Therapy In Multiple Myeloma Patients Research Articles

Lenalidomide plus Dexamethasone Combination as First-Line Oral Therapy of Multiple Myeloma Patients: A Unicentric Real-Life Study.

Based on the results obtained in clinical trials, the use of the combination of lenalidomide and dexamethasone (Len/Dex) has become a potential therapeutic choice for newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation. This study evaluated 89 frail NDMM patients treated with first-line oral association. At the last follow-up, 34 out of 89 patients (38.2%) were alive, and 22 were still in treatment with Len/Dex. Among 73 evaluable patients who received at least two cycles, the overall response rate was 71% (N = 52). The disease control rate, defined as any level of clinical response to therapy, occurred in 71 patients (97%). We reported one or more adverse events of grade 3 or 4 (G3/4) in 65.2% (N = 58) of patients, with a prevalence of hematological toxicity (24 patients), leading to an overall discontinuation of treatment in two cases. In univariate analysis, high ISS, high serum β2-microglobulin, and creatinine clearance <30 mL/min negatively impact OS, while the depth of response positively impacts OS. Moreover, G3-4 anemia, ISS, frailty score, and ECOG negatively impacts PFS. In conclusion, elderly and more frail patients benefit from the Len/Dex combination also in the era of monoclonal antibodies, ensuring an increased PFS and OS in patients where the therapeutic choice is often limited and usually not very effective.

The quantification of circular RNA 0007841 during induction therapy helps estimate the response and survival benefits to bortezomib-based regimen in multiple myeloma.

Circular RNA_0007841 (Circ_0007841) facilitates multiple myeloma (MM) progression and resistance of the bortezomib by experimental studies, while its clinical implication in MM patients is still unclear. This study intended to evaluate the longitudinal change and prognostic role of circ_0007841 expression in MM patients receiving bortezomib-based induction therapy. In this prospective study, bone marrow plasma cell (BMPC) samples were gained from 97 MM patients at diagnosis and after bortezomib-based induction therapy, and from 30 healthy controls (HCs) proposing BM donation. Then, circ_0007841 expression in BMPC samples was measured by reverse transcription-quantitative polymerase chain reaction. Additionally, MM patients were followed up for a median of 29.4months. Circ_0007841 expression was increased in MM patients compared to HCs (P < 0.001), but it was decreased after bortezomib-based induction therapy in MM patients (P < 0.001). Moreover, circ_0007841 expression at diagnosis was associated with the presence of t (4; 14) (P = 0.034), while its expression after bortezomib-based induction therapy was linked with higher revised international staging system stage (P = 0.025) in MM patients. Interestingly, circ_0007841 expression after bortezomib-based induction therapy was lower in MM patients who achieved complete remissions (P = 0.001) and overall responses (P = 0.002) compared to those who did not. Prognostically, circ_0007841 expression after bortezomib-based induction therapy (over the median vs. below the median) independently predicted shorter progression-free survival (hazard ratio (HR): 2.497, P = 0.002) and overall survival (HR: 3.107, P = 0.008) in MM patients. Circ_0007841 quantification during induction therapy may reflect the response and survival benefits to bortezomib-based regimen in MM patients.

Cellular immunity in the era of modern multiple myeloma therapy.

Multiple myeloma (MM) is a relapsing clonal plasma cell malignancy and incurable thus far. With the increasing understanding of myeloma, highlighting the critical importance of the immune system in the pathogenesis of MM is essential. The immune changes in MM patients after treatment are associated with prognosis. In this review, we summarize currently available MM therapies and discuss how they affect cellular immunity. We find that the modern anti-MM treatments enhance antitumour immune responses. A deeper understanding of the therapeutic activity of individual drugs offers more effective treatment approaches that enhance the beneficial immunomodulatory effects. Furthermore, we show that the immune changes after treatment in MM patients can provide useful prognostic marker. Analysing cellular immune responses offers new perspectives for evaluating clinical data and making comprehensive predictions for applying novel therapies in MM patients.

Feasibility of cryocompression for bortezomib-induced peripheral neuropathy (BIPN) among patients with multiple myeloma (MM).

