Transplant-eligible Multiple Myeloma Patients Research Articles

Optimizing Autologous Stem Cell Transplantation in Multiple Myeloma: The Impact of Intensive Chemomobilization

Most transplant-eligible multiple myeloma (MM) patients undergo autologous peripheral blood stem cell collection (PBSC) using G-CSF with on-demand plerixafor (G±P). Chemomobilization (CM) can be used as a salvage regimen after G±P failure or for debulking residual tumor burden ahead of autologous peripheral blood stem cell transplantation (ASCT). Prior studies utilizing cyclophosphamide-based CM have not shown long-term benefit. At our center, intensive CM (ICM) using a PACE- or HyperCVAD-based regimen has been used to mitigate "excessive" residual disease based on plasma cell burden or MM-related biomarkers. Given the lack of efficacy of non-intensive CM, we sought to determine the impact of ICM on event-free survival (EFS), defined as death, progressive disease, or unplanned treatment escalation. We performed a retrospective study of newly diagnosed MM patients who collected autologous PBSCs with the intent to proceed immediately to ASCT at our center between 7/2020 and 2/2023. Patients were excluded if they underwent a tandem autologous or sequential autologous-allogeneic transplant, had primary plasma cell leukemia, received non-ICM treatment (i.e., cyclophosphamide and/or etoposide), or had previously failed G±P mobilization. To appropriately evaluate the impact of ICM among those who potentially could have received it, we utilized a propensity score matching (PSM) approach whereby ICM patients were compared to a cohort of non-CM patients matched on pre-ASCT factors most strongly associated with the receipt of ICM. Of 451 patients identified, 61 (13.5%) received ICM (PACE-based, n=45; hyper-CVAD-based, n=16). Post-ICM/pre-ASCT, 11 patients (18%) required admission for neutropenic fever and/or infection. Among 51 evaluable patients, the overall response rate was 31%; however, 46 of 55 evaluable patients (84%) saw a reduction in M-spike and/or involved FLCs. Among those evaluated with longitudinal peripheral blood flow cytometry (n=8), 5 patients (63%) cleared circulating blood PCs post-ICM. Compared to patients mobilized with non-CM, ICM patients collected a slightly greater median number of CD34+ cells (10.8 vs 10.2 × 10⁶/kg, p=.018). The median follow-up was 30.6 months post-ASCT. In a PSM multivariable analysis, ICM was associated with significantly improved EFS (HR 0.30, 95% CI 0.14 to 0.67, p=.003), but not improved OS (HR 0.38, 95% CI 0.10 to 1.44, p=.2). ICM was associated with longer post-ASCT inpatient duration (+4.1 days, 95% CI, 2.4 to 5.8, p<.001), more febrile days (+0.96 days, 95% CI 0.50 to 1.4, p<.001), impaired platelet engraftment (HR 0.23, 95% CI 0.06 to 0.87, p=.031), more bacteremia (OR 3.41, 95% CI 1.20 to 9.31, p=.018), and increased antibiotic usage (cefepime: +2.3 doses, 95% CI 0.39 to 4.1, p=.018; vancomycin: +1.0 doses, 95% CI 0.23 to 1.8, p=.012). ICM was independently associated with improved EFS in a matched analysis involving MM patients with excessive disease burden at pre-ASCT workup. This benefit came at the cost of longer inpatient duration, more febrile days, greater incidence of bacteremia, and increased antibiotic usage in the immediate post-ASCT setting. Our findings suggest that ICM could be considered for a subset of MM patients, but its use must be weighed carefully against additional toxicity.

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.

Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

Symptom clusters and their impact on quality of life in multiple myeloma survivors: Secondary analysis of BMT CTN 0702 trial.

