Relapsed And/or Refractory Multiple Myeloma Patients Research Articles

Cardiovascular Toxicity after Carfilzomib, Lenalidomide, and Dexamethasone Combination Chemotherapy in the Real-World 364 Asian Multiple Myeloma Patients on Behalf of the Korean Multiple Myeloma Working Party (KMM2201 study)

Background: Carfilzomib, a selective and irreversible epoxyketone proteasome inhibitor (PI), in combination with lenalidomide and dexamethasone (KRd) significantly improved the survival of relapsed and/or refractory multiple myeloma (RRMM) patients as well as newly diagnosed MM patients. The major dose-limiting toxicity of carfilzomib, cardiovascular adverse events (CVAE), have been reported in a variety of studies, which necessitates cautious risk management for patients who are treated with carfilzomib-based combination regimen. By far, the incidence and risk factors, as well as the outcome of CVAE in a large cohort of Asian patients after KRd regimen is lacking. Patient and method: Retrospective data of 364 RRMM patients who have received KRd regimen for RRMM in 21 centers participating in the Korean multiple myeloma working party (KMMWP) between February, 2018 and October, 2020, was analyzed. 41% of the patient was trial-ineligible, which was defined by patient-, disease-, and treatment-related features that were insufficient to meet the eligibility criteria for ASPIRE trial. CVAE was defined by dyspnea, hypertension (HTN), congestive heart failure (CHF), ischemic heart disease (IHD), arrhythmias, and venous thromboembolism (VTE). Time to onset of CVAE was defined by the first date of KRd therapy to the onset date of first CVAE. Results: The median age was 63 years (range, 28-85). CVAEs were observed in 16% of total analyzed patients after a median 9 months (range, 0-36 months) of KRd treatment, among which 3 patients (1%) showed fatal CVAEs. More specifically, dyspnea, HTN, CHF, IHD, arrhythmias, and VTE occurred in 11%, 3%, 3%, 1%, 2%, and 3% of the patients after a median of 9, 21, 16, 31, 8, and 16 months after KRd therapy. CVAE resulted in dose reduction and discontinuation of carfilzomib in 13 (4%) and 14 patients (4%), respectively. 5 patients (1%) discontinued KRd treatment due to any CVAE. By univariate analysis, among the factors affecting the cardiovascular events, such as age ≥75 years, ECOG performance status ≥ 3, creatinine clearance < 30 ml/min, Hb < 8g/dL, diabetes mellitus, HTN, underlying heart disease, cerebrovascular disease, prior bortezomib, thalidomide, doxorubicin, and cyclophosphamide therapy, and autologous stem cell transplantation, HTN was the only factor that significantly affected the occurrence of CVAEs after KRd therapy (odds ratio 1.877, 95% confidence interval, 1.025-3.440, P=0.041). CVAEs after KRd regimen did not affect progression-free or overall survival in the study cohort (Figure1A, and 1B). Conclusion: The incidence of CVAE after KRd therapy in this large cohort of real-world Asian RRMM patients was comparable with previous prospective and retrospective studies. Cardiovascular event after carfilzomib-based regimen did not affect progression-free or overall survival in RRMM patients. The recognition and management of underlying HTN has the utmost importance amongst the CV risk factors to mitigate CVAE in the Asian RRMM patients treated with KRd regimen. Acknowledgement This study would not have been possible without the collaboration of the Korean multiple myeloma working party. We especially thank the patients, families, caregivers who participated in this study. This work was supported by Amgen.