e24147 Background: BIPN is a dose-limiting side effect of bortezomib therapy occurring in over three-quarters of bortezomib-treated patients and results in increased morbidity secondary to decreased quality of life and increased mortality due to treatment discontinuation or dose-reduction. Cryocompression therapy acts at the level of the nerve and does not limit bortezomib anti-tumor activity, making it ideal for clinical testing in patients with BIPN. This study evaluated the feasibility of cryocompression therapy in MM patients with BIPN. Methods: MM patients with Common Terminology Criteria for Adverse Event (CTCAE) Grade 1-3 BIPN who previously received a bortezomib-containing regimen (Arm 1) or were currently receiving a bortezomib-containing regimen (Arm 2) were enrolled at a Comprehensive Cancer Center outpatient clinic. Patients were instructed to complete daily home cryocompression treatments on non-dominant hand and foot for 30 continuous minutes for 8-weeks. Primary outcome was compliance measured by device-recorded data and defined as completion of at least 25 of 30 minutes, 60% of prescribed treatment days. Change in patient reported symptoms was assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 questionnaire. Proportion of compliant patients was calculated. Spearman’s rank correlation coefficients were used to evaluate the association between treatment compliance and QLQ-CIPN20 scores. Here we report on Arm 1. Results: 12 patients (median age 63.9+11.8 years, 41.7% female, 66.7% white, 25.0% black) participated in Arm 1. 75% of patients were compliant. The mean proportion of treatment-compliant days was 65.8% (95% CI 46.5% – 85.0%). Patient-reported BIPN symptoms improved with QLQ-CIPN20 total and sensory sub scores of 39.2+9.2 and 22.5+4.7 at baseline, 33.7+6.2 and 19+3.5 at week 4, and 34.1+7.8 and 19.9+5.5 at week 8. This accounted for a statistically significant decline in total QLQ-CIPN20 score at week 4 (-5.9+9.1, p = 0.035), week 8 (-4.6+5.0, p = 0.020), and sensory sub score at week 4 (-3.5+3.4, p = 0.008) and week 8 (-2.6+3.5, p = 0.050). There was no correlation between compliance and change in total QLQ-CIPN20 score (r = -0.31, p = 0.380) or sensory sub score (r = -.054, p = 0.109) in the per protocol analysis (N = 10). Using a last-time-point available analysis, no correlation was observed for total QLQ-CIPN20 score (r = -0.44, p = 0.149) but a moderate-to-strong inverse correlation was observed between amount of cryocompression use and change in QLQ-CIPN20 sensory sub score (r = -0.62, p = 0.031). Conclusions: Cryocompression therapy is feasible in MM patients with BIPN who previously received a bortezomib-containing regimen. The observed biologic gradient with greater improvement in patient-reported sensory neuropathy with longer duration of cryocompression treatment supports the rationale and further study. Clinical trial information: NCT03870451 .

Effect of Hemoglobin on Efficacy of CAR-T Therapy in Patients with Multiple Myeloma

To investigate the effect of hemoglobin (Hb) on the efficacy of chimeric antigen receptor T cell therapy (CAR-T) in patients with multiple myeloma (MM). From June 2017 to December 2020, 76 MM patients who received CAR-T therapy in the Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, with complete clinical data and evaluable efficacy, were selected as the research objects. According to the receiver operating characteristic (ROC) curve, the best cut-off value was obtained. The patients were divided into groups on the basis of Hb 105.5 g/L as the cut-off value. The age, sex, serum calcium, β2-microglobulin, serum creatinine, lactate dehydrogenase (LDH), and the influencing factors of CAR-T treatment efficacy in MM patients were analyzed. Hb was an influencing factor of efficacy. Univariate analysis showed that Hb, LDH, and albumin affected the efficacy of CAR-T therapy. Multivariate analysis showed that Hb ( OR=1.039, 95% CI: 1.002-1.078) and LDH ( OR=1.014, 95% CI: 1.000-1.027) were the influencing factors for the efficacy of CAR-T therapy. The efficacy of CAR-T therapy in MM patients with low Hb is poor, and Hb is a factor affecting the efficacy of CAR-T therapy.

Mitochondrial dysfunction and drug targets in multiple myeloma.

Multiple myeloma (MM) is the second most common hematological cancer that has no cure. Although currently there are several novel drugs, most MM patients experience drug resistance and disease relapse. The results of previous studies suggest that aberrant mitochondrial function may contribute to tumor progression and drug resistance. Mitochondrial DNA mutations and metabolic reprogramming have been reported in MM patients. Several preclinical and clinical studies have shown encouraging results of mitochondria-targeting therapy in MM patients. In this review, we have summarized our current understanding of mitochondrial biology in MM. More importantly, we have reviewed mitochondrial targeting strategies in MM treatment.

Cyclophosphamide, Thalidomide and Dexamethasone (CTD) as First-Line Therapy in Multiple Myeloma Patients: An Experience in a Clinical Haematology Centre in Dakar, Senegal

Introduction: Induction therapy followed by high-dose chemotherapy with autologous stem cell transplantation remains the gold standard for myeloma patients who can tolerate this treatment approach. In a developing country setting, in the absence of availability of bone marrow transplantation, the CTD protocol is an accessible treatment regimen whose efficacy and lower toxicity compared to the Melphalan Prednisone protocol has been reported. This protocol has been administered since 2018 in first line. It’s against this backdrop we perform this study to assess the efficacy of this CTD protocol in first line therapy. Methods: We conducted a descriptive and analytical study including clinical, paraclinical and evolutionary data of 50 patients with MM treated during the period range from 01 September 2018 and 01 July 2022 with the CTD protocol of cyclophosphamide (500 mg at D1, D8 and D15), dexamethasone (40 mg weekly) and thalidomide (100 mg/day) in 28-day cycles. Survival outcomes were estimated by the Kaplan-Meier method. Results: The mean age was 62.3 ± 9.1 years and the sex ratio was 0.7. An advanced prognostic score at diagnosis was found in 73.5% of patients according to the Salmon and Durie score and in 32% according to the ISS. Overall remission was noted in 64%, of which 34% were in very good partial remission and partial remission in 12% of cases. Progression was noted in 4 patients. Treatment-related side effects were mainly peripheral neuropathy and anaemia in 3 patients respectively. The median survival was 38.4 months. The progression-free survival was 60%. An advanced age (≥65 years) is correlated with negative impact on survival (p = 0.04). Conclusion: Cyclophosphamide, thalidomide and dexamethasone give good outcome with less toxicity. Thus, it remains a first-line treatment alternative for newly diagnosed and low-income patients.