Autologous haematopoietic cell transplantation (autoHCT) and continuous post-transplant maintenance therapy are the standard of care in transplant-eligible multiple myeloma (MM) patients. We sought to describe symptom burden and identify symptom clusters occurring in MM patients after autoHCT using data from the BMT CTN 0702 randomized controlled trial comparing the outcomes of three treatment interventions after an autoHCT in 758 MM patients. We analysed individual transplant-related symptoms assessed via the FACT-BMT questionnaire at enrolment and annually for 4-year post-autoHCT. We also described the effect the individual symptoms and symptom clusters have on quality of life (QoL). We identified three stable symptom clusters: malaise symptom cluster (lack of energy, feeling ill, having pain, experiencing nausea, loss of appetite), physical symptom cluster (having skin problems, tremors, worsening eyesight, change in taste, shortness of breath, frequent colds) and emotional symptom cluster (feeling sad, being nervous, experiencing sleep problems). Malaise and emotional symptom clusters have a greater impact on QoL than the physical symptoms cluster. Identifying these symptoms warrant additional support in terms of psychosocial support, in addition to treatment of the physical symptoms themselves.

Serum indicators in functional high-risk multiple myeloma patients undertaking proteasome inhibitors therapy: a retrospective study

ABSTRACT Objectives Multiple myeloma (MM) is a class of malignant plasma cell diseases. An increasing application of autologous stem cell transplantation (ASCT) and anti-myeloma agents represented by proteasome inhibitors (PIs) has improved the response rates and survival of MM patients. Patients progressing within 12 months were recently categorized with functional high-risk (FHR), which could not be clarified by existing genetic risk factors, with poor outcomes. Our study aimed to investigate clinical indices related to FHR and seek prognostic roles in transplant-eligible MM patients. Methods Demographic and individual baseline clinical characteristics were compared by using the Pearson's chi-square and Mann-Whitney U test. Progression-free survival (PFS) and overall survival (OS) were described by Kaplan-Meier estimates and compared using the log-rank test. Logistic regression analysis was used to assess the association of baseline characteristics at MM diagnosis with FHR status. Results From 18th January 2010 to 1st December 2022, 216 patients were included and divided into two groups according to the FHR status. There was no difference in baseline data between the two groups. Renal impairment (RI, Scr > 2 mg/dL) was common in MM patients and made sense in FHR status. AST levels were validated as independent predictors for FHR status (p = 0.019). Discussion Patients with RI or higher AST levels (AST > 40 U/L) tended to have worse outcomes. However, transplants had apparently improved prognoses. Conclusion Therefore, in the PIs era, transplantations are still effective therapies for transplant-eligible MM patients.

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.

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.

Impact of the Addition of Daratumumab to the Standard Bortezomib-Thalidomide-Dexamethasone Regimen on Hematopoietic Stem Cell Mobilization and Collection, Post-Transplant Engraftment and Infectious Complications: A Case-Control Multicentre Real-Life Analysis