Updated Results from a Matching-Adjusted Indirect Comparison of Efficacy Outcomes of Isatuximab Plus Carfilzomib and Dexamethasone Versus Daratumumab Plus Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: Findings from a previously conducted matching-adjusted indirect comparison (MAIC) between isatuximab plus carfilzomib with dexamethasone (IsaKd) and daratumumab plus lenalidomide and dexamethasone (DRd) among relapsed and/or refractory multiple myeloma (RRMM) patients receiving one to three prior lines of therapy (LoT) demonstrated a significantly better progression-free survival (PFS) and a positive trend for overall survival (OS) in favor of IsaKd compared with DRd (median follow up of 20.7 months for IKEMA trial). Additionally, IsaKd demonstrated an acceptable safety profile with significantly lower rates of several treatment-emergent adverse events than DRd [Richter J et al, Cancer Med 2023;12(7):8005-8017; Richter J et al.(Publication Number 1962), 63 rd ASH Annual Meeting and Exposition, 2021; Richter J, et al. P-213, Clin Lymphoma Myeloma Leuk. 2021;21(Suppl 2):S156-S157]. The present study used longer follow-up data from the phase 3 IKEMA trial (NCT03275285) to update the previous MAIC evaluating the comparative efficacy of IsaKd versus DRd. Methods: A MAIC was performed with the latest available individual patient-level data (IPD) from the IKEMA trial (IsaKd arm, n = 179) (data cutoff: February 2023 for OS and January 2022 for PFS), and aggregate data from study publications of phase 3 POLLUX trial (DRd arm, n = 286, NCT02076009) [Bahlis NJ et al. Leukemia 2020;34(7):1875-1884; Dimopoulos MA et al. Hemasphere 2022;6:13]. Patients were selected from the IsaKd arm of the IKEMA trial to match the inclusion and exclusion criteria of the POLLUX trial. Individual patients from the IKEMA trial were then assigned weights such that (1) weighted mean baseline characteristics for patients in the IsaKd arm matched those reported for patients in the DRd arm, and (2) each patient's weight was equal to their estimated odds (propensity) of being in the POLLUX trial versus the IKEMA trial. After matching, outcomes were compared across the two trial populations. For PFS and OS, hazard ratio (HR) and 95% confidence interval (CI) were reported from a Cox proportional hazards (PH) model using the weighted sample for IsaKd and the pseudo-IPD for DRd extracted from published Kaplan-Meier curves via digitization software [Mark M et al, Engauge Digitizer Software; http://markummitchell.github.io/engauge-digitizer]. For any violations of the PH assumption, the restricted mean survival time (RMST) at median follow-up of IKEMA for the outcome of interest was calculated instead. Results: After the MAIC adjustment, all available baseline characteristics were well balanced across the trial populations. For PFS, as the PH assumption was violated ( χ2 = 5.52, p = 0.019), RMST method was used to compare the two treatments. PFS was significantly better with IsaKd versus DRd (mean difference [95% CI]: 3.63 months [0.14-7.12]; p = 0.04) at 44 months follow-up using RMST method. For OS, the PH assumption ( χ2 = 0.89, p =0.35) was not violated. A numeric, statistically non-significant trend in favor of IsaKd versus DRd was observed for OS (Figure 1). Conclusions: This MAIC analysis demonstrated a significant benefit in PFS and a positive trend in the improvement of OS with IsaKd compared with that with DRd. These findings with a longer follow-up were consistent with the previous analyses conducted with a follow-up of 2 years. These data highlight the therapeutic potential of IsaKd, a lenalidomide-free regimen, in RRMM patients receiving one to three prior LoT compared with a lenalidomide-based regimen.

BCMA-targeting chimeric antigen receptor T cell therapy for relapsed and/or refractory multiple myeloma.

Recently, many new therapies have improved the outcomes of patients with relapsed and/or refractory multiple myeloma (RRMM). Nevertheless, recurrence is still unavoidable, and better treatment choices for RRMM are urgently needed. The clinical success of Chimera antigen receptor (CAR) T cell therapy in many hematological diseases, including leukemia and lymphoma, has drawn considerable attention to RRMM. As CAR T cell therapy continues to mature and challenge traditional therapies, it is gradually changing the treatment paradigm for MM patients. The B cell maturation antigen (BCMA), expressed in malignant plasma cells but not normal ones, is an ideal target for MM treatment, due to its high expression. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) has approved two BCMA-targeting CAR T cell products, idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel), for use in RRMM. In this review, we focus on data from RRMM patients involved in clinical trials of Ide-cel and Cilta-cel and discuss the present situation and future direction of CAR T cell therapy for this condition.

Real-world treatment outcomes of carfilzomib plus dexamethasone in patients with relapsed and/or refractory multiple myeloma, focusing on the impact of trial-fitness: CAtholic REsearch network for Multiple Myeloma study (CAREMM-2203).

Carfilzomib plus dexamethasone (Kd) is widely used in patients with relapsed and/or refractory multiple myeloma (RRMM). However, the treatment outcomes of Kd, especially in trial-unfit patients, have not been extensively studied in the real-world setting. We analyzed the outcomes of 152 RRMM patients who received Kd at our hospitals from April 2018 to March 2022. At the commencement of Kd, patients received a median of two (range 1-7) lines of prior anti-myeloma therapy. According to the ENDEAVOR study criteria, 93 (61.2%) and 59 (38.8%) patients were classified as the trial-fit and the trial-unfit group, respectively. The overall response (OR) rate for the entire cohort was 71.1% (95% CI 63.2-78.1%). Progression-free survival (PFS) and overall survival (OS) were 5.6months (95% CI 3.9-6.9months) and 24.0months (95% CI 13.4-38.0months), respectively. There was no significant difference in the OR rate between the trial-fit and the trial-unfit groups (76.3% vs. 62.7%; P = 0.105). However, the median PFS (3.6months vs. 7.3months; P < 0.001) and OS (15.0 vs. 36.8months; P = 0.009) were significantly shorter in the trial-unfit group. On multivariate analysis, trial-fitness (unfit vs. fit) remained a significant covariate influencing the TRM (HR: 4.84, 95% CI 1.66-14.06; P = 0.004) and PFS (HR: 1.82, 95% CI 1.27-2.62; P = 0.001). Our data suggest that the treatment outcomes of Kd are acceptable in the real-world setting with significant differences between the trial-fit and the trial-unfit groups, although they are relatively inferior to those of a pivotal trial.