Evaluating the Impacts of CYP3A4*1B and CYP3A5*3 Variations on Pharmacokinetic Behavior and Clinical Outcomes in Multiple Myeloma Patients With Autologous Stem Cell Transplant.

There exists considerably large interpatient variability in pharmacokinetic exposure of high dose melphalan in multiple myeloma patients with hematopoietic stem-cell transplantation. In this study, we aimed to evaluate the potential impacts of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) variations on pharmacokinetic properties of melphalan and clinical outcomes in multiple myeloma (MM) patients. Genotypes of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) were determined by validated gene-specific real-time PCR (RT-PCR) assays using DNA samples from 108 MM patients; plasma concentrations of melphalan at different time points were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). CYP3A4*1B/*1B and CYP3A5*3/*3 carriers appeared to have a short median progression-free survival time and a higher maximum melphalan plasma concentration than non-carriers [792 vs. over 950 days, p=0.08; 9.91 (2.67, 34.03) vs. 8.66 (4.46, 17.61) mg/l, p=0.039]. CYP3A4*1B/*1B and CYP3A5*3/*3 variations might influence melphalan therapy in MM patients through yet-to-be-identified mechanisms.

Advancing CAR T-Cell Care in Relapsed/Refractory Multiple Myeloma: Insights from a Collaborative Quality Improvement Initiative

Background Multiple myeloma (MM) is most often diagnosed in late stages where the risk of relapse or progression is highest. Treatment of patients with relapsed disease refractory to many available treatment options poses a substantial clinical challenge for providers. Recently approved chimeric antigen receptor (CAR) T-cell therapies have proven efficacious in highly relapsed/refractory MM. Despite CAR T-cell therapy's efficacy, many challenges and barriers to optimal treatment exist in the integration, communication, and care collaboration between centers related to CAR T-cell therapy for MM patients. To improve quality care related to T-cell therapy treatment in MM, we conducted a quality initiative (QI) study focused on evidence-based integration of CAR T-cell therapy, communication, and care coordination between community oncology clinics and regional CAR T-cell therapy performing centers. Methods Building on the design of our prior QI programs (Hussein ASCO 2020), this initiative includes baseline (n = 93) and follow-up provider surveys, and small-group, team-based audit-feedback (AF) sessions. Survey questions were designed to assess knowledge, confidence, and experiences using CAR T-cell therapy in MM treatment. Care teams from each clinic, along with a CAR T-cell expert from the regional center and nationally renowned expert CAR T-cell physician, participated in audit and feedback sessions to (a) assess system-specific practice gaps identified via the provider surveys, (b) prioritize areas for improvement, and (c) develop action plans for addressing root causes. Additional surveys completed before and after the AF sessions will measure changes in participants’ beliefs and confidence in care delivery. Results Provider Surveys: Providers top reported challenges encountered with CAR T-cell therapy include identifying patients eligible for treatment with CAR T-cell therapy (63%), transferring the patient to a CAR T-cell center for infusion (24%), gaining approval from the insurance company for CAR T-cell therapy (23%) and managing the patient post-CAR T-cell therapy (22%). When asked about the level of communication and collaboration between centers, most providers rated very good/excellent (49%) versus good (29%) and poor/fair (22%). Barriers to very good/excellent communication are insufficient sharing of patient information including test results, premedication documents and details of CAR T-cell therapy administration (30%) followed by lack of expertise in CAR T-cell therapy administration among infusion faculty/clinic staff and lack of time for our clinic's staff to communicate with infusion facility staff (figure 1). HCPs reported vastly different frequencies of referring eligible patients for treatment with CAR T-cell therapy, with a combined 36% often or always referring eligible patients and 34% rarely/never initiating a referral. Small Group A/F Sessions: HCPs participating in the small group A/F sessions also reported identifying patients eligible for treatment with CAR T-cell therapy as the biggest challenge regarding treatment with CAR T-cell therapy. Very high/high confidence in identifying eligible patients for CAR T-cell therapy treatment reported by providers increased from 37% to 72%. HCPs also noted increases in their confidence in managing adverse/late effects of CAR T-cell therapy in patients with MM (38% to 63% very high/high confidence). Conclusions Through this QI initiative, clinical teams created and implemented action plans to close gaps in identifying eligible patients, coordinating CAR T-cell therapy referral and approval, and providing counseling and obtaining consent among hematology/oncology team members. Following the initiative, meaningful confidence gains were observed in identifying eligible patients for CAR T-cell therapy and managing adverse/late effects of treatment. Follow-up surveys will assess self-reported practice changes stemming from the action plans. These data underscore clinical practice gaps that can be addressed in future initiatives to support safe, effective, and evidence-based integration of CAR T-cell therapies into MM care to optimize patient outcomes. Study Sponsor Statement The study reported in this abstract was funded by independent educational grants from Bristol Myers Squibb, who had no role in the study design, execution, analysis, or reporting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Cancer-Related Circrna Cirs-7 (CDR1-AS) Is Differentially Expressed in CD138+ Cells of Patients with Plasma Cell Disorders and Predicts Unfavorable Overall Survival in Multiple Myeloma