Background The pivotal clinical trial CASSIOPEIA established the quadruplet Daratumumab-Bortezomib-Thalidomide-Dexamethasone (Dara-VTD) as superior with regards to the standard Bortezomib-Thalidomide-Dexamethasone (VTD) regimen as induction therapy in newly diagnosed transplant-eligible (NDTE) multiple myeloma (MM) patients. As a matter of facts, Dara-VTD is currently the approved induction scheme in NDTE MM patients in Italy. Previous reports showed that adding Daratumumab in induction therapy patients yielded to a higher number of poor mobilizers, with a lower median number of collected hematopoietic stem cells (HSC). However, these reports included different types of induction therapies, merging patients on and off clinical trials, and real-life data focusing exclusively on Dara-VTD is lacking. We report our experience on the impact of Dara-VTD on HSC mobilization and collection, with a retrospective comparison with a cohort of patients treated with VTD and we also provided data concerning post-transplant engraftment and infectious complications. Methods From January 2022 to June 2023, 109 NDTE MM patients from 5 Haematology Institutions received Dara-VTD treatment induction according to the approved doses and schedule. The control group consisted of 116 age-matched patients treated with VTD in the years 2015-2016. Mobilizing therapy consisted of cyclophosphamide 1-3 gr/sqm followed by granulocyte colony-stimulating factor (G-CSF) 10 mcg/kg starting the 5th day thereafter, with HSC harvest planned on the 11th day. Patients received only G-CSF 10 mcg/kg if they were older than 70 years or had renal impairment (i.e., eGFR &amp;lt; 50 ml/min). Poor mobilizer was defined as having less than 20 CD34+/µL in peripheral blood on the 11th day after cyclophosphamide and G-CSF or on the 4th day of G-CSF alone administration. In that case, plerixafor was added at the standard dose of 0.24 mg/kg. Results In the Dara-VTD group, 96/109 patients received cyclophosphamide and G-CSF; among them, 3 patients had failed a previous G-CSF mobilizing therapy, even with the addition of plerixafor. Thirteen patients received G-CSF only. In the VTD group, all patients had received cyclophosphamide and G-CSF. Pre-harvest median number of CD34+/mL in the Dara-VTD group was 26 (range 0.8-279) vs 76 (range 20-294) in the VTD group and the incidence of poor mobilizing patients was 41.7% vs 5.9%, respectively (OR 0.3, 95% CI 0.16-0.54, P &amp;lt; 0.0001). Baseline disease characteristic did not have an impact on poor mobilizing events. On the contrary, patients who developed hematologic toxicity during induction turned out to be poor mobilizers (OR 3.5, 95% IC 1.36-9.59, p= 0.011). Plerixafor was used in 54/109 patients in the Dara-VTD group and in 16/116 patients of the VTD group. Two patients failed HSC mobilization both with G-CSF and cyclophosphamide and G-CSF. All patients that received G-CSF only resulted in poor mobilizers and required plerixafor before HSC harvest; therefore, cyclophosphamide showed to be superior with regards to G-CSF as mobilizing therapy (p= 0.011). The median number of collected HSC was significantly lower in the Dara-VTD group vs VTD group: 5.17 x 10^6/Kg (IQR 3.9-5.47) vs 8.7 x 10^6/kg (IQR 6.35-11.15), respectively (p &amp;lt; 0.0001). 33% of patients in Dara-VTD group collected at least 6 x 10^6 CD34+/Kg). Median time to neutrophils and platelets engraftment were different between the two groups (13 and 11 days, respectively, P &amp;lt; 0.0001), but we did not observe any difference in terms of infection incidence. Notably, post-transplant infections incidence in Dara-VTD group was 43%. Although the second transplant was planned for 36 patients treated with Dara-VTD, it was performed in 10 patients only, mainly because of insufficient HSC harvest. Conclusions Our experience with Dara-VTD confirms an increased number of poor mobilizers, a higher need for the use of plerixafor and a lower number of collected HSC. We observed a slightly lower engraftment in Dara-VTD group, probably because of a lower number of infused HSC. The lower number of collected HSC hampers the possibility of a double transplant.

Comparison of Response and Survival Outcomes in Standard- and High-Risk Newly Diagnosed Transplant-Eligible Multiple Myeloma (NDMM) Patients Treated with Lenalidomide, Bortezomib and Dexamethasone (RVD) Versus Daratumumab, Lenalidomide, Bortezomib and Dexamethasone (D-RVD)