Real-world toxicity and effectiveness of ixazomib, lenalidomide, and dexamethasone in Korean patients with relapsed and/or refractory multiple myeloma.

Ixazomib, lenalidomide, and dexamethasone (IRd) have proven efficacy and an excellent safety profile in relapsed and/or refractory multiple myeloma (RRMM). However, there are limited reports on the real-world safety and effectiveness of IRd regimens in Asian patients with RRMM. This was a retrospective study of 60 patients with RRMM who were treated with IRd. The median patient age was 68years. Forty percent of patients did not meet the eligibility criteria for the TOURMALINE-MM1 trial. Patients received a median of one prior line of therapy. Non-hematologic adverse events (AEs) were more common than hematologic AEs. The most common AE was skin rash, followed by gastrointestinal toxicities. Most grade 3 or higher AEs were observed in less than 5% of the patients, except for skin rashes and infections. IRd therapy did not aggravate peripheral neuropathy (PN) in 20 of the 24 patients with pre-existing peripheral neuropathy. The overall response rate was 85%. After a median follow-up of 26.3months, the median progression-free survival was 25.9months and overall survival was not reached. Ixazomib and Rd combination therapy had a comparable toxicity profile and effectiveness in real-world RRMM patients.

MM-086 Real-World Experience With Isatuximab (Isa) in Patients With Relapsed and/or Refractory Multiple Myeloma: IONA-MM First Interim Analysis

Based on Phase 3 ICARIA-MM and IKEMA studies, Isatuximab+pomalidomide+dexamethasone (Isa-Pd) or Isa+carfilzomib+dexamethasone (Isa-Kd), respectively, are approved for patients with relapsed and/or refractory multiple myeloma (RRMM). Limited real-world evidence (RWE) exists for patients treated with Isa-Pd/Isa-Kd. Describe baseline characteristics, treatment exposure, and treatment-emergent adverse events (TEAEs) for Isa-treated RRMM patients in a real-world setting. First interim analysis of non-interventional IONA-MM study (NCT04458831). RRMM patients ≥18 years who received ≥1 prior treatment line were enrolled prospectively/retrospectively (Isa-exposed ≤3 months pre-enrollment). Treating physicians determined Isa treatment before and independent of enrollment; treatment duration was based on local prescribing regulations. Adverse events (AEs) and laboratory abnormalities were graded according to CTCAE v5.0. Between 13-Aug-2020 and 22-Feb-2022, 112 patients (38 sites, 6 countries) received ≥1 dose of Isa-Pd (n=81), Isa-Kd (n=26), or other Isa regimens (n=5). Compared with baseline characteristics in Phase 3 Isa studies, a higher proportion of Isa-Pd/Isa-Kd patients in IONA-MM were ≥75 years old and ISS stage III, a lower proportion of Isa-Kd patients had high-risk cytogenetics, and 31.5% of Isa-Pd and 23.1% of Isa-Kd patients received ≥4 prior lines of therapy. Data on prior treatments and study drugs' relative dose intensities will be shared at the Congress. At data cutoff, median (min-max) duration of Isa exposure was 5.4 (0-18.8) and 6.2 (0-10.6) months, with 79.0% and 74.1% of patients still receiving Isa-Pd and Isa-Kd, respectively. For Isa-Pd and Isa-Kd, all-grade TEAEs occurred in 52 (64.2%) and 16 (61.5%); Grade 3-4 TEAEs in 36 (44.4%) and 10 (38.5%); serious TEAEs in 21 (25.9%) and 8 (30.8%); fatal TEAEs during study treatment in 4 (4.9%; sepsis [2], septic shock [1], failure to thrive [1]) and 1 (3.8%; pneumonia); and TEAEs leading to Isa discontinuation in 6 (7.4%) and 3 (11.5%) patients, respectively. Response data are forthcoming. In IONA-MM first interim analysis, we report comparable baseline characteristics to those seen in ICARIA-MM/IKEMA with few imbalances. Isa-Pd/ Isa-Kd have manageable safety profiles in routine clinical practice. These data provide RWE to support Isa use in RRMM outside clinical trials and in wider populations. Enrollment in IONA-MM is ongoing until sample size n=1,100 is reached.