Introduction: During the last decades, different non-coding RNAs have been implicated in the biology and prognosis of multiple myeloma (MM). Circular RNAs (circRNAs) constitute a class of non-coding RNAs with a high potential as molecular biomarkers. Recently, ciRS-7 (also known as CDR1-AS), an important circRNA regulating miR-7-5p and other cancer-related miRNAs, was shown to be downregulated in MM patients’ cells exhibiting acquired resistance to immunomodulatory drugs (IMiDs). Our goal was to study the expression of this circRNA in MM, compare the results with those of patients with smoldering myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) and evaluate its prognostic significance. Methods: Bone marrow aspirate (BMA) samples were collected from 177 adult patients with plasma cell disorders. The presence of high-risk cytogenetic abnormalities, namely del(17p), t(4;14), t(14;16), and (+1q), was assessed using fluorescence in situ hybridization (FISH). MM patients were classified according to the ISS and revised ISS (R-ISS) staging systems. Whole-body low-dose computed tomography was used to assess osteolysis. Next, CD138-positive selection of plasma cells among mononuclear cells of BMA samples was performed. Moreover, three human MM cell lines (L-363, H929 and U266) were propagated. Total RNA was extracted from CD138+ enriched BMA samples and the MM cell lines, and reverse-transcribed. A first-round PCR was used to pre-amplify ciRS-7 and GAPDH (i.e. reference gene) transcripts, before their quantification via real-time qPCR. In both reactions for ciRS-7 amplification, divergent PCR primers were used, to achieve high specificity and accuracy. ciRS-7 expression was measured in relative quantification units (RQU). Results: The cohort of patients consisted of 111 newly diagnosed MM, 35 SMM and 31 with MGUS. In total, 107 out of the 177 cases (60.5%) were male and 70 (39.5%) were female. The median age of all patients at diagnosis was 70 years (range: 35-93 years). According to the R-ISS staging system, 24 (21.6%) MM patients had R-ISS stage I, 62 (55.9%) R-ISS stage II and 25 (22.5%) had R-ISS stage III. Seventy-seven (69.4%) MM patients presented with osteolytic disease at diagnosis. Regarding front-line therapy of MM patients, 12/111 (10.8%) received proteasome inhibitor (PI)-based therapy, 7 (6.3%) received IMiD-based treatment, 74 (66.7%) were treated with combinations of PI and IMiD, and 18 (16.2%) received anti-CD38-based treatment. The intracellular levels of the ciRS-7 circRNA were different between MM, SMM and MGUS patients’ CD138+ plasma cells (median values were: for MM patients 0.40 RQU vs. 1.74 RQU for SMM patients vs. 2.79 RQU for MGUS patients; P<0.001). Moreover, ciRS-7 levels in U266 and H929 cells were much lower (2,165- and 26,616-fold) than in L-363 cells. ROC analysis showed that ciRS-7 expression can effectively discriminate between MM and SMM patients (AUC=0.65, 95% CI=0.56-0.75, P=0.007). ciRS-7 levels did not significantly differ among MM patients with different ISS or R-ISS stages and were not associated with any assessed cytogenetic abnormality or the presence of osteolytic lesions. Regarding the progression-free (PFS) and overall survival (OS), out of 106 MM patients with survival data, patients with high levels of ciRS-7 have lower survival probabilities. As shown in Figure 1, the median PFS of MM patients with high ciRS-7 (high: defined as higher of the median value) was 19 months vs. 25 months for patients with low ciRS-7 (lower values than the median) (P=0.046); similarly, the mean OS of ciRS-7 (high) MM patients was 25 months vs. 30.5 months for ciRS-7 (low) MM patients (P=0.008). Bootstrap multivariate Cox regression analysis showed that the unfavorable prognostic value of ciRS-7 expression with regard to OS is independent of R-ISS stage and age of MM patients (HR=2.6, BCa 95% CI=0.91-4.75, bootstrap P=0.041). Conclusions: Expression levels of ciRS-7, a cancer-related circRNA, in CD138+ plasma cells are significantly different among patients with MM, SMM and MGUS. Most likely, high ciRS-7 levels predict an unfavorable prognosis in MM, independently of the R-ISS stage and age. Combining our results with the limited existing literature providing evidence for ciRS-7 implication in response to IMiD therapy, its biological role in MM deserves further elucidation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 2 Evaluation of Daratumumab-Based Induction Therapy in Multiple Myeloma Patients with Severe Renal Insufficiency