Introduction: The combination of lenalidomide, bortezomib, and dexamethasone (RVD) is highly effective for newly diagnosed myeloma (NDMM) patients. However, the addition of daratumumab to RVD (D-RVD) has shown improved depth of response and trend towards PFS benefit. Here, we present a real-world comparison of the largest cohort of patients consecutively treated with either D-RVD or RVD induction therapy in terms of response and long-term outcomes for both standard- and high-risk patients. Methods: 1000 consecutive NDMM patients treated with RVD between January 2007- August 2016, and 326 NDMM patients treated with D-RVD induction therapy from April 2018 - August 2022 were included in this analysis. Daratumumab was dosed either IV or subcutaneously weekly throughout induction; lenalidomide was started at 25 mg on days 1-14, bortezomib 1.3 mg/m2 on days 1,4,8,11 and dexamethasone 40 mg on days 1,8,15 all on a 21-day cycle. Of note, in contrast to GRIFFIN, no consolidative cycles were administered in either DRVD or RVD cohorts, and maintenance therapy for standard risk patients with lenalidomide alone while high-risk MM patients were managed with a triplet induction regimen for 3 years (Nooka et al, Leuk 2014). Demographic and clinical characteristics and outcomes data were obtained from our institutional review board-approved myeloma database and with manual abstraction. Responses and progression were evaluated per International Myeloma Working Group Uniform Response Criteria. Results: Patient characteristics for DRVD vs RVD are found in Table 1. Of note, for DRVD vs RVD, 13.8% vs 15.8% had HR disease, and 16% vs 23.3% had ISS 3 and 4.6% vs 11.5% with RISS 3 disease. 98.6% and 99.7% of patients in the RVD vs D-RVD cohorts underwent ASCT. High-risk disease was defined as presence of del(17p), t(4;14), t(4;16), and complex karyotype. Post-induction overall response rate (ORR) was 99.6% in D-RVD versus 97.1% in RVD, with ≥VGPR rates of 86.5% vs 67.6%, respectively. Post-transplant ORR was 99.3% vs 98.5%, with ≥VGPR rates of 95.6% vs 86.8%, respectively. Though the median follow-up for the Dara-RVD cohort is significantly shorter (19.1 months) compared to the RVD cohort (88.4 months), there is already a PFS benefit demonstrated with quadruplet induction for both standard- and high-risk patients. For all patients, the 2-year PFS and OS for D-RVD vs RVD is 93% and 94% compared to 82% and 91%, respectively. For standard risk patients, the 2-year PFS for D-RVD vs RVD is 94% vs 84%, and for high risk patients, 83% vs 69%, respectively. 2-year OS for standard risk patients was 96% in D-RVD vs 93% in RVD, and 94% vs 79% in HR patients, respectively. OS estimates for HR patients also favored D-RVD, though this is more likely than PFS to be impacted by changes in treatment patterns over the past decade. Conclusions: D-RVD is a highly effective induction regimen that can improve upon outcomes in a historical NDMM population treated with RVD in terms of depth of response and PFS benefit. In the absence of phase 3 data supporting D-RVD vs RVD as standard of care induction, this analysis provides evidence of benefit with the addition of daratumumab to RVD in increasing depth of response, and provides an early glimpse of the promising PFS and OS benefit not only in standard risk patients, but also in patients with high-risk cytogenetic and disease features.

CD16, CD57 and DNAM-1 Positive NK Cells Predict MRD Negativity in Newly Diagnosed Multiple Myeloma Patients Treated with Daratumumab, Bortezomib, Thalidomide and Dexamethasone

Introduction: Daratumumab-based quadruplets are the current standard of care for newly diagnosed transplant-eligible multiple myeloma (MM) patients, because of improved depth of response and survival, compared with triplet regimens without daratumumab. Since one of the primary mechanisms of action of daratumumab is the induction of antibody-dependent cellular cytotoxicity (ADCC) via the Fc-gamma receptor CD16 on natural killer (NK) cells, it is crucial to understand the role of NK cells in combination therapy. We therefore set out to comprehensively profile NK cells by flow cytometry in newly diagnosed MM (NDMM) patients treated with either daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTD) or VTD. Methods: A subset of NDMM patients (n = 152) who were treated in the Cassiopeia trial (EudraCT: 2014-004781-15) was included in this immunomonitoring analysis. In this trial, patients were first randomized to receive either four induction cycles and two consolidation cycles of D-VTD or VTD in conjunction with autologous stem cell transplantation (ASCT). In the second part of this trial, patients who achieved partial response or better at day 100 post-ASCT were randomized to either receive daratumumab maintenance or observation for the duration of two years. Bone marrow (BM) and peripheral blood (PB) samples were collected at study entry (baseline), and for PB at additional time points: cycle 1 day 28, cycle 4 day 28, day 100 (post-ASCT) and week 52 (maintenance). All baseline BM and PB samples and a selection of longitudinal PB samples were profiled by flow cytometry, with a focus on NK cell phenotype (CD56, CD16, CD57, DNAM-1, TIGIT, KLRG1, PD1, TIM3, NKG2A, NKG2C, NKG2D). To identify NK cell profiles associated with minimal residual disease (MRD) negativity, baseline PB and BM data were compared between MM patients based on MRD status after consolidation. Additionally, longitudinal data of PB samples collected during treatment were assessed to understand the impact of D-VTD and VTD on NK cell profiles. Results: In this cohort, 49 patients out of 77 (64%) randomized to the D-VTD arm achieved MRD negativity post-consolidation, while this was the case in 28 out of 75 patients (37%) in the VTD arm (fisher exact-test, p = 0.008). Patients with a higher proportion of BM-residing NK cells expressing the ADCC receptor CD16 (median 86 vs 72%, p = 0.007), the activating receptor DNAM-1 (median 94 vs 89%, p = 0.029), or the maturation marker CD57 (median 58 vs 48 %, p = 0.049) at baseline were more likely to achieve MRD-negativity post-consolidation in the D-VTD arm (Figure 1). Notably, this association was not present in the VTD arm. Although not significant, we found a similar trend for CD16 in PB in the D-VTD arm. During D-VTD treatment, we observed an increase in the proportion of CD56 bright and NKG2A + in PB NK-cells, and a corresponding decline in cells expressing CD16, CD57 and DNAM-1 (linear mixed effect model (LME) p &amp;lt;0.001). During VTD treatment we also observed a decrease in CD16 + NK-cells and an increase in CD56 bright and NKG2A + NK-cells (LME p &amp;lt;0.05), although these changes were more pronounced in the D-VTD arm. In patients who were assigned D-VTD at the first randomization and were subsequently randomized to the observation arm, we observed a restoration of the proportion of CD16 +, CD57 +, and CD56 bright NK cells to baseline values at week 52 after ASCT (Figure 2). As expected, the daratumumab associated NK cell changes persisted in the group that was randomized to the daratumumab maintenance arm. Conclusion: This study highlights the importance of NK cell immunophenotypic profiles in bone marrow as predictive markers for MRD negativity in NDMM patients treated with D-VTD in in conjunction with ASCT. Additionally, our findings illustrate that NK cell changes associated with daratumumab return to baseline levels after treatment cessation, indicating the potential for sequential NK cell-based therapies. In conclusion, this study not only provides valuable insights into the role of NK cells in the treatment of NDMM patients with D-VTD and ASCT, but also indicates that further research to optimize NK cell function in the context of combination therapies is warranted.