Patient perspectives on symptoms, health-related quality of life, and treatment experience associated with relapsed/refractory multiple myeloma

PurposeThis study aimed to better understand the patient perspective and treatment experience of relapsed and/or refractory multiple myeloma (RRMM).MethodsThis qualitative study enrolled adult RRMM patients from 6 US clinics who had ≥ 3 months of life expectancy, ≤ 6 prior lines of therapy, and ≥ 1 treatment regimen with a proteasome inhibitor and immunomodulator, or a CD38 monoclonal antibody or an alkylating agent, and a steroid. In-person semi-structured qualitative interviews were conducted to capture concepts that were relevant and important to patients. Topics included RRMM symptoms and impacts and the mode of administration, frequency, duration, convenience, side effects, and overall experience with RRMM treatment.ResultsA total of 22 patients completed interviews. At enrollment, 59.1% of participants were using regimens containing dexamethasone, 36.4% daratumumab, 27.3% carfilzomib, and 18.2% lenalidomide. More participants had experience using intravenous or injectable therapy alone (40.9%) than oral therapy alone (18.2%). Back pain and fatigue were the most frequently reported symptoms (40.9% each); 27.3% reported no symptoms. Most participants reported physical function limitations (86.4%), emotional impacts (77.3%), MM-related activity limitations (72.7%), and sleep disturbances (63.6%). Most participants perceived treatment effectiveness based on physician-explained clinical signs (68.2%) and symptom relief (40.9%). Participants experienced gastrointestinal adverse events (59.1%), fatigue (59.1%), sleep disturbances (31.8%), and allergic reactions (31.8%) with treatment. Key elements of treatment burden included the duration of a typical treatment day (68.2%), treatment interfering with daily activities (54.5%), and infusion duration (50.0%).ConclusionsThese results provide treatment experience–related data to further understand RRMM treatment burden and better inform treatment decision-making.

Pomalidomide in Patients With Relapsed and/or Refractory Multiple Myeloma: A Prospective Study Within the Nationwide Netherlands Cancer Registry.

Patients with relapsed and/or refractory multiple myeloma (RRMM) generally have limited treatment options and a poor prognosis. Previous trials demonstrated that pomalidomide combined with low-dose dexamethasone (Pd) is effective in these patients with significant responses and improved progression-free survival (PFS). Pd has been approved in RRMM patients who received ≥2 prior lines of therapy. Here, we present the results of a population-based study of patients with RRMM treated with Pd in The Netherlands from time of pomalidomide approval. Using the nationwide Netherlands Cancer Registry, data from all nontrial patients with RRMM treated with Pd were collected. Data were analyzed of response, PFS, and overall survival (OS). A total of 237 patients were included in this analysis. Previous treatment consisted of a proteasome inhibitor in 227 patients (96%) and/or an immune-modulating agent in 235 patients (99%). One hundred forty patients (59%) were refractory to an immune-modulating agent in their last line of therapy. Median time from diagnosis to treatment with Pd was 4.9 years (interquartile range, 2.7–7.9), and the median number of prior treatments was 4 (interquartile range, 3–5). Median PFS and OS for all patients were 3.6 months (95% confidence interval [CI], 3.1–3.8) and 7.7 months (95% CI, 5.7–9.7), respectively. For patients achieving ≥PR, median PFS and OS were 10.6 months (95% CI, 8.3–12.9) and 16.3 months (95% CI, 13.6–23.2), respectively. This nationwide, population-based registry study confirms data shown in pivotal clinical trials on Pd. PFS in this analysis is comparable to PFS observed in those clinical trials.

Clinical and Sociodemographic Characteristics of Patients With Relapsed and/or Refractory Multiple Myeloma and Their influence on Treatment in the Real-World Setting in Spain: The CharisMMa Study

IntroductionTreatment of relapsed and/or refractory multiple myeloma (RRMM) should be established based on multiple factors, including previous treatment and the sociodemographic/clinical characteristics of the patients. However, patients enrolled in randomized-controlled trials often do not mirror the scenario encountered in real-world practice, thus challenging therapeutic decisions in day-to-day practice. Patients and methodsThis observational, cross-sectional, multicenter study aimed to investigate the sociodemographic and clinical characteristics of patients with RRMM treated in routine practice in Spain and their influence on treatment regimens. ResultsThe study included 276 RRMM patients (median age 69 years; no gender predominance). Seventy-four percent of patients had CRAB features at the time of study inclusion, 65.9% bone lesions, 28.7% high-risk cytogenetics, and 27.0% were at ISS stage III; 65.1% were retired and lived in urban areas (75.7%) with their relatives (85.8%); 28.7% had some dependence degree. Patients had experienced their last relapse in a median of 1.61 months before enrollment and had received a median of 2 treatment lines (range 1-10). Second-and third-line therapies were mostly based on immunomodulatory drugs, followed by proteasome inhibitors (PIs), whereas monoclonal antibodies prevailed in later treatment lines. The presence of extramedullary plasmacytomas, the absence of osteopenia, and being in the second or third treatment line (vs. later lines) significantly increased the odds of receiving PIs. ConclusionsRRMM treatment in the real-world setting is highly heterogeneous and is primarily influenced by the number of previous lines. The consideration of patients’ clinical and sociodemographic characteristics may support clinicians in making therapeutic decisions.

