (45% vs. 13%, P < 0.001), unsuccessful stem cell mobilization was more frequent (11% vs. 3%, P = 0.024) and the mean amount of collected stem cells was lower (6.9 vs. 9.8 × 106, P < 0.001) than in the chemotherapy group. However, infections were less frequent (4% vs. 27%, P < 0.001) and the number of days spent in hospital was significantly lower (6 vs. 14 days, P < 0.001). Plerixafor was more frequently administered in those who had received lenalidomide or daratumumab than in those who had been treated with other regimens (41% vs. 23%, P = 0.007 and 78% vs. 23%, P < 0.001, respectively). Steady-state mobilization is a safe method; however, the higher rate of plerixafor administration and unsuccessful attempts may question its superiority to chemomobilization.

Single-Cell DNA Sequencing Reveals an Evolutionary Pattern of CHIP in Transplant Eligible Multiple Myeloma Patients

Clonal hematopoiesis of indeterminate potential (CHIP) refers to the phenomenon where a hematopoietic stem cell acquires fitness-increasing mutation(s), resulting in its clonal expansion. CHIP is frequently observed in multiple myeloma (MM) patients, and it is associated with a worse outcome. High-throughput amplicon-based single-cell DNA sequencing was performed on circulating CD34+ cells collected from twelve MM patients before autologous stem cell transplantation (ASCT). Moreover, in four MM patients, longitudinal samples either before or post-ASCT were collected. Single-cell sequencing and data analysis were assessed using the MissionBio Tapestri® platform, with a targeted panel of 20 leukemia-associated genes. We detected CHIP pathogenic mutations in 6/12 patients (50%) at the time of transplant. The most frequently mutated genes were TET2, EZH2, KIT, DNMT3A, and ASXL1. In two patients, we observed co-occurring mutations involving an epigenetic modifier (i.e., DNMT3A) and/or a gene involved in splicing machinery (i.e., SF3B1) and/or a tyrosine kinase receptor (i.e., KIT) in the same clone. Longitudinal analysis of paired samples revealed a positive selection of mutant high-fitness clones over time, regardless of their affinity with a major or minor sub-clone. Copy number analysis of the panel of all genes did not show any numerical alterations present in stem cell compartment. Moreover, we observed a tendency of CHIP-positive patients to achieve a suboptimal response to therapy compared to those without. A sub-clone dynamic of high-fitness mutations over time was confirmed.

Longitudinal Screening of Mutant Hematopoietic Progenitor Cells (HPC) in Multiple Myeloma (MM) and Its Association with Secondary Primary Malignancies (SPM)

Background: The incidence of SPM in transplant eligible MM patients (pts) receiving lenalidomide maintenance is ≥ 12% and is associated with inferior overall survival (OS). Recent evidence suggests that while clonal hematopoiesis does not increase the risk of SPM, specific TP53 mutant HPC may expand under lenalidomide treatment and give rise to therapy related myeloid neoplasms and acute lymphoblastic leukemia. Genetic screening may facilitate personalized treatment to minimize the risk of SPM. However, there are no longitudinal studies in purified HPC to inform on the evolution of specific gene mutations and its association with clinical outcomes. Aim: Analyze the mutational landscape of HPC at diagnosis and throughout lenalidomide based regimens. Methods: This study included 335 pts: 43 with high risk smoldering MM, 223 transplant eligible and 69 ineligible active MM respectively enrolled in the CESAR, GEM2012MENOS/GEM2014MAIN and CLARIDEX clinical trials. Of the 335 pts analyzed at diagnosis, 60 were further investigated after induction, 30 at day 100 after autologous transplant (ASCT) and 47 during maintenance. Two or more studies were available throughout treatment in 36 pts. Fluorescence activated cell sorting of CD34+ HPC was performed in a total of 500 bone marrow aspirates. DNA was analyzed with a panel of 55 genes recurrently mutated in myeloid neoplasms. Sequencing depth was &amp;gt;1000x in 95% of nucleotides. Criteria to filter out included synonymous, intronic, invalid-transcript, 5'UTR, panel error and single nucleotide polymorphisms. The criteria to filter in was a AMP/ACMG classification of uncertain significance, likely pathogenic or pathogenic. Only the latter two were included in downstream analysis. Results: HPC from 184 of the 335 (55%) pts were mutated. The frequency in high-risk smoldering MM, transplant eligible and ineligible active MM was 46%, 26% and 35%, respectively. The genes more frequently mutated were DNMT3A (n=94, 52%), TP53 (n=29, 16%) and TET2 (n=28, 15%). The median variant allele frequency was 4.9, 7.5 and 7.0, respectively. In a pt-paired analysis between diagnosis and induction, 8 mutations were present in both time points, 25 became undetectable and 22 were acquired during treatment. The latter (eg, PPM1D and SF3B1) were observed in 14 of the 60 (23%) pts. In the 30 pts with paired samples at diagnosis and at day 100 after ASCT, 4 mutations were present in both time points, 48 became undetectable and only 3 were acquired during treatment ( ATRX, MPL and SAMDL9). Thus, the frequency of mutant HPC was higher at diagnosis vs ASCT (23% vs 5%, P &amp;lt;.001). In a pt-paired analysis between diagnosis and maintenance, 13 mutations were present in both time points, 12 became undetectable and 30 were acquired during treatment. The latter (eg, PPM1D and SF3B1) were observed in 24 of the 47 (51%) pts screened at both time points, and after a median of 5 years since diagnosis. With a median follow-up of 6 years, 17 of the 335 (5%) pts developed SPM. Mutant HPC were detected in 13 of the 17 pts. Accordingly, presence of mutant HPC was associated with a 2-fold increased risk of SPM (OR: 2.3; P = .03). Of the 13 pts, 3 showed mutations at diagnosis and in 8 these emerged during maintenance. The only case developing a myeloid neoplasm had a TP53 mutation present during maintenance that was undetectable at diagnosis. Pts with mutant vs non-mutated HPC at diagnosis showed similar OS (6y rates of 86% and 81%, respectively; P =.46). Similarly, there were no differences in OS of pts with emerging mutations vs those without mutant HPC after treatment (6y rates of 85% and 83%, respectively; P =.65). Specific mutations in DNMT3A, TP53 and TET2 and were not associated with inferior OS. Conclusions: To our knowledge this is the first study analyzing the mutational landscape of purified HPC throughout lenalidomide based regimens in high risk smoldering MM as well as transplant eligible and ineligible active MM. Deep sequencing of CD34+ HPC uncovered that the frequency of mutations is similar between precursor and malignant disease, and that TP53 is amongst the top mutated genes. There was considerable volatility with presence of both transient and emerging mutations throughout treatment. Importantly, the detection of mutant HPC was associated with increased risk of SPM without differences in survival. Thus, this study supports the longitudinal screening of HPC for the identification of patients at risk of developing SPM.