Use of Combination Premedication Prior to Motixafortide Administration Reduced Severity and Frequency of AEs in the Phase 3 Genesis Trial - a Single Center Analysis

Background: Motixafortide is a novel, high affinity CXCR4 antagonist with extended receptor occupancy that facilitates the migration of hematopoietic stem and progenitor cells from the bone marrow into the peripheral blood in preparation for autologous stem cell transplantation (ASCT). In prior pre-clinical and clinical studies, motixafortide was associated with transient hypersensitivity and injection site reactions. Strategies to mitigate such adverse events (AEs) commonly include agents with antihistamine activity. The Phase 3 GENESIS trial demonstrated that 88.8% of Multiple Myeloma patients mobilized ≥6x10 6 CD34+ cells/kg (local labs) in 1 leukapheresis procedure (LP) following the administration of 1 dose of motixafortide in combination with GCSF. Per initial protocol, premedication with an antihistamine H1 blocker prior to motixafortide administration was provided to all patients. However, during the course of the GENESIS study a protocol amendment was implemented to include premedication with an antihistamine H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen prior to motixafortide administration. Here we report the safety findings in a cohort of patients at who received single drug premedication with an H1 antihistamine prior to the protocol amendment and those who received the updated combination pre-medication regimen following protocol amendment. Methods:The GENESIS trial was a multicenter, randomized, double-blind, placebo-controlled study in 122 transplant-eligible multiple myeloma patients, as previously described (PMID: 37069359). Included in this analysis are 46 patients enrolled at the Washington University in St. Louis; 32 patients were randomized to the motixafortide treatment arm and 14 patients were randomized to the placebo arm. Among motixafortide-treated patients, 22 received a single-agent H1 blocker pre-medication and 10 received a combination pre-medication regimen comprising of an H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen. All pre-medications were administered within 1 hour prior to motixafortide administration. Hypersensitivity AEs included all events coded to the MedDRA terms of urticaria, pruritus, flushing, erythema, rash, hypersensitivity or anaphylaxis. Injection site reactions included all events coded to the MedDRA High Level Term of Injection Site Reaction. All AEs were graded using CTCAE criteria and were recorded up to 30 days from the last dose of motixafortide. Results: Overall, motixafortide was safe and well tolerated with no episodes of anaphylaxis, no Grade 4 AEs and no deaths. The most commonly observed AEs included transient hypersensitivity and injection site reactions. The frequency of motixafortide-associated hypersensitivity AEs of any grade was reduced from 90.9% with single-agent H1 blocker pre-medication to 20% with the combination pre-medication regimen, similar to the 20-25% rate of hypersensitivity AEs reported in the placebo + GCSF cohort (Table 1). In addition, all hypersensitivity AEs that occurred following combination pre-medication were graded mild in severity (Figure 1). Meanwhile the frequency of injection site AEs of any grade was reduced from 95.5% with single-agent H1 blocker pre-medication to 80.0% with the combination pre-medication regimen (Table 1). Furthermore, a notable improvement in severity of injection site AEs was observed, with moderate-severe injection site AEs reduced from 27% with single-agent H1 blocker pre-medication to 0% with the combination pre-medication regimen (Figure 1). Conclusions:Motixafortide was safe and well tolerated with no episodes of anaphylaxis, no Grade 4 AEs and no deaths. Following implementation of a protocol amendment using combination pre-medication with an antihistamine H1 blocker, an H2 blocker, a leukotriene inhibitor and acetaminophen, the frequency and severity of hypersensitivity and injection site AEs associated with motixafortide were markedly improved.