Carfilzomib, Lenalidomide, and Dexamethasone Followed by Salvage Autologous Stem Cell Transplant with or without Maintenance for Relapsed or Refractory Multiple Myeloma.

Simple SummaryHigh-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a standard treatment in patients with newly diagnosed multiple myeloma (MM). At relapse, salvage HDCT/ASCT is a treatment option in patients with sufficient benefit from frontline HDCT/ASCT, but no evidence is currently available regarding its role in the era of triplet regimens combining the most active drug classes for relapsed MM. To evaluate the outcome after salvage HDCT/ASCT following re-induction treatment with carfilzomib/lenalidomide/dexamethasone (KRD) and to identify prognostic factors, we conducted a retrospective analysis of patients that had previously undergone frontline HDCT/ASCT. We found that deep remissions achieved with KRd followed by salvage autologous transplantation were associated with favorable PFS and were enhanced by maintenance treatment. Salvage autologous transplantation after state-of-the-art triplet re-induction was a safe and effective strategy for RRMM patients that may offer the chance to avoid refractoriness to multiple novel agents at the next relapse.Salvage high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) is a treatment option for relapsed and/or refractory multiple myeloma (RRMM). No data are available on salvage HDCT/ASCT following re-induction treatment with state-of-the-art triplet regimens. We retrospectively report on 44 patients receiving salvage HDCT/ASCT following re-induction with carfilzomib/lenalidomide/dexamethasone (KRd). All patients received frontline HDCT/ASCT with median time to progression (TTP1) of 2.9 (1.2–13.5) years, enabling paired comparison of frontline and salvage HDCT/ASCT. After re-induction and before salvage transplant, 25/44 patients (57%) attained ≥ very good partial response (VGPR), which increased to 34/44 (77%) at best response after salvage HDCT/ASCT. Median progression-free survival (PFS) was 23.3 months from salvage HDCT/ASCT. Patients with ≥ VGPR at the time of salvage HDCT/ASCT and those receiving maintenance treatment post salvage HDCT/ASCT had significantly superior PFS (hazard ratio (HR) 0.19, p = 0.001 and HR 0.20, p = 0.009). In patients achieving at least an equal depth of response before salvage HDCT/ASCT as before frontline HDCT/ASCT, PFS after salvage HDCT/ASCT was comparable to the frontline situation (p = 0.3). This is the first report of state-of-the-art triplet re-induction and salvage HDCT/ASCT for RRMM after frontline transplantation. Deep remissions achieved with KRd translate into prolonged PFS following salvage HDCT/ASCT and are enhanced by maintenance treatment.

Daratumumab in Combination with Pomalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma (RRMM) Patients with ≥2 Prior Lines of Therapy: Updated Analysis of MMY1001

Daratumumab in Combination with Pomalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma (RRMM) Patients with ≥2 Prior Lines of Therapy: Updated Analysis of MMY1001

Role of Aneuploidy in Transcriptional Regulation and Clinical Prognosis in Relapsed and/or Refractory Multiple Myeloma (RRMM)