Lenalidomide Maintenance after VTD Induction and Autologous Stem Cell Transplantation: An Italian Real-Life Study of 558 Patients

According to 2021 ESMO guidelines, treatment of newly diagnosed (ND) transplant eligible (TE) Multiple Myeloma (MM) patients is settled by an induction phase followed by single or tandem autologous stem cell transplantation (ASCT) and Lenalidomide (Len) maintenance. Len maintenance was approved in Italy in May 2018 due to the results of the meta-analysis by McCarthy et al. of three large randomized clinical trials. Before the approval of daratumumab-bortezomib-thalidomide-dexamethasone (D-VTD) regimen, VTD triplet combination was the most used induction regimen across Italian centers. In addition, given the data from the EMN02 trial, in the last years tandem ASCT has been a consolidated practice especially for high-risk cytogenetic patients. However, only a minority of patients enrolled in the meta-analysis of McCarthy received VTD induction and in most of them a single ASCT has been performed. In this context, the aim of this real-life study was to evaluate the efficacy and the safety of Len maintenance after VTD plus single or tandem ASCT in ND TE MM patients. The study cohort included 558 patients with a median age of 59 years (24-74) followed in 21 Italian referral centers. Baseline clinical and biological features are reported in table 1. ISS III and R-ISS III were detected in 111/518 (21.4%) and 44/405 (10.9%) cases, respectively, moreover, 30/327 (9.2%) patients showed R2 ISS stage IV. FISH analysis was available in 408 patients with 70 of them displaying high risk (HR) alterations [including t(4;14), t(14,16) and del17p]. Among the 338 standard risk patients, information about 1q status was available for 320 of them, with 60 patients harboring +1q abnormalities (18.75%). All patients received VTD induction (median number of cycles 4) and single or tandem ASCT was performed in 63.7% and 36.3% of cases, respectively. A median number of 22 cycles of Len maintenance was administered. Complete response (CR) and stringent CR (sCR) rates before starting Len were 31.8% and 14.2%, respectively (overall 46%) and increased with maintenance to 39.6% and 16.6%, respectively (overall 56.2%). Most importantly, 2-year CR and sCR rates in evaluable patients were superimposable (40.6% and 14.9% respectively, 55.5% overall). One hundred ninety-seven patients (35.3%) discontinued treatment, mostly due to progressive disease (134/197, 68.0%). Toxicities were mostly hematological with neutropenia found in 50.4% of cases (grade ≥3 in 17.2%), followed by thrombocytopenia and anemia in 24.4% and 16.1% of cases, respectively (grade ≥3 in 2.1% and 1.8% of cases, respectively). Non-hematological adverse events were primarily gastrointestinal (31.2%, grade ≥3 in 2.3%) and infections (42.3%, grade ≥3 in 3.9%) while skin related disorders affected 7.9% of patients. With a median follow up of 30 months, the 2-year PFS and OS from starting maintenance were 80.6% and 96.7%, respectively. No significant PFS difference was found according to age (&amp;gt;65 years vs ≤65 years, p=0.5924) or ASCT (single vs tandem, p=0.4694). Patients with low-risk disease including ISS I and R-ISS I showed improved PFS as compared to patients with ISS &amp;gt;I and R-ISS &amp;gt;I (2y PFS 84.6% vs 76.6%, p=0.0587 and 87.8% vs 72.7%, p=0.0195, respectively). By R2-ISS, low risk disease (R2-ISS I) confirmed a better outcome as compared to R2-ISS II-III (2y PFS 88.9% vs 72.2%, p=0.0333) and to R2-ISS IV (2y PFS 47.2%, p&amp;lt;0.0001). Finally, considering cytogenetic risk status, standard risk patients displayed a significantly prolonged PFS as compared to high-risk patients (2y PFS 81.6 % vs 56.3%, p&amp;lt;0.0001) and an improved although not significant outcome than patients harboring isolated +1q (2y PFS 77.2%, p=0.09). Moreover, we demonstrated that the accumulation of HR cytogenetic abnormalities reduces patients' outcome, in detail the PFS of patients with at least 2 HR abnormalities was significantly lower than patients with only 1 and without HR aberrations, respectively [2y PFS 44.8% (≥2) vs 73.5% (1), p=0.0301, and 2y PFS 44.8% (≥2) vs 82.8% (0), p&amp;lt;0.0001, figure 1]. To our knowledge, this is the first study evaluating the safety and efficacy of Len maintenance after VTD plus single or tandem ASCT. Our results provide evidence that patients with clinical and biological low risk disease, and more specifically those with R2- ISS I, benefit the most from Len maintenance with a favorable safety profile.

Age-Based Comparison of Stem Cell Transplantation during the First Line of Therapy for Multiple Myeloma Patients