Evidence-Based Recommendations for Induction Treatment of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients; A Scoping Review

Introduction Multiple myeloma is a hematological malignancy characterized by the uncontrolled proliferation of plasma cells within the bone marrow, with an increasing incidence and mortality in the last decade. Eligibility for stem cell transplantation plays a crucial role in determining the approach to treatment, with transplant eligible patients undergoing triple induction therapy with an immunomodulatory agent, a proteasome inhibitor, and steroid. We aimed to review the recent data on the available treatment options for newly diagnosed multiple myeloma (NDMM) in transplant eligible patients. Methods A scoping review was conducted according to the PRISMA 2020 guidelines utilizing the PubMed and Embase databases. The inclusion criteria was phase II or III clinical trials pertaining to the use of triple and quadruple therapy in NDMM patients, from the year 2010 onwards. A total of 2377 search results were screened, with 510 undergoing full-text screening against the inclusion criteria. Covidence was used to facilitate the screening process (Figure 1). Results Forty studies were included in the analysis. Eleven trials were based on Daratumumab induction. Additionally, two trials each utilized Isatuximab and Carfilzomib-based induction. One trial employed induction therapy containing Elotuzumab, and another utilized Cyclophosphamide. Addition of Daratumumab to the triplet regimen resulted in significant improvements in response rates and depth of responses. CASSIOPEIA trial demonstrated a notable improvement in minimal residual disease (MRD), with VTd treatment yielding 44% MRD, while Dara-VTd regimens achieved 64% MRD. Similarly, complete response (CR) rates increased from 26% to 39%, respectively. GRIFFIN trial revealed a remarkable 55% reduction in the risk of disease progression for patients with Dara-RVd . Moreover, the estimated 48-month progression-free survival (PFS) rate was 87.2% in the Dara-RVd group, compared to 70% in the RVd group. Notably, the median PFS was not reached in either treatment arm. The Lyra trial, which analyzed Dara-CyBorD followed by Dara maintenance, demonstrated a CR rate of 48.7% for transplant patients and 29.8% for non-transplant patients, respectively. Additionally, the MASTER trial revealed that Dara-KRd/autologous hematopoietic cell transplant (AHCT) led to a high rate of MRD negativity, with 80% of patients achieving MRD negativity. The two-year PFS was 87%. Furthermore, the addition of Isatuximab and Carfilzomib to the treatment regimen demonstrated favorable outcomes in terms of MRD and PFS (Table 1). The addition of Elotuzumab did not lead to a significant improvement in outcomes. Moreover, caution is warranted when using Cyclophosphamide, given its less favorable safety profile and limited additional benefit in survival outcomes (MRD: 27% in +Cyclophosphamide arm vs. 35% without), including a temporary decline in health-related quality of life. Conclusion In conclusion, this scoping review underscores the significance of individualized treatment approaches for multiple myeloma based on clinical trial results. Each induction regimen has shown varying levels of efficacy and safety, offering clinicians flexibility to tailor treatments for different patient populations. The results from these trials will serve as valuable benchmarks and inform future research in the quest for improved therapies for NDMM patients.