BACKGROUND Aneuploidy, defined by abnormal copy number changes of chromosomes, contributes to genome instability in multiple myeloma and has potential prognostic impact. Previous research has explored transcriptional pathways affected by aneuploidy. We aim to evaluate aneuploidy, clinical prognosis, and gene expression in RRMM patients (pts) who participated in MMRF (Multiple Myeloma Research Foundation) sequencing study at University of Michigan. We further used gene set analysis to identify enrichment and variation of genetic pathways associated with aneuploidy and overall survival (OS). This was a pilot study in view of applying similar methods to larger populations. METHODS DNA and RNA materials were obtained from 51 RRMM pts at the time of disease relapse. Targeted sequencing was performed with the Onco1700 panel and RNA sequencing was performed with a capture protocol using Agilent SureSelect All Exon V4, followed by paired end sequencing. Copy number variation (CNV) was estimated using an in-house pipeline using matched normal samples. Arm-level aneuploidy was defined as copy number status (gain, loss or neutral) with maximal proportion for each chromosomal arm. Aneuploidy score was determined by total number of arm-level CNV aberrations, with the median score defining high and low aneuploidy groups. Survival analysis was performed using Kaplan-Meier (KM) and Cox regression. RNA-seq libraries were aligned with STAR aligner to the hg38 reference and read quantification were performed with featureCounts. We used gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) to obtain genetic pathway-level summaries for 50 hallmark pathways representative of cancer from the GSEA Molecular Signatures Database (https://www.gsea-msigdb.org/). Supervised GSEA was performed, based on differential analyses comparing gene expression profiles between high versus low aneuploidy groups to identify the differences in genetic pathways in RRMM pts. Unsupervised GSVA was applied to RNAseq count data of RRMM and newly-diagnosed multiple myeloma (NDMM) pts from the MMRF CoMMpass study (797 pts). Univariate Cox proportional hazard model was used to identify pathways having significant association with OS. RESULTS Arm scale aneuploidy analysis revealed high frequency of gains and losses in multiple chromosomes (Figure 1). RRMM pts with high aneuploidy scores had worse OS (median 15.9 months since study enrollment) compared to those with low scores (median not reached, p=0.027). Multivariate analysis demonstrated that high aneuploidy score is persistently associated with poor OS (hazard ratio (HR): 3.9, p=0.006), adjusting for t(4;14) and t(11;14). Hyperdiploidy (any whole chromosome carrying &amp;gt;2 copies) was identified in chromosomes 3, 5, 7, 9, 11, 19, 21, with frequency &amp;gt;20%. Pts with hyperdiploidy had better OS via KM (p=0.04). Using RNAseq gene expression data and GSEA analysis, we found enrichment of gene markers involving the pathways for targets of E2F transcription factors (Normalized Enrichment Score (NES) = 2.07), G2-M checkpoint in the cell division cycle (NES = 1.87), MYC proto-oncogene (NES = 1.93 and 1.85), and DNA repair (NES = 1.68) in RRMM pts with high aneuploidy compared against those with low scores (Benjamini-Hochberg adjusted p-value &amp;lt;0.001 for all pathways, Figure 2). GSVA analysis revealed 21 genetic pathways associated with survival in NDMM and RRMM pts, with 8, 2, and 11 pathways associated with OS in NDMM only, RRMM only, and both, respectively (Figure 3). Enrichment of several biological pathways involved with cellular growth, cell cycle regulation, and stress response (E2F, G2-M, MYC, DNA repair, mTORC1 signaling, UV radiation, mitotic spindle assembly, unfolded protein response, and peroxisome) are associated with poor survival (HR&amp;gt;1) in both NDMM and RRMM pts. Downregulation of KRAS signaling pathway is associated with better survival (HR&amp;lt;1) in both groups. CONCLUSION Aneuploidy, adjusted for chromosomal translocations, is an independent adverse prognostic factor for RRMM. Aneuploidy is correlated with dysregulation of major biological pathways involving cell cycle regulation, cellular division, oncogenes, and DNA damage repair. The majority of common pathways shared between RRMM and NDMM are linked to or reflective of genomic instability, and may explain association with poor survival. Disclosures Talpaz: IMAGO: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Ye:Janssen: Research Funding; Portola: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Nektar: Research Funding; AbbVie: Research Funding.

Patient Perspectives on Treatment Experience and Health-Related Quality of Life in Patients with Relapsed/Refractory Multiple Myeloma