Background High-dose chemotherapy followed by stem cell transplantation (SCT) has been the standard first-line therapy for eligible multiple myeloma (MM) patients for over three decades. However, most studies evaluating SCT in MM have focused on patients under 65 years old, despite the increasing number of older patients diagnosed with MM. Retrospective data suggest that SCT can offer good survival outcomes with acceptable toxicities in patients over 65. This registry retrospective study aims to compare the time to next treatment (TTNT) of SCT versus non-SCT treatments in MM patients, assessing those aged &amp;lt;65 and ≥65 years old. Methodology Using HealthTree Cure Hub for Multiple Myeloma (PMID: 35271305), we analyzed real-world data from 1279 patients with multiple myeloma. Patients were categorized into two groups based on age at the start of their first line of therapy (&amp;lt;65 and ≥65). Kaplan-Meier ‘Time to Next Treatment’ (TTNT) R analysis was employed to compare patients who underwent stem cell transplant (SCT) and those who did not (NSCT) within each age group. SCT patients received a high-dose melphalan preparative regimen (140-200 mg/m2). Age groups were also subclassified by high-risk cytogenetics, using mSMART staging by fluorescence in situ hybridization (FISH), and Revised International Staging System (R-ISS) stage. Chi-square tests were used to assess the association with R-ISS and mSMART stages. Results We analyzed the data of 1279 MM patients, of whom 830 (64.9%) were &amp;lt;65 and 449 (35.1%) were ≥65. The &amp;lt;65 group had a mean age of 55±7, whereas the group ≥65 had a mean age of 70±5. 52.5% were female. The majority of patients were White (78.2% in the &amp;lt;65 group and 81.77% in ≥65), with other relevant groups including Blacks (5.8% in the &amp;lt;65 group and 4.2% in the ≥65 group), and Hispanics or Latinos (4.0% in the &amp;lt;65 group and 2.8% in the ≥65 group). The median year of diagnosis was 2018 (2006-2022).R-ISS staging was available for 664 patients and not dissimilar between groups ( p = 0.69): in the &amp;lt;65 group, 159 (37.2%) patients were classified as R-ISS stage I, 188 (44.0%) patients stage II, and 81 (18.9%) patients stage III. In the ≥65 group, 81 (34.3%) were stage I, 118 (50.0%) stage II, and 37 (15.7%) stage III. 1196 patients had mSMART staging available, of whom, patients with high-risk, double, and triple hit, represented 15.9%, 4.6%, and 0.4%, respectively. Age group high-risk characteristics proportions were not dissimilar ( p = 0.7). In the &amp;lt;65 group, 69.2% had a transplant during their first line of therapy, while in the ≥65 group, 48.8% had a transplant. For patients aged &amp;lt;65, the mean TTNT was 32.5 mo (SD 25) in the SCT group, and 16 mo (SD 21.6) in the NSCT group. For patients aged ≥65, the mean TTNT was 28.6 mo (SD 18.9) in the SCT group, and 16.5 mo (SD 18.3) in the NSCT group. The TTNT survival at 4 years was significantly higher in patients that experienced an SCT in both groups, &amp;lt;65 (SCT=40%, NSCT=18%, p = &amp;lt;0.0001) and ≥65 (SCT=43%, NSCT=14%, p = &amp;lt;0.0001). Conclusions Our findings add to the compelling evidence that SCT demonstrates favorable outcomes in both age groups of MM patients. The mean TTNT difference of SCT vs NSCT observed in the &amp;lt;65 group is 16.5 mo, and in the ≥65 group, it is 12.1 mo. Furthermore, patients who underwent SCT in both age groups had significantly higher TTNT survival rates at 4 years, doubling the rates to 40% in the &amp;lt;65 group and 43% in the ≥65 group, emphasizing the substantial benefits of SCT as a first-line therapy for multiple myeloma. These results contribute to the growing body of evidence supporting the efficacy and acceptability of SCT in the management of multiple myeloma across all age groups. It also emphasizes the importance of considering SCT as a viable treatment option for eligible MM patients, including those aged 70 and above, to improve long-term outcomes.

Real-world results of autologous stem cell transplantation in newly diagnosed multiple myeloma: a report from the Canadian Myeloma Research Group database

Autologous stem cell transplant (ASCT) remains an important option for eligible multiple myeloma (MM) patients as part of initial therapy. Using the Canadian Myeloma Research Group (CMRG) national database, we examined the details and outcomes of ASCT performed as first-line therapy in eligible Canadian MM patients between 2007 to 2021. We included 3821 patients with 72% receiving CyBorD induction and 2061 patients receiving maintenance, consisting of lenalidomide +/- steroids in 78.3%. The median PFS and OS for patients given a single ASCT were 35.4 and 126 months. Those receiving a second induction regimen had significantly inferior outcomes, although when maintenance was used, results were comparable regardless of the number of induction regimens administered (median PFS 55.3 vs 51.1 months [p = 0.11]; median OS 158.6 vs not yet reached [p = 0.13]). Consolidation patients had a longer median PFS (55.3 vs 34.4 months [p = 0.001]), but no significant gain in median OS (p = 0.065). Patients who received lenalidomide-based maintenance experienced a median PFS of 53.7 months and OS of 159 months. In the multivariable analysis, use of any type of maintenance therapy vs no maintenance was associated with a lower risk of progression (HR 0.52 (95% CI 0.47-0.57)) and death (HR 0.58 (95% CI 0.51-0.67)). This real-world study demonstrates that, overall, first-line treatment sequence in transplant-eligible patients produces a median OS of ≥10 years. It also highlights the contribution of post-ASCT maintenance, particularly lenalidomide given until progression.

Carfilzomib, lenalidomide and dexamethasone followed by a second ASCT is an effective strategy in first relapse multiple myeloma: a study on behalf of the Chronic malignancies working party of the EBMT.

In the setting of a first relapse of multiple myeloma (MM), a second autologous stem cell transplant (ASCT) following carfilzomib-lenalidomide-dexamethasone (KRd) is an option, although there is scarce data concerning this approach.We performed a retrospective study involving 22 EBMT-affiliated centers. Eligible MM patients had received a second-line treatment with KRd induction followed by a second ASCT between 2016 and 2018.Primary objective was to estimate progression-free survival (PFS) and overall survival (OS). Secondary objectives were to assess the response rate and identify significant variables affecting PFS and OS. Fifty-one patients were identified, with a median age of 62 years. Median PFS after ASCT was 29.5 months while 24- and 36-months OS rates were 92.1% and 84.5%, respectively. Variables affecting PFS were an interval over four years between transplants and the achievement of a very good partial response (VGPR) or better before the relapse ASCT. Our study suggests that a relapse treatment with ASCT after KRd induction is an effective strategy for patients with a lenalidomide-sensitive first relapse. Patients with at least four years of remission after a frontline ASCT and who achieved at least a VGPR after KRd induction appear to benefit the most from this approach.

Impact of timing of stem cell return following high dose melphalan in multiple myeloma patients with renal impairment: a single center experience

High dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) remains the standard consolidation in transplant eligible multiple myeloma (MM) patients. The timing between HDM administration and hematopoietic stem cell return (HSCR) varies among institutions, with a ‘rest period’ of 48 hours (h) employed by some for patients with renal impairment (RI). We investigated the differences in hematopoietic recovery and HDM toxicity between MM patients with RI who had HSCR after 24 vs 48 h from HDM. Fifty MM patients with RI (48 h group; n = 31 and 24 h group; n = 19) were included. No statistically significant differences were noted in surrogates for hematopoietic recovery and HDM toxicity between both groups. Only one death occurred in the 24 h group. No patients required renal replacement therapy. Therefore, a 24 h period between HDM and AHSC infusion appears safe for MM patients with RI.