A Phase 2 Evaluation of Daratumumab-Based Induction Therapy in Multiple Myeloma Patients with Severe Renal Insufficiency

Similar Benefits of High-Dose Melphalan Based Conditioning Regimens Followed By Autologous Hematopoietic Cell Transplantation in Elderly Myeloma Population Compared to the Younger Group: Single Center Experience

Background: Multiple myeloma (MM) remains an incurable plasma cell malignancy and predominantly affects elderly population with a median age at onset around 70 years. High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) remains an important consolidative measures even in the era of novel agents including anti-CD38 antibodies. HCT in elderly patients is typically met with concerns for increased toxicity in this age group. Here, we evaluated our single center experience of autologous HCT in the elderly for the last decade. Methods: Clinical transplant data on MM patients who underwent HCT at Moffitt Cancer Center (MCC) were retrospectively reviewed. BMT Research Analysis Information Network (BRAIN) database was used for data query. The study population was limited to first autologous HCT for MM and receiving high-dose melphalan based conditioning regimens. Patients were divided into 3 groups based on their age at HCT: Age < 65 (n=1044), 65-69 (n=428), and 70+ (n=222). Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier method and compared with log-rank testing. Cumulative incidence function was compared with Gray's test. Results: There were 1694 MM patients who underwent autologous HCT with high-dose melphalan-based regimen at MCC from 2010 to 2021. Over 100 transplants per year were performed at our institution for MM since 2011 at both inpatient and outpatient settings. Median HCT-CI was 2, 3, and 3 for ages <65, 65-69, and 70+, respectively. Median serum creatinine (range) was 0.9 (0.5-10.1), 0.8 (0.4 - 11.9), and 0.9 (0.4 - 8.4) for ages <65, 65-69, and 70+, respectively. Reduced melphalan dosing (MEL140) was used in 5.6%, 10.1%, and 82.7% for ages <65, 65-69, and 70+, respectively. Univariate analysis showed that the 5-year OS for ages <65, 65-69, and 70+ was 71.1% (95% confidence interval (CI): 67.7-74.3), 69.6% (95%CI: 63.9-74.6), and 65.4% (95%CI: 56.4-73.0), respectively (Log rank, p=0.34, Figure). The 5-year PFS for ages <65, 65-69, and 70+ was 48.0% (95%CI: 44.3-51.5), 46.0% (95%CI: 40.0-51.8), and 46.0% (95%CI: 37.3-54.3), respectively (Log rank, p=0.64). The 5-year cumulative incidence of relapse for ages <65, 65-69, and 70+ was 44.9% (95%CI: 41.4-48.4), 44.4% (95%CI: 38.6-50.1), and 38.6% (95%CI: 31.1-46.0), respectively (Gray's test, p=0.2). The 3-moth, 1-year, and 5-year cumulative incidences of nonrelapse mortality (NRM) were 0.5% (95%CI: 0.2-1.2), 1.9% (95%CI: 1.2-2.9) and 7.0% (95%CI: 5.3-9.0) for age < 65, 0.7% (95%CI: 0.1-1.9), 0.9% (0.3-2.2%) and 9.4% (95%CI: 6.4-13.2) for ages 65-69, and 0.0% (95%CI: 0.0-0.0), 0.4% (95%CI: 0.0-2.4) and 15.2% (95%CI: 9.2-22.5) for age 70+, respectively, respectively (Gray's test, p=0.16). Additional multivariate analysis will be provided at the presentation. Conclusions: Overall, there were no differences in the MM HCT outcomes in different age groups at our center. Our data demonstrate the safe application of high-dose therapy in MM patients across the age group. Older MM patients appear to derive comparable survival benefits from HCT and should remain a standard consolidative measure. There is a suggestion that the NRM may be numerically higher in elderly population, and further analysis on long-term outcomes in elderly population is planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Spliced X-Box binding protein 1 predicts satisfying responsiveness and survival benefit toward bortezomib-based therapy in multiple myeloma patients