Clinical factors associated with autologous stem cell transplantation outcomes in multiple myeloma: upfront transplant with MEL200 remains the standard of care.

Autologous stem cell transplantation (ASCT) remains the mainstay of the treatment in newly diagnosed transplant-eligible multiple myeloma (MM) patients. This retrospective study was performed to investigate the potential prognostic markers which may modify transplant course in a total of 256 ASCT recipients [median age: 58 (30-74) years; male/female: 138/118], including pretransplant (PET0) and day + 60 (PET2) PET/CT assessments and comparative analysis of melphalan (Mel) dose. Better responses with significantly higher complete response/very good partial response rates were achieved in patients who proceeded to transplant within 301days from diagnosis (p < 0.001). Patients who had received < 1.5 lines of treatment prior to transplant had significantly higher probability of overall survival (OS) (p = 0.004) and progression-free survival (PFS) (p < 0.001). The probability of OS was significantly higher in patients with low Eastern Cooperative Oncology Group (ECOG) performance score (PS = 0-1) (p = 0.003) and HCT-Comorbidity Index (HCT-CI = 0) (p = 0.011). The number of involved areas (p = 0.028) and maximum standardized uptake value (SUVmax) (p = 0.021) in PET0 represented significant impact on OS. The probabilities of OS (p < 0.001) and PFS (p = 0.01) were significantly better with Mel200 mg/m2 conditioning compared to Mel140 mg/m2. Conditioning with Mel200 mg/m2, early and upfront ASCT and low pretransplant treatment burden were found to be significantly associated with ASCT outcome in MM patients. Despite its predictor impact on survival and prognosis, further studies are warranted to standardize PET/CT-based response assessments before being used as a guide for treatment decisions in clinical practice.

Steady-state versus chemotherapy-based hematopoietic cell mobilization after anti-CD38-based induction therapy in newly diagnosed multiple myeloma.

The incorporation of anti-CD38 monoclonal antibodies (mAb) in induction regimens of newly diagnosed transplant-eligible multiple myeloma (MM) patients has been established as a new standard. However, the optimal strategy of stem cell mobilization in this context is not yet clear. From May 2020 till September 2022, we retrospectively reviewed patients receiving anti-CD38 mAb-based induction therapy followed by stem cell mobilization either in a steady-state protocol (SSM) using 10 μg/kg granulocyte colony-stimulating factor (G-CSF) for 5 days or in a chemotherapy-based protocol (CM) using 1-4 g/m2 cyclophosphamide and G-CSF. Overall, 85 patients (median age 61 years) were included in the analysis. In total, 90 mobilization attempts were performed, 42 with SSM and 48 with CM. There was no significant difference in the median concentration of CD34+ cells in peripheral blood (PB) prior to apheresis between SSM and CM (61/μL vs. 55.4/μL; p = .60). Cumulative CD34+ yields did not differ between the groups with median of 6.68 and 6.75 × 106 /kg body weight, respectively (p = .35). The target yield (≥4 × 106 CD34+ cells/kg body weight) was reached in 88% (CM) and 86% (SSM), with a high proportion even after a single apheresis session (76% vs. 75%). Plerixafor was found to be more frequently used in SSM (52%) than in CM (23%; p < .01). A total of 83 patients underwent autologous transplantation and all were engrafted. Stem cell collection in patients undergoing anti-CD38-based induction therapy is feasible with either CM or SSM, although SSM more frequently requires plerixafor.

Clinical Benefit of Autologous Stem Cell Transplantation for Patients with Multiple Myeloma Achieving Undetectable Minimal Residual Disease after Induction Treatment.

Achieving and maintaining undetectable MRD is the current treatment goal for multiple myeloma. Our results emphasized the remarkable clinical benefit of ASCT on MRD-negative duration, PFS, and OS in patients with multiple myeloma regardless of early MRD status. These favorable impacts were more evident in patients with aggressive features. Importantly, dynamic MRD monitoring among ASCT could facilitate personalized stratification of therapeutic approaches.

OA-12 Predictors of unsustained measurable residual disease (MRD) negativity in transplant-eligible multiple myeloma (MM) patients

OA-12 Predictors of unsustained measurable residual disease (MRD) negativity in transplant-eligible multiple myeloma (MM) patients

Peripheral blood stem cell mobilisation following bortezomib, lenalidomide and dexamethasone induction for multiple myeloma: a real-world single-centre experience.