Real-world treatment patterns of triple-class refractory (TCR) multiple myeloma (MM) across the United States (US), Canada, and western Europe: A retrospective chart study.

e18826 Background: Many patients with MM relapse or become refractory to various therapeutic approaches and typically cycle through many lines of treatment. The present study sought to understand how patients with TCR MM (ie, refractory to ≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 therapy) are managed across various countries. Methods: A non-interventional, retrospective chart review study was conducted across the US, Canada (CA), the UK, France (FR), Germany (DE), Italy (IT), and Spain (ES). Oncologists/hematologists were recruited to abstract medical chart information into an electronic case report form from eligible MM patients (eg, refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody treatment, ECOG≤2, and initiated their first therapy after their TCR status [ie, their index therapy] between 1/1/2018 and 12/31/2020 to ensure at least 1 year of follow-up). Abstractions were performed from January through April 2022. Demographics, clinical characteristics, and treatment patterns were descriptively analyzed and reported here. Results: N = 314 patients with TCR MM were included (56.7% male; median age = 70). Clinical characteristics were similar to other TCR MM studies (eg, 26.1% had an ECOG score of 2, 25.8% had high cytogenetic risk (ie, t(4:14), t(14:16), and/or del(17p), and 10.2% had extramedullary disease). Patients received a median of 3 treatment lines prior to their index therapy, with 70 unique treatment regimens reported as part of their index therapy line (Table 1). The most common regimens (&gt; 10%) were Pd and Kd. Conclusions: This global chart review across the US, Canada, and Western Europe highlights the consistent lack of a standard of care for the management of MM among patients who are refractory to the three main classes of therapies. [Table: see text]

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

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

Impact of Clinical Parameters and Induction Regimens on Peripheral Blood Stem-Cell Mobilization and Collection in Multiple Myeloma Patients

Introduction: High-dose chemotherapy (HDCT) followed by autologous blood stem-cell transplantation (ABSCT) remains the standard consolidation therapy for newly diagnosed eligible multiple myeloma (MM) patients. As a prerequisite, peripheral blood stem cells (PBSCs) must be mobilized and collected by leukapheresis (LP). Many factors can hamper PBSC mobilization/collection. Here, we provide a comprehensive multiparametric assessment of PBSC mobilization/collection outcome parameters in a large cohort. Methods: In total, 790 MM patients (471 [60%] male, 319 [40%] female) who underwent PBSC mobilization/collection during first-line treatment were included. Evaluated PBSC mobilization/collection outcome parameters included the prolongation of PBSC mobilization, plerixafor administration, number of LP sessions, and overall PBSC collection goal/result. Results: 741 (94%) patients received cyclophosphamide/adriamycin/dexamethasone (CAD) and granulocyte-colony-stimulating factor (G-CSF) mobilization. Plerixafor was administered in 80 (10%) patients. 489 (62%) patients started LP without delay. 530 (67%) patients reached the PBSC collection goal at the first LP session. The mean overall PBSC collection result was 10.3 (standard deviation [SD] 4.4) × 106 CD34+ cells/kg. In a multiparametric analysis, variables negatively associated with PBSC mobilization/collection outcomes were female gender, age >60 years, an advanced ISS stage, and local radiation pre-/during induction, but not remission status postinduction. Notably, the identified risk factors contributed differently to each PBSC mobilization/collection outcome parameter. In this context, compared to all other induction regimens, lenalidomide-based induction with/without antibodies negatively affected only the number of LP sessions required to reach the collection goal, but no other PBSC mobilization/collection outcome parameters. In contrast, the probability of reaching a high collection goal of ≥6 × 106 CD34+ cells/kg body weight was higher after lenalidomide-based induction compared to VCD/PAD or VAD – taking into account – that a higher G-SCF dosage was given in approximately one-third of patients receiving lenalidomide-based induction with/without antibodies. Conclusion: Considering the identified risk factors in the clinical setting can contribute to optimized PBSC mobilization/collection. Moreover, our study demonstrates the necessity for a differentiated evaluation of PBSC mobilization/collection outcome parameters.

Strategies to Optimize the Utilization of Stored Autologous Peripheral Blood Stem Cells for Second Transplantation in Multiple Myeloma