Background Multiple myeloma (MM) is a plasma cell malignancy characterized by the production of monoclonal light chains and immunoglobulin (M-protein), leading to impaired immune function, bone destruction, renal failure, and death. Existing and emerging MM therapies, including proteasome inhibitors (PI), immunomodulators (IMiDs), and monoclonal antibodies (mAB), delay progression and extend the lifespan but MM is incurable. However, more knowledge about patient experiences with treatments and their impact on everyday activities, including health-related quality of life (HRQOL) is needed for physicians and patients to make informed treatment decisions. This study aimed to gain a better understanding of the patient perspectives on treatment for relapsed and/or refractory multiple myeloma (RRMM). Methods This non-interventional, cross-sectional study involved semi-structured qualitative interviews with RRMM patients recruited from 6 U.S. clinics. Eligible RRMM patients (≥18 years) had at least 3 months of life expectancy, up to 6 prior lines of therapy, and at least one treatment regimen with a PI, IMiD, daratumumab, or an alkylating agent. Prior to conducting the patient interviews, a semi-structured qualitative interview guide was developed based on a literature review and formative/pilot discussions with MM expert clinicians (n=5) and patients (n=3). Within the interview guide, open-ended questions and targeted probes were used to facilitate discussions on topics including symptoms and impact of MM, mode of administration of treatment, tolerability, patients' perception of indicators of effectiveness and overall experience. Qualitative coding and content analysis were conducted using Atlas.ti v8.0. Results Demographic characteristics, symptoms, and HRQOL impacts reported by interview participants (N=22) are presented in Table. At enrollment, 59% of patients were using regimens containing dexamethasone, 36% daratumumab, 27% carfilzomib, 18% lenalidomide. Most common co-morbidities included hypertension (41%), respiratory illnesses (32%), and GERD (27%). More patients had experience using IV/injectable (41%) alone compared with oral therapy (18%) alone; 41% of patients reported having experience with both modes. Back pain (41%) and fatigue (41%) were the symptoms reported most frequently by patients; 27% of patients reported no symptoms (See Table). Among impact concept categories most commonly reported by patients, 86% experienced physical function limitations (e.g. difficulty walking or standing), 77% reported emotional impacts (e.g. worry/fear or sadness/depression), 73% reported activity limitations related to MM, and 64% reported sleep disturbances (see Table). Regarding treatment experiences, most patients (68%) perceived effectiveness of their treatment based on laboratory test results explained by their physician, while 41% based treatment effectiveness on symptom relief. When asked about treatment tolerability, most patients described experiencing gastrointestinal side effects (59%), fatigue (59%), sleep disturbances (32%) and allergic reactions (32%). Regarding mode of treatment administration and regimens, participants most commonly reported the overall length of each treatment day (68%), treatment interfering with daily activities (55%), and length of infusion (50%) as key elements of treatment burden. Conclusions This study provides key insights into the impact on HRQOL from symptoms and treatment burden as well as patient perspectives on treatment effectiveness, tolerability, and modes of administration. Considering the evolution and complexity of MM management, and increasing regulatory emphasis on patient-centeredness, patient-relevant factors should be incorporated into future evaluation of MM treatments and patient outcomes. Disclosures Bell: Millennium Pharmaceuticals, Inc.: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Ginchereau Sowell:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Shah:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. McCarrier:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding. Hari:Amgen: Consultancy; BMS: Consultancy; GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy.

Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy, in Patients with Relapsed and Refractory Multiple Myeloma: Updated Results from Phase 1 CRB-401 Study

Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy, in Patients with Relapsed and Refractory Multiple Myeloma: Updated Results from Phase 1 CRB-401 Study

Real-world outcomes and factors impacting treatment choice in relapsed and/or refractory multiple myeloma (RRMM): a comparison of VRd, KRd, and IRd

ABSTRACTLack of head-to-head trials highlights a need for comparative real-world evidence of proteasome inhibitors plus Rd.Methods: In this retrospective, US population-representative EHR study of RRMM patients initiating IRd, KRd, or VRd in line of therapy (LOT) ≥2 between 1/2014 and 9/30/2018, 664 patients were treated in LOT ≥2 with: IRd, n = 168; KRd, n = 208; VRd, n = 357. Median age was 71/65/71 years; 67%/70%/75% had a frailtymodified score of intermediate/frail; 20%/28%/13% had high cytogenetic risk in I-/K-/V-Rd groups. Risk of PI-triplet discontinuation was lower for I- vs. K-Rd (HR: 0.71) and I- vs. V-Rd (HR: 0.85); unadjusted, median TTNTs (months): 12.7/8.6/14.2 (LOT ≥2) and 16.8/9.5/14.6 (LOT 2–3) (I-/K-/V-Rd). Adjusted TTNT was comparable between I-/K-/V-Rd in LOT ≥2 with a TTNT benefit among intermediate/frail patients for I- (HR: 0.70; P=0.04) and V- (HR: 0.73; P<0.05) vs. K-Rd. I/K/V-Rd triplets were comparable in TTNT overall, but IRd and VRd were associated with longer TTNT in intermediate/frail patients than KRd. The results suggest a trial-efficacy/real-world-effectiveness gap, especially for KRd, underlining the limited generalizability of trial results where >50% of patients are excluded. Individualized treatment based on patient characteristics, such as frailty status, is especially pertinent in an elderly RRMM population.

How are patient-reported outcomes and symptoms being measured in adults with relapsed/refractory multiple myeloma? A systematic review.

Patients with relapsed and/or refractory multiple myeloma (RRMM) are living longer due in part to changing treatment patterns. It is important to understand how changing treatment patterns affect patients' lives beyond extending survival. Research suggests that direct patient report is the best way to capture information on how patients feel and function in response to their disease and its treatment. Therefore, the purpose of this review is to summarize evidence of patients' experience collected through patient-reported outcomes (PRO) in RRMM patients, and to explore PRO reporting quality. We conducted a systematic search to identify manuscripts reporting PROs in RRMM and summarized available evidence. We assessed PRO reporting quality using the Consolidated Standards of Reporting Trials (CONSORT) PRO Extension checklist. Our search resulted in 30 manuscripts. Thirteen unique PRO measures were used to assess 18 distinct PRO domains. Pain, fatigue, and emotional function were commonly assessed domains though reporting formats limited our ability to understand prevalence and severity of PRO challenges in RRMM. Evaluation of PRO reporting quality revealed significant reporting deficiencies. Several reporting criteria were included in less than 25% of manuscripts. Existing evidence provides a limited window for understanding the patient experience of RRMM and is further limited by suboptimal reporting quality. Observational studies are needed to describe prevalence, severity and patterns of PROs in RRMM overtime. Future studies that incorporate PROs would benefit from following existing guidelines to ensure that study evidence and conclusions can be fully assessed by readers, clinicians and policy makers.