Bortezomib, lenalidomide and dexamethasone (VRd) is now the standard-of-care induction therapy for newly diagnosed transplant-eligible multiple myeloma patients, replacing bortezomib, cyclophosphamide and dexamethasone (VCD) therapy. Lenalidomide can negatively impact stem cell yield because of its myelosuppressive effects, although studies have shown that the latter can be overcome with the use of cyclophosphamide for peripheral blood stem cell (PBSC) mobilisation. To investigate whether lenalidomide impacts on PBSC mobilisation and to evaluate the optimal mobilisation strategy post VRd induction, we performed a retrospective review of 56 myeloma patients at a single centre who had PBSC mobilisation between January 2019 and March 2021 and compared three cohorts: (i) VCD induction; mobilisation with granulocyte colony-stimulating factor (G-CSF) alone (n = 23); (ii) four cycles VRd induction; mobilisation with G-CSF and cyclophosphamide (G-CSF + Cyclo) (n = 20); and (iii) three cycles VRd induction; mobilisation with G-CSF alone (n = 13). There was no difference in the mean total CD34 count between VCD and VRd patients who had G-CSF mobilisation (6.27 × 106 /kg vs 5.50 × 106 /kg, P > 0.99). VRd patients mobilised with G-CSF + Cyclo achieved higher mean total CD34 counts compared with G-CSF alone (8.89 × 106 /kg vs 5.50 × 106 /kg, P = 0.04). The majority of VRd patients who had G-CSF + Cyclo (19 of 20; 95%) collected sufficient cells for two or more autologous stem cell transplants (ASCTs), regardless of whether this was required, compared with eight of 13 (62%) VRd patients who had G-CSF alone. We conclude that successful PBSC mobilisation for at least one ASCT is possible after three cycles of VRd induction using G-CSF alone. The upfront use of a cyclophosphamide-based mobilisation strategy has a role in patients who have had VRd induction, where the aim is to collect enough stem cells for two or more ASCTs.

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 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.

Prospective evaluation of minimal residual disease in the phase II FORTE trial: a head-to-head comparison between multiparameter flow cytometry and next-generation sequencing.

Limited data are available on the concordance between multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for minimal residual disease (MRD) detection in a large trial for multiple myeloma (MM) patients. MRD was explored in the FORTE trial for transplant-eligible MM patients randomised to three carfilzomib-based induction-intensification-consolidation treatments and carfilzomib-lenalidomide (KR) vs R maintenance. MRD was assessed by 8-colour 2nd-generation flow cytometry in patients with ≥very good partial response before maintenance. NGS was performed in case of suspected complete response (CR) in a correlative subanalysis. Biological/prognostic concordance between MFC and NGS, conversion to MRD negativity during maintenance, and 1-year/2-year sustained MRD negativity were explored. Between September 28, 2015 and December 22, 2021, 2020 samples were available for MFC and 728 for the simultaneous MFC/NGS correlation in the "suspected CR population". Median follow-up was 62 months. Biological agreement was 87% at the 10-5 and 83% at the 10-6 cut-offs. A remarkable prognostic concordance was observed: hazard ratios in MFC-MRD and NGS-MRD-negative vs -positive patients were 0.29 and 0.27 for progression-free survival (PFS) and 0.35 and 0.31 for overall survival, respectively (p<0.05). During maintenance, 4-year PFS was 91% and 97% in 1-year sustained MFC-MRD-negative and NGS-MRD-negative patients (10-5), respectively, and 99% and 97% in 2-year sustained MFC-MRD-negative and NGS-MRD-negative patients, regardless of treatment received. The conversion rate from pre-maintenance MRD positivity to negativity during maintenance was significantly higher with KR vs R both by MFC (46% vs 30%, p=0.046) and NGS (56% vs 30%, p=0.046). The significant biological/clinical concordance between MFC and NGS at the same sensitivity suggests their possible use in the evaluation of one of the currently strongest predictors of outcome. Amgen, Celgene/Bristol Myers Squibb, Multiple Myeloma Research Foundation.