Introduction: Autologous stem cell transplantation (ASCT) is the standard of care and a mainstay in the management of eligible patients with multiple myeloma (MM) and remains relevant in the era of novel therapeutics. ASCT requires stem cell mobilization to collect ample stem cells to provide hematological recovery after myeloablative conditioning. Second ASCT (ASCT2) as salvage therapy in relapsed/refractory MM (RRMM) is a treatment option for patients who achieved disease control for 2 to 3 years after first ASCT (ASCT1). The reported difficulties in mobilizing and collecting additional stem cells following myeloablative ASCT1 have led to the currently adopted practice to collect and store adequate peripheral blood stem cells (PBSCs) for two transplants before ASCT. The preferred PBSC cell dose is 2 to 5 × 106 CD34+ cells per kilogram of recipient weight (CD34+ cells/kg) per transplant; however, with the influx of effective novel agents available for RRMM, the use of ASCT2 is declining. A retrospective cost utilization study showed that at a median follow-up of 3.5 years, only 3% of the cohort received ASCT2. The additional cost of collecting and storing these products is an average of 16,590 USD/patient. Given the limited use of salvage ASCT2, current practice of collecting PBSCs for two transplants should be re-evaluated and carefully selected case-by-case. We investigated potential strategies to reduce the financial burden of PBSC collection, processing, and storage by identifying a subgroup of patients who are less likely to receive an ASCT2, herein avoiding storing extra cells. Materials and Methods: With Institutional Review Board approval, we performed a retrospective descriptive analysis of all MM patients who underwent frontline ASCT from 1/1/2012 to 6/23/2022. We excluded patients who had planned tandem transplants and those who underwent a single ASCT and had all cells infused with no remaining stored cells. We classified all patients who collected a sufficient cell dose for ASCT1 and ASCT2 into two cohorts according to the number of ASCT received; those who received ASCT1 and those who received ASCT1 and ASCT2. Results: We report the descriptive statistics of eligible MM patients from a single stem cell transplant center. Over a median follow-up of 2.0 years, we report findings of 240 patients who collected sufficient PBSCs for ASCT1 and ASCT2. Patients’ median age at PBSC collection was 61 (range 32-77). We classified our cohort by gender, age, race, and average number of days for PBSC collection. We aim to collect a cell dose of 10 x 106 CD34+ cells/kg. Our cohort included more males than females (132/108) and a higher prevalence of African Americans (59%) than Caucasians. Our study showed that only 7% of patients underwent ASCT2 (17/240) with average time between ASCT1 and ASCT2 of 2.9 years. We noticed that 88% (15/17) of patients who received ASCT1 and ASCT2 were ≤ 61 years old at the time of ASCT1 and two patients (12%) were ≥ 70 years. Additionally, a higher proportion of patients utilizing ASCT2 in the youngest age groups is noticeable. Six of 30 patients under 50 years and three of seven patients under 40 years of age (20% and 43%, respectively) underwent ASCT2. The data highlights that utilization of ASCT2 is less common in the elderly population; hence considering PBSC collection for one transplant among the elderly would be a cost-effective strategy. Most stem cell transplant centers inherited a strategy to collect PBSC 10 x 106 CD34+ cells/kg. We noticed that 102 patients required >1 day of PBSC collection to meet the collection goal. Of these patients, 35% were age 65 or older. If we were to change practice and consider PBSC collection for one transplant among the elderly, we could have reduced the number of collection days by 25 and reduced the associated costs of collection, processing, storage, and staffing, as well as space requirements for storage. Conclusion: The utilization of ASCT2 in MM patients is decreasing with the influx of novel therapeutics. Potential strategies are needed to change the practice and reduce the additional financial burden of excess stem cell collection and storage. We suggest that elderly MM patients be considered for PBSC collections for a single transplant. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Regulatory T Cell Depletion during Stem Cell Mobilization Enhances Anti-Myeloma Immunity after Experimental Autologous Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) with G-CSF/plerixafor mobilized peripheral blood stem cells (PBSC) remains the standard of care for newly diagnosed eligible multiple myeloma (MM) patients and prolongs progression-free survival. However, most patients eventually progress and require additional therapy. We have previously demonstrated that experimental ASCT can enhance myeloma-specific immunity and limits disease progression characterized by immunological escape. Here we explored the ability of stem cell mobilization (SCM) to mobilize putative myeloma-specific T cells from the bone marrow (BM) and concurrent effects of regulatory T cell depletion (Treg), hypothesizing that this may represent an opportunity to optimize myeloma-specific immunity prior to ASCT. In myeloma patients we noted increased proportions of subsets of effector memory CD8 T cells, including a CX3CR1/granzyme B (GzmB)+ subset in PBSC grafts relative to BM (P<0.01). TIGIT+ Treg were also significantly expanded in PBSC (P <0.01). To study the relevance of these effects, we transferred congenically marked BM T cells into syngeneic mice. We noted that BM-derived effector (CD44+) CD8 cells preferentially homed back to BM (vs. spleen/blood), consistent with T cell residency at this site. SCM subsequently promoted the migration of these resident effector CD8 T cells from BM (4-fold reduction, P <0.001) to blood (5-fold expansion, P <0.001), confirming that PBSC contain BM resident T cells. BM Foxp3+ Treg were also reduced in BM and increased in blood after SCM. Mobilized Treg were characterized by an immunosuppressive phenotype with high levels of CD73, Nrp-1, CTLA4 and TIGIT, and this represents a possible suppressive pathway invoked by SCM. We thus examined the role of BM Treg in limiting myeloma-specific immunity during SCM with Foxp3-GFP-DTR mice. Depletion of Treg with diphtheria toxin (DT) during SCM promoted the expansion of antigen experienced CD8 T cells that secreted IFNg, TNF and GzmB. We next hypothesized that expansion of these polyfunctional cells would enhance myeloma-specific immunity after ASCT. To test this, we treated Vk*MYC bearing Foxp3-GFP-DTR donor mice with DT (vs. saline) 1 week after tumor injection followed by SCM. CD8 T cells from mobilized grafts were transplanted with BM and CD4 T cells from naïve B6 into lethally irradiated Vk*MYC bearing recipients (Figure 1A). Recipients transplanted with CD8 T cells from Treg depleted donors had dramatically improved tumor control (Figure 1B) after ASCT compared to recipients of cells from Treg intact donors (survival 100 days post-ASCT; 100% for DT group vs 13% for saline group, P <0.0001). Rechallenge of mice surviving over 100 days after ASCT confirmed MM clone-specific immunity with complete elimination of the MM seen at initial ASCT, but not an unrelated clone. We next studied clinically relevant approaches to mimic this scenario. Administration of TIGIT, CTLA4, CD25 or LAG3 antibodies resulted in inadequate Treg depletion in BM to recapitulate this effect. In contrast, a synthetic IL-2/IL-15 mimetic NL-201 that selectively binds the beta and gamma chains of IL-2 receptor but not the high affinity IL-2Ra (CD25) reduced BM Treg (45.9% vs 18.6%, P <0.05) and expanded polyfunctional effector cells expressing IFNg+TNF+GzmB+ in SCM grafts. MM-bearing mice transplanted with NL-201 mobilized CD8 T cells were also protected against relapse after ASCT (survival 100 days post-ASCT; 87.5% for NL-201 group vs 25% for saline group, P <0.05). This protection was characterized by expansion of antigen experienced (CD38+) and cytokine secreting (TNF, IFNg) memory (CD44+) CD8 T cells in the BM 3 weeks after ASCT. BM CD8 T cells and Treg are efficiently mobilized after G-CSF/plerixafor. Depletion of Treg in donors during SCM dramatically increases myeloma specific T cells in stem cell grafts and enhances myeloma-specific immunity after ASCT. Stem cell mobilization in the presence of the synthetic IL-2/15 mimetic NL-201 is a promising clinically tractable approach to recapitulate these effects. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Results of Autologous Stem Cell Transplantation in Newly Diagnosed Patients with Multiple Myeloma: A Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