ABSTRACT Objective Spliced X-Box binding protein 1 (sXBP1) modulates malignant cell activities and enhances the bortezomib sensitivity in multiple myeloma (MM) cells, while its clinical value in MM patients remains elusive. Hence, the current study aimed to explore this issue, particularly the correlation of sXBP1 with treatment outcomes of bortezomib-based therapy in MM patients. Methods Totally, 97 newly-diagnosed MM patients undergoing bortezomib-based therapy, 20 disease controls (DCs), and 20 health controls (HCs) were enrolled. Bone marrow plasma cell samples were acquired to determine sXBP1 by RT-qPCR. Results sXBP1 was lowest in MM patients, followed by DCs, and highest in HCs (P < 0.001). Beyond that, sXBP1 discriminated MM patients from DCs with area under curve (AUC) of 0.728 (95% confidence interval (CI): 0.610–0.847) and HCs with AUC of 0.855 (95% CI: 0.771–0.939). sXBP1 was negatively associated with t (4; 14) (P = 0.047), Revised International Staging System stage (P = 0.008). There was a trend that sXBP1 was negatively correlated with β2-MG, LDH, and t (14; 16) (without statistical significance). sXBP1 was higher in patients with complete response (CR) compared to those with non-CR (P = 0.017) and higher in patients with objective response rate (ORR) compared to those with non-ORR (P = 0.006). sXBP1 (high vs. low) was linked with longer progression-free survival (PFS) (P = 0.011) and overall survival (P = 0.045) in MM patients. Additionally, sXBP1 (high vs. low) (P = 0.025) independently estimated a longer PFS. Conclusion sXBP1 forecasts a favorable treatment response and survival benefit toward bortezomib-based therapy in multiple myeloma patients.

Emodin Ameliorates the Efficacy of Carfilzomib in Multiple Myeloma Cells via Apoptosis and Autophagy.

Background: Carfilzomib, the proteasome inhibitor, can increase the overall survival rate of multiple myeloma (MM) patients undergoing targeted therapy. However, relapse and toxicity present great challenges for such treatment, so an urgent need for effective combination therapy is necessary. Emodin is a natural chemical compound that inhibits the proliferation of various cancers and can effectively combine with other treatments. In this study, we evaluated the sensitizing effect of emodin combined with carfilzomib on MM cells. Methods: The cells were treated with emodin, carfilzomib, and a combination of drugs to determine their effects on cell proliferation and viability. The cell cycle distribution and reactive oxygen species (ROS) expression were measured by flow cytometry. The level of RNA and protein were analyzed through real-time qPCR and immunoblotting. Results: Emodin acted synergistically with carfilzomib to reduce the proliferation and viability of MM cell lines in vitro. Furthermore, the combination of emodin and carfilzomib increased ROS production, inducing apoptosis and autophagy pathways via caspase-3, PARP, p62, and LC3B. Conclusions: These results provide a molecular target for combination therapy in MM patients.

Programmed Cell Death-1 and Its Ligands as Targets for Therapy of Multiple Myeloma Patients.

PurposeAmong hematological malignancies, the expression profile of programmed cell death-1 (PD-1) and its ligands in multiple myeloma (MM) is still debated by numerous research groups. In current study, we characterized the expression of PD-1 and its ligands both on RNA and protein levels in MM patients. We have also attempted to analyze whether daratumumab therapy might overcome CD38-mediated immunosuppression that inhibits in particular CD8+ T-cell function.Patients and MethodsThis study included 149 newly diagnosed MM patients and 15 relapsed/refractory MM patients before and after daratumumab treatment. The mRNA levels of PDCD1, PDCD1LG1, PDCD1LG2 and their splicing variants was assessed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Flow cytometry was used to characterize the surface expression of PD-1 and its ligands on plasma cells, B and T cells. The surface expression of PD-1 on T cells was assessed by flow cytometry before and after daratumumab treatment.ResultsThe mRNA expression of PDCD1LG1, PDCD1LG2 and their splicing variants were higher in plasma cells as compared to bone marrow mononuclear cells (BMMCs). Our results show that the percentage of plasma cells expressing PD-L1 was significantly higher than plasma cells expressing PD-L2 (p<0.0001) in bone marrow (BM) of MM patients. There was no significant difference between the percentage of plasma cells expressing PD-1 and B cells expressing PD-1 in BM of MM patients (11.19% vs 8.91%). We also found that the percentage of CD8+PD-1+ T cells was significantly higher than CD4+PD-1+T cells in BM (p<0.0001) of MM patients. Here, we observed no change in PD-1 expression on CD4+ and CD8+ T cells after the daratumumab treatment.ConclusionThe PD-1 and its ligands might represent an interesting target for MM immunotherapy, as one would target both malignant plasma cells as well as the immune cells that play a key role in tumor escape mechanisms.

Adjusted comparison between elotuzumab and carfilzomib in combination with lenalidomide and dexamethasone as salvage therapy for multiple myeloma patients.