Phase I Trial of Ibrutinib, Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Phase I Trial of Ibrutinib, Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Aneuploidy Is Associated with Inferior Survival in Relapsed Refractory Multiple Myeloma Patients

Objective To identify the association between aneuploidy and clinical outcome in patients with relapsed and/or refractory multiple myeloma (RRMM) who participated in MMRF (Multiple Myeloma Research Foundation) sequencing study at University of Michigan. Background: Aneuploidy, defined by abnormal copy number changes of chromosomes, is one of the hallmarks in cancer, reflecting and also contributing to genome instability (Ye, Regan et al. 2018). Approximately 90% of cancers have gained or lost one or both arms of at least one chromosome (Taylor, Shih et al. 2018). In recent years, large scale sequencing efforts have extended aneuploidy study, identifying DNA somatic copy number alterations (SCNAs). Published data suggest aneuploidy has a stronger impact on prognosis than gene mutations in multiple myeloma (Walker, Boyle et al. 2015; Bolli, Biancon et al. 2018; Jamal-Haniani, Wilson et al. 2017). Methods: Fifty one RRMM patients from our institute participated in Clinical-Grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies (MMRF-002) from Multiple Myeloma Research Foundation (MMRF) between March 2016 and November 2018. Genomic DNA was obtained from CD138+ sorted myeloma cells and a peripheral blood sample from each patient. Capture exome sequencing on a targeted panel of 1500 genes was performed by the Illumina HiSeq 2500 (2x115bp paired-end reads, average 520X coverage). Copy number changes, loss of heterozygosity (LOH) and tumor purity were jointly estimated using an in-house pipeline for matched tumor/normal libraries. We assessed aneuploidy using chromosomal and arm level SCNAs which are determined by the median of SCNAs and summation of gain and loss of SCNAs for a given chromosomal arm, which are then used for a time-to-event analysis of overall survival (OS) of the patients. The differences between Kaplan-Meier overall survival curves were tested using the log-rank test. Hazard ratios (HR) were estimated from Cox proportional hazard regression. A threshold of significance was taken as p&lt;0.05. Results Patient demographic data is summarized in Table 1. All the patients in this study harbor DNA somatic copy-number abnormalities (SCNAs) on the arm level for at least one chromosome (Figure 1). Gain of a chromosome or a whole arm mostly occurs on 1q, 3, 5, 7, 9, 11, 15, 19, 21 while loss was noted in 1p, 8p, 13, 16q, and 17p. At a global-level, we find that whole genomic aneuploidies (genomic-level across all chromosomes) have a significant association with inferior OS. Specifically, patients with a high frequency of genomic aneuploidies (defined as number of SCNA &gt;8, the first quartile) had a significantly worse prognosis than those with low number of SCNA events (&lt;=8) (p=0.037, Figure 2). Arm-level aneuploidies with high incidences include 11q (54.9%), 13q (52.9%), 15q (51.0%), 1q (51.0%), 9q (51.0%), a finding consistent with previous studies (Walker, Leone et al. 2010). Aneuploidies in 10p (11.8%) and 10q (7.8%) are uncommon in agreement with previous studies (Tricot G, Sawyer et al. 2017) as myeloma structural or numerical abnormalities rarely occur on chromosome 10. Using univariate analysis, we identified five arm-level aneuploidies which are significantly associated with worse OS: 10p, 10q, 11p, 18q and 20q. It is noteworthy that aneuploidies in either arm of chromosome 10 (10p and 10q) had significant negative OS prognostic effect: 10p (median survival for diploid 28.9 vs. aneuploid 4.1 mo; p&lt;0.001) and 10q (28.9 vs 3.8 mo; p=0.015). Similar results with a negative impact on OS were found from 11p (not reached vs 13.8 mo; p=0.036); 18q (28.9 vs 8.5 mo; p=0.025); and 20q (28.9 vs 3.1 mo; p=0.009). Given the small sample size we did not conduct a multivariable analyses and multiplicity adjustment in this preliminary analyses. Conclusion Aneuploidy measured by SCNAs is correlated with unfavorable survival in relapsed/refractory myeloma. The higher