INTRODUCTION Autologous stem cell transplant (ASCT) remains an important option for eligible multiple myeloma (MM) patients (pts) as part of initial therapy. In Canada, fit younger pts are typically offered ASCT; selected centers offer tandem ASCT to high-risk (HR) pts; and current standard practice involves continuation of maintenance (maint) therapy until disease progression, which is facilitated by public funding for lenalidomide (len) in this setting. Using our national database, we examined the details and outcomes of ASCT performed as part of initial therapy in eligible Canadian MM pts. Methods The Canadian Myeloma Research Group database (CMRG-DB) contains both legacy and ongoing prospective data and can track and characterize real-world outcome of pts treated at 17 major Canadian institutions. All pts who received an ASCT as part of initial MM therapy between 01/Jan/2007 to 31/Dec/2021 were included. Progression-free survival (PFS) was calculated from the time of first ASCT until disease progression, death due to any cause or last follow up, whichever comes first, while overall survival (OS) was defined as the time from ASCT to the date of death or last follow up. Results 3821 pts underwent ASCT as frontline therapy and were included in the analysis. Median age was 61 (range 26-77) years, 15.2% had a creatinine > 177 umol/L and 18% had HR FISH [del17p, t(4;14) and t(14;16)] (FISH was unknown/missing in 50% of pts). The majority (82%) received bortezomib (btz)-based induction; this consisted of CyBorD in 72% with rates of ≥PR (≥VGPR) of 92% (60%). Only 1.6% received a proteasome inhibitor (PI) + len; rates of ≥PR (≥VGPR) were 96.5% (63.2%) in this subgroup. Median time to ASCT from start of induction was 5.6 months (mos). A second induction regimen, including len in 78.5%, was administered to 376 pts for suboptimal response/progression on first induction. The ≥PR (≥VGPR) rates in these 376 pts was 72.9% (35.4%) with a median time from start of second induction to ASCT of 4.2 mos. Tandem ASCT was performed in 314 pts, primarily in HR pts (64%). In HR FISH pts, the median PFS (mPFS) for single vs tandem ASCT was 25.1 vs 35.4 mos (p 0.018) and median OS (mOS) 91.5 vs 84.4 mos (p 0.048), respectively. For those without HR FISH, mPFS and mOS for single vs tandem ASCT were, respectively, 46.5 vs 33.8 mos (p <0.001) and 158.6 vs NYR (p <0.001). After ASCT, only 205 (5%) pts received consolidation that consisted of a PI + len in 93.2%. However, 2060 pts (53.9%) received post-ASCT maint (len +/- steroids in 63.1%, btz +/- steroids in 2.1 %, len + btz +/- steroids in 1.7%, other PI +/- steroids in 1.6%, len + other PI +/- steroids in 5.7 % and thalidomide +/- steroids in 8.5%). The mPFS and mOS for all pts was 35.4 mos (95% CI 33.7-37.3) and 125 mos (95% CI 120-138) from first ASCT. Table 1 summarizes the mPFS and mOS according to treatment. Those given a second induction regimen had significantly inferior outcomes (mPFS 27.9 vs 36.2 mos [p 0.001]; mOS 118 vs 126 mos [p 0.011]), although the use of maintenance led to comparable results regardless of number of induction regimens (mPFS 55.3 vs 51.1 mos [p 0.11]; mOS 158.6 vs not yet reached (NYR) [p 0.13]). Consolidation pts had a better mPFS (55.3 vs 34.4 mos [p 0.001]), but no significant gain in mOS (p 0.065). The mPFS and mOS were 48.8 vs 24.5 mos and 159 vs 105 mos for the maint vs non-maint cohorts, respectively, when all types of maint were included. For pts receiving len, btz or both (+/- steroids), the mPFS was 53.7 mos vs 48.2 mos vs 43.5 mos, respectively, while the mOS was 159 mos vs NYR vs 115 mos, respectively. Amongst pts receiving such maint, outcomes for pts with HR FISH were compared with those without HR FISH: mPFS was 36.6 mos vs 55.2 mos and the mOS was 97.4 mos vs 164.4 mos, respectively. CONCLUSIONS This large study demonstrates that the integration of btz and len into the transplant sequence produces a mOS of ≥10 yrs in most ASCT pts in the real-world setting. Our observations highlight the contribution of post-ASCT maint, particularly len given until progression, when used in multiple pt groups including those with and without HR, as well as those requiring a second induction regimen. Nevertheless, HR pts require additional strategies to optimize results. Further analyses to assess the relationship of pt characteristics, specific treatment details and outcomes are in progress. These results serve as Canadian benchmarks for comparison with newer approaches that combine immunotherapy with ASCT as initial therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Despite Use of Upfront Plerixafor and G-CSF, Daratumumab Exposure Reduces Stem Cell Mobilization in Patients with Multiple Myeloma

Introduction Daratumumab is an anti-CD38 IgG1k monoclonal antibody with direct tumor killing and immunomodulatory mechanisms of action which was shown to have clinical benefits when added to the standard-of-care induction regimen in transplant eligible multiple myeloma (MM) patients. However, prior studies have indicated a potential reduction in stem cell yield in patients exposed to daratumumab prior to stem cell mobilization. Additionally, prior studies have not utilized combination mobilization regimens with G-CSF and the CXCR4 antagonist plerixafor as standard-of-care, which may overcome the deleterious effect of daratumumab. In this study, we investigated the stem cell yield of plerixafor-treated patients with daratumumab exposure compared to those without. Methods We conducted a retrospective study of patients with MM at our institution who underwent autologous stem cell mobilization and collection during first-line treatment over a 15-month period from 2021-2022. Following induction, patients underwent mobilization with a regimen of G-CSF for 5 days with plerixafor on the 4th day. Circulating CD34+ stem cells were enumerated on the 5th day, after which patients underwent approximately 20L apheresis with a collection goal of 5x106 CD34+ cells/kg of body weight. The primary endpoint of this study was the comparison of circulating CD34+ cells between patients who received daratumumab during induction and those who did not. Secondary endpoints included collection CD34+ yield and proportion who met the collection goal. Results 123 patients were included in the analysis. The median age was 65 (range: 34-77), 54% were male, and 84% were White. Twenty-two percent were stage I, 58% stage II, and 19% stage III by the Revised International Staging System. Forty-seven percent received daratumumab during induction. Of those, the median number of cycles administered was 4 (range: 1-5). Ninety percent received daratumumab in combination with bortezomib, lenalidomide and dexamethasone. The two cohorts were balanced in terms of age, gender, race, and exposure to lenalidomide, alkylators and radiation during induction. Patients with daratumumab exposure had a mean mobilization of 57.5 CD34+ cells/mcl compared to 96.4 for those without (p < 0.001). The mean CD34+ cell collection yield in 1 apheresis procedure was 6.0 x 106 cells/kg compared to 10.6 x 106 cells/kg (p < 0.001). Fifty-three percent of patients with daratumumab exposure met the collection goal compared to 80% of patients without (p < 0.001). Of the patients who did not meet the goal in one apheresis procedure, the majority were able to meet the goal with 1-3 additional days of apheresis (Figure 1). However, only 86% of patients with daratumumab exposure met the collection goal compared to 97% of those without (p < 0.001). Ten patients failed to collect 2.0 x 106 cells/kg, the institutional minimum for transplantation, 9 of which received daratumumab during induction. Eight were able to collect the minimum with an additional 1-3 days of apheresis; 2 patients required an additional mobilization procedure and collection but were able to proceed to transplantation. After adjusting for covariates including age, gender, race, weight, and exposure to lenalidomide, alkylators, and radiation, daratumumab exposure was associated with a 37.9 cells/mcl decrease in mean mobilization of CD34+ and 4.2 x 106 cells/kg decrease in CD34+ cell collection (both p < 0.001). Alkylator exposure was associated with a 43.3 cells/mcl decrease in mean mobilization of CD34+ (p = 0.040) and 4.1 x 106 cells/kg decrease in CD34+ cell collection (p = 0.057). Lenalidomide exposure was associated with a 103.4 cells/mcl decrease in mean mobilization of CD34+ (p <0.001) and 8.7 x 106 cells/kg decrease in CD34+ cell collection (p <0.001). Conclusion Inclusion of daratumumab in the induction regimen for transplant-eligible patients with MM resulted in a significant reduction in stem cell mobilization and stem cell yield, even with the use of plerixafor-containing mobilization regimens. This reduction was similar to alkylator exposure but less than lenalidomide exposure. With the increasing use of quadruplet induction regimens, the frequency of mobilization failure is likely to increase in the future and new mobilization regimens and approaches are needed to guarantee adequate cell yields without the need for additional days of apheresis and/or mobilizations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Belantamab Mafodotin in Combination with Vrd for the Treatment of Newly Diagnosed Transplant Eligible Multiple Myeloma Patients: Results from the Phase II, Open Label, Multicenter, GEM-BELA-Vrd Trial

Introduction: The use of bortezomib, lenalidomide and dexamethasone (VRd) as induction triplet has resulted in deep and durable responses in newly diagnosed transplant-eligible multiple myeloma (NDTE MM) patients, as shown by the Spanish group in the GEM2012 trial. The addition of anti-CD38 monoclonal antibodies to VRd deepen responses without impairing safety. The BCMA antibody-drug conjugated belantamab mafodotin (belamaf) is approved for relapsed and refractory MM, but its role in the frontline setting is not established. Patients and methods: 50 patients (pts) were planned to be recruited in this phase II, open label, multicenter, non-randomized single arm clinical trial (GEM-BELA-VRd). Treatment consisted of six induction cycles with VRd every 4 wks and belamaf 2.5 mg/kg iv every 8 wks (on day 1 of cycles 1, 3 and 5), followed by high dose melphalan (200mg/m2) and autologous stem cell transplant. Patients also receive two consolidation cycles with VRd (Q4W) and belamaf (Q8W), and maintenance with R until progression/toxicity and belamaf (Q8W) for 2 yrs. Primary endpoint was safety, evaluated in terms of incidence of adverse events (AEs) [according to CTCAE v. 4.0], of ocular events (OEs) [according to Visual Acuity - KVA scale] and of deaths. Main key secondary endpoints were overall response rate (ORR), complete response rate (CR), and progression-free survival (PFS). Cut-off date: July 7th 2022. Here, we report the initial safety and efficacy results of patients included after 4 cycles of induction with Belamaf-VRd. Results: Forty pts had already completed the four induction cycles and were included in this analysis. Half of them were women and the median age at diagnosis was 58 years old (27-74). Ocular toxicity was the most frequent AE. Thirty-eight pts (95%) presented any eye symptom, the most frequent one was blurred vision (77.5%; G3-4: 27.5%); followed by eye irritation (57.5%; G3-4: 10%) and dry eye (50%; G3-4: 10%). Four wks from first belamaf dose (C2 of VRD), 24 pts (60%) had any grade of keratopathy related to belamaf (mild: 50.0%; moderate: 45.8%, and severe: 4.2%); that persisted 4 wks later (C3), as 21 pts (52.5%) still had keratopathy (mild: 47.6%; moderate: 47.6%, and severe: 4.8%). Seven pts (17.5%) did not receive the second planned belamaf dose, 9 (22.5%) received reduced dose (1.9 mg/kg) and the remaining 24 pts received the full planned dose. At C4D1, four wks after the second planned belamaf dose, 32 pts (80%) had keratopathy (mild: 37.5%; moderate: 53.1%, and severe: 9.4%) and, after 8 wks, 27 pts (67.5%) (mild: 48.1%; moderate: 37.0%, and severe: 14.8%). In addition, hematological toxicity was reported in 24 pts (60%). Neutropenia and thrombocytopenia were the most frequent hematological AEs (both 20%; G3-4 in 12.5 and 7.5%, respectively). Twenty-two patients (55%) had any infection during this induction period, with respiratory infection as the most frequent one, in 20 pts (50%; G3-4: 22.5%). Pneumonia was registered in 8 patients (20%), in 7 of them was considered as a serious adverse event, 3 were caused by SARS-CoV-2 and 2 pts died. Skin toxicity, like maculo-papular rash, was reported in 35% of pts, G3-4 was present in 6 pts (15%). Peripheral neuropathy (PN) occurred in 27.5% of pts, none of them had G3-4 PN. With a median follow-up of 6 mo (3-12), 2 pts died, both due to COVID pneumonia and 1 progressed resulting in 6-mo PFS of 89.3%. After 4 cycles, ORR was 82.1%; VGPR or better was achieved in 69.2% of pts, and CR in 5 patients (12.8%), all of them with MRD negativity (except one that was not evaluable). Conclusions: The results of adding belamaf to VRD seem encouraging, although ocular toxicity is a concern. The study is ongoing with belamaf as part of the maintenance and longer follow-up will confirm whether the combination improves outcomes in NDTE MM patients. "Funding and product for this study was provided by GSK [NCT04802356]. GSK was provided the opportunity to review a preliminary version of this manuscript for factual accuracy, but the authors are solely responsible for final content and interpretation".

Secondary Analysis of the MM21 Trial: Response Adaptive Salvage Treatment with Daratumumab-Lenalidomide-Dexamethasone (DRd) for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients Failing Front-Line Bortezomib-Based Induction Therapy

Secondary Analysis of the MM21 Trial: Response Adaptive Salvage Treatment with Daratumumab-Lenalidomide-Dexamethasone (DRd) for Newly Diagnosed Transplant Eligible Multiple Myeloma Patients Failing Front-Line Bortezomib-Based Induction Therapy

P-222: A prospective phase 2 study to assess minimal residual disease after ixazomib plus lenalidomide plus dexamethasone (IRd) treatment for newly diagnosed transplant eligible multiple myeloma patients

P-222: A prospective phase 2 study to assess minimal residual disease after ixazomib plus lenalidomide plus dexamethasone (IRd) treatment for newly diagnosed transplant eligible multiple myeloma patients

PB1997: DARATUMUMAB, LENALIDOMIDE, BORTEZOMIB, AND DEXAMETHASONE FOR TRANSPLANT-ELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA: OUTCOME AND SAFETY PROFILE FROM A REAL-WORLD SINGLE CENTER EXPERIENCE