The lack of a randomized trial comparing carfilzomib (K) versus elotuzumab (Elo) associated with lenalidomide and dexamethasone (Rd) prompted us to assess the relative usefulness of one triplet over the other. Five independent retrospective cohorts of 883 relapsed/refractory multiple myeloma (RRMM) patients, including 300 EloRd and 583KRd cases, outside clinical trials, entered this non-randomized comparison. KRd cohort accounted for a higher incidence of younger patients, cases with ≥3lines of therapy, already exposed to lenalidomide, International Staging System (ISS) stage III, and abnormal lactic dehydrogenase (LDH) level compared with EloRd cohort. Moreover, cytogenetic risk categories, detected in roughly one-third of cases, were equally distributed between the two therapy arms. The probability of CR+VGPR response was significantly higher in KRd (n=314, 53.9%) than in EloRd patients (n=111, 37.0%). Likewise, the cumulative incidence function of CR+VGPR, taking into account the competitive risk of death, was significantly higher in KRd arm patients than those in the EloRd arm (p=.003). Moreover, KRd treatment significantly reduced the progression or death risk by 46% in an adjusted multivariate analysis (HR: 0.54, 95% CI 0.42-0.69, p<.0001). Finally, in an adjusted illness-progression/death model, the effect of KRd versus EloRd was of higher magnitude among those who achieved CR+VGPR (-39% hazard ratio reduction, p=.02) than among those who achieved<VGPR (-29% hazard ratio reduction, p=.007). With limitations characteristic to any retrospective analysis, this current clinical practice study's overall results demonstrated potential benefits of KRd therapy compared with EloRd. This observation may help the daily clinical practice.

Ixazomib-based maintenance therapy after bortezomib-based induction in patients with multiple myeloma not undergoing transplantation: A real-world study.

BackgroundMaintenance therapy with proteasome inhibitors (PIs) can improve outcomes of multiple myeloma (MM) patients, however, the neurotoxicity and parenteral route of bortezomib limit its long‐term use. An efficacious, tolerable, and convenient PI option is needed.MethodsIn this single‐center, real‐world study, we retrospectively analyzed the outcome and safety profile of ixazomib‐based maintenance therapy in patients who plateaued with the responses of steady disease or better after bortezomib‐based induction therapy in MM patients not undergoing transplantation.ResultsOf all the 71 patients, 37 cases (52.1%) were newly diagnosed MM (NDMM) and 34 cases (47.9%) were relapsed and/or refractory MM (RRMM). The overall response rate (ORR) was 81.7%, including 34 patients (47.9%) with a very good response rate or better (≥VGPR) after a median of nine cycles (6–14) of bortezomib‐based induction therapy. Then the ORR was transformed to 74.6% including 39 patients of ≥VGPR (54.9%) after a median of six courses (2–25) of ixazomib‐based maintenance therapy. Of these, 18 patients (25.4%) exhibited responses deepened. With 26.5 months median follow‐up, median progression‐free survival (PFS) was 28.4 and 16.5 months from the start of bortezomib and 16.2 and 10.0 months from the initiation of ixazomib in NDMM and RRMM group, respectively. Moreover, responses deepened during the maintenance phase (hazard ratio: 0.270, p = 0.007), and responses of ≥VGPR during the induction phase (hazard ratio: 0.218, p < 0.001) were confirmed to independently predict longer PFS after multivariate analyses. Severe adverse events (grade 3/4) were relatively rare. Bortezomib‐emergent peripheral neuritis (PN) was significantly relived after the transition to ixazomib (p < 0.001).ConclusionThis real‐world analysis has demonstrated oral ixazomib is a favorable option of long‐term administration for maintenance with efficacy and feasibility and confirmed the association between deepening responses with ixazomib and prolonged PFS.

Prognostic Relevance of Concordant Expression CD69 and CD56 in Response to Bortezomib Combination Therapy in Multiple Myeloma Patients

Objective Multiple myeloma is an incurable hematological malignancy. Currently, the use of proteasome inhibitors could be superior to chemotherapy-based regimen in the treatment of this disease. However, resistance to bortezomib combination therapy still occurs in some patients. So, this research work aims to assess CD69 and CD56 expression in these cases and their relation to the response to therapy. Materials and Methods Immunophenotyping by 4-color multi-parameter flow cytometry was carried out on 98 multiple myeloma cases. Clonal plasma cells were gated by co-expression of CD38 with CD138 with low SSC, negative or dim CD45. Results Double negative CD69 and CD56 (47.9%) multiple myeloma cases were associated with high serum β2 microglobulin, creatinine, calcium and low serum albumin. There was also a significant correlation between the absence of these markers with osteolytic lesions and unfavorable cytogenetic t (4;14) (p < 0.001). Moreover, there was a highly significant correlation between CD69- and CD56- with non-response to bortezomib combination therapy in multiple myeloma patients (p < 0.0001). Regression analysis for the prediction of non- response to treatment in these cases using different prognostic indicators revealed that high serum β2 microglobulin, unfavorable cytogenetic, advanced stage, and low expression of CD69 and CD56 were poor predictors of non-response. Conclusion CD69 in association with CD56 could be an independent prognostic factor in multiple myeloma cases. It could be used in the routine laboratory assessment for refining stratification and timely therapeutic decision for highly cost therapy in developing countries.