Background: lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplant is standard frontline therapy for transplant eligible newly diagnosed multiple myeloma (MM).The addition of daratumumab (D) to RVd improve the depth of response (Stringent complete remission and MRD negativity). RVd-D combination is now being suggested as first-line treatment. Real-word data is lacking. Aims: We aim to share our experience regarding clinical response and safety profile of D-RVd for treatment of newly diagnosed transplantation eligible MM patients. Methods: We conducted a retrospective study with medical review of all patients diagnosed with multiple myeloma and treated with D-RVd at The National Center for Cancer Care and Research (NCCCR) in Qatar between January 2019 to December 2021. Overall response rate and safety profile were evaluated. All analyses were descriptive and exploratory in nature. Results: Fifteen newly diagnosed MM patients had received D-RVd in the time period of the study. The median age of patients was 58 year (range, 36-68 years) and the majority 12 (80 %) were male. The immunoglobulin (Ig) subtypes were IgG 9 (60%), IgA 3 (20%), free light chain 3 (20%). At diagnosis, 14 patients had bone lesions and 4 had extramedullary plasmacytoma. Anemia, hypercalcemia (serum calcium > 2.6 mmol/L) and/or renal impairment (serum creatinine > 133µmol/L) was present in 66%, 66% and 33% of patients respectively. Bone marrow plasmacytosis more than 60% on bone marrow examination was reported in 11/14 (78%) of patients. The proportion of patients at ISS stage I, II, and III were 1 (7%), 6 (40%), 8 (53%) respectively. Cytogenetic abnormalities detected via karyotyping and/or FISH were present in 9 of 12 evaluated patients. The average number of D-RVd were 4 cycles. The overall response rate (ORR) post induction therapy was evaluated in 14 patients (one patient was not evaluated for response due to early death), 9 (64%) patients had a complete response (CR), 4(29%) had very good partial response (VGPR) and one had partial response (PR). No myeloma progression while receiving induction therapy occurred. So far, seven patients have undergone autologous stem cell transplant. Median CD 34+ cell yield was 5,2 million cells per kg body weight, plerixafor were used in 5 patients and 5 patients required more than one apheresis session. Survival data to be collected and reported after a longer follow up period. The most common adverse events (AEs) were hematological toxicities; grade 3/4 neutropenia was detected in 6 patients (40%), thrombocytopenia in 3 patients (20%), lymphopenia in 4 patients (27%) and leukopenia in 2 patients (13%). Infusion reactions occurred in 2 patients (13%), one of them experienced anaphylactoid reaction that required infusion interruption. Non-hematological AEs where uncommon and included grade 2 hepatotoxicity in one patient and venous thrombosis in one patient. None of the AEs lead to treatment discontinuation. One death occurred early during the second cycle due to streptococcus pneumoniae meningitis. Image:Summary/Conclusion: Our real-world results show a high response rate (CR/VGPR) to D-RVd as first-line treatment in transplantation eligible patients with MM. However, the feasibility and safety of this treatment regimen needs to be confirmed in larger prospective studies.

Abstract CT186: Pharmacokinetic (PK) profile of a novel IKZF1/3 degrader, CFT7455, enables significant potency advantage over other IKZF1/3 degraders in models of multiple myeloma (MM) and the results of the initial treatment cohort from a first-in-human (FIH) phase 1/2 study of CFT7455 in MM

Abstract Introduction: CFT7455 is a highly potent and novel Ikaros Family Zinc Finger Protein 1/3 (IKZF1/3) degrader. In xenograft models, CFT7455 has more potent IKZF1/3 degradation compared to other degraders. Early observations from the FIH clinical trial (NCT04756726) along with supporting translational studies are presented here. Methods: Pre-clinical studies comparing CFT7455 and CC-92480 in both in vitro and xenograft models were performed. The pre-clinical studies’ results coincided with observations from the on-going clinical trial. The clinical trial is an open-label, Phase 1/2, multi-center, FIH study in heavily pretreated relapsed/refractory (R/R) MM and non-Hodgkin’s lymphoma (NHL) patients evaluating safety, tolerability, and PK of CFT7455. Eligible MM patients are R/R to therapy and are not candidates for regimens known to provide clinical benefit. A starting dose of 50 μg QD 21 days on/7 days off (21/7) in 28-day cycles was administered. Results: CFT7455 and CC-92480 showed similar cereblon binding profiles and in vitro IKZF1/3 degradation kinetics, translating into sub-nanomolar GI50 values in proliferation assays across a panel of MM cell lines. In the NCI-H929 xenograft model, 100 μg/kg/day of CFT7455 resulted in durable tumor regressions, while 1000 μg/kg/day of CC-92480 gave tumor stasis. Similar results were seen in a systemic model of MM, MM1.S. Both compounds achieved &amp;gt;95% IKZF3 degradation in tumors 4h post dose. At 48h post dose, CFT7455 was more effective than CC-92480 in maintaining IKZF3 degradation (65% vs. 6% respectively). When levels of CFT7455 and CC-92480 in plasma and tumor were compared, CFT7455 concentrations were &amp;gt; DC80 in tumor 48h post dose, while CC-92480 levels were undetectable in tumor and plasma, demonstrating CFT7455 has longer exposure resulting in sustained IKZF1/3 degradation in pre-clinical models. In cohort A, 5 heavily pre-treated MM patients (pts) received single agent CFT7455. 4 pts have received at least 3 cycles, with 2 pts receiving 5 cycles. Neutropenia (grade 4) was observed in 3/5 pts without coincident fever or infection. Additionally, a 2-4 fold accumulation in plasma CFT7455 exposure at steady state was observed. Early pharmacodynamic (PD) data demonstrates deep persistent degradation of IKZF3 (~100%) and serum free light chain reduction (up to 72%) in response to treatment. Stable disease has been observed in 34 pts, suggesting clinical benefit. Conclusions: While CFT7455 showed clinical benefit at 50 ug with deep target degradation, neutropenia was dose limiting. PK/PD modeling suggests alternative dosing regimens may result in increased tolerability with preserved efficacy, and evaluation of them is underway. Updated results will be presented at the meeting. Citation Format: Sagar Lonial, Shambavi Richard, Jeffrey V Matous, Andrew J. Yee, Urvi Shah, Neha Mehta-Shah, Thomas Martin, Eli Muchtar, Sikander Ailawadhi, Paul G. Richardson, Manisha Bhutani, Samantha Perino, Jason Kirby, Roman V. Agafonov, Prasoon Chaturvedi, Bradley Class, Matthew Schnaderbeck, Michael R. Palmer, Cathleen Gorman, Oliver Schoenborn-Kellenberger, Amanda Hoerres, Stewart L. Fisher, Roy M. Pollock, Adam Crystal, Michelle Mahler, Jesus Bardeja. Pharmacokinetic (PK) profile of a novel IKZF1/3 degrader, CFT7455, enables significant potency advantage over other IKZF1/3 degraders in models of multiple myeloma (MM) and the results of the initial treatment cohort from a first-in-human (FIH) phase 1/2 study of CFT7455 in MM [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 CT186.