Abstract 2961: The novel roles of fatty acid binding proteins in multiple myeloma

Abstract Background: Our goal was to determine the role of the fatty acid binding protein (FABP) family in multiple myeloma (MM) using cancer dependency mapping and RNA sequencing, and to assess the potential for combined targeting of FABPs with other MM therapies. We reported at the ASH 2020 Meeting that targeting FABPs in vitro induces apoptosis, cell cycle arrest, and cell death using the FABP inhibitors BMS309403 and SBFI-26. These inhibitors alone, or in combination, reduced tumor bioluminescence and increased survival in a SCID-beige MM1S mouse model. Lastly, we showed the clinical relevancy and excellent potential for targeting the FABPs by analyzing published human MM datasets. Methods: Herein, we searched Crispr screen data from The Cancer Dependency Map (DepMap.org) to quantify MM cell dependency on all the FABP members. We also performed RNA sequencing of human MM1S MM cells treated with BMS309403, SBFI-26, or both for 24 hours and analyzed the gene and pathway changes using dbString analysis. Lastly, we tested dexamethasone (dex) with SBFI-26 in the SCID-beige GFP+Luc+MM1S in vivo model. Results: Using DepMap, MM cells were most highly dependent on FABP5, which fell within the top 25% of essential genes for MM cells. FABP5 was also the most highly expressed FABP in 3 cell lines (MM1S, OPM2 and RPMI8226) in our RNA sequencing data, and was expressed by primary MM cells. Our RNA sequencing data revealed many changes in MM1S cells after treatment with BMS309403, SBFI-26, or both; the greatest number of genes changed was with the combination treatment BMS309403 + SBFI-26 (either up- or down-regulated) versus vehicle controls. Interestingly, the central node in the dbString analysis of downregulated genes after combination treatment (FC&amp;lt;-1.5, p&amp;lt;0.05) out of 154 genes was Myc, suggesting that disruption of the Myc pathway caused the cell cycle arrest, decreased proliferation, and increased apoptosis in MM cells treated with FABP inhibitors. 196 upregulated genes (p&amp;lt;0.05, FC&amp;gt;1.5) were identified in MM cells with the combination treatment including CD44, PECAM, and IGFBP7; the “cellular response to interferon gamma” gene ontology term was an up-regulated biological process. Lastly, although our in vitro data supported the combination of SBFI-26 + dex, we did not observe a decrease in tumor bioluminescence using the combination of 1 or 9 mg/kg dex plus 1 mg/mL SBFI-26 3X/week in the MM1S mouse model. Future studies using different doses of these and other drugs (eg. lenalidomide and bortezomib) to more thoroughly investigate the combination potential for FABP inhibitors with common anti-MM therapies are planned. Conclusion: Targeting the FABPs holds great potential as a novel, safe therapy for MM patients. We identified the Myc signaling pathway as a potential mediator of FABP action. As Myc is a commonly upregulated oncogene in MM and other cancers, we believe there may be great untapped potential for targeting FABPs, especially FABP5, in MM and other cancers. Citation Format: Mariah Farrell, Anastasia D'Amico, Heather Fairfield Campbell, Connor Murphy, Michaela Ruth Reagan. The novel roles of fatty acid binding proteins in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2961.

Post-Autologous Stem Cell Transplantation Therapy for Multiple Myeloma Patients: Impact on Clinical Outcomes

Introduction Autologous stem cell transplantation (auto-SCT) has dramatically improved the outcomes for patients with MM. While the outcomes are better, still most patients will inevitably relapse. Two different approaches have been reported aiming to improve clinical outcomes: consolidation and maintenance. In the present study, we evaluate the impact of post-autoSCT therapy over survival outcomes. Methods All consecutive patients who underwent single auto-SCT at Tom Baker Cancer Center from 01/04 to 03/17 were evaluated. A p value of <0.05 was considered significant. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Results 302 consecutive patients with MM who underwent single auto-SCT at our Institution over the defined period were evaluated. Clinical characteristics are shown in Table 1. 78 patients did not receive any form of post-autoSCT therapy, 93 patients had received consolidation followed by maintenance and 130 received some form of maintenance only. At the time of analysis, 201 patients are still alive and 161 have already progressed. A trend towards better median overall survival (OS) was observed for those patients receiving post-autoSCT therapy (95.9 vs 69.7 months, p=0.2) (Fig 1a). Furthermore, patients receiving consolidation followed by maintenance and maintenance only had a median PFS of 45 and 36.9 months, compared to 24.1 months for those with no post-autoSCT therapy (p=0.0001) (Fig 1b). In addition, high-risk cytogenetic (HRC) patients defined by FISH (t(4;14), t(14;16) and p53 del) had a better OS in the post-autoSCT therapy group (56 vs 26 months, p=0.04). Median PFS was also longer in the post-autoSCT therapy group for the HRC group (22.5 vs 9.1 months, p=0.001). In conclusion, post-autoSCT therapy is an important approach that has improved clinical outcomes for MM patients undergoing single autoSCT. Patients with HRC MM seemed to have better outcomes as a result of this strategy. However, survival still remains poor compared to standard risk myeloma patients. The effect of consolidation is currently controversial and requires further assessment with long-term follow-up and subset analysis to better estimate patients that might benefit from it. [Display omitted] DisclosuresJimenez-Zepeda:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Neri:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Bahlis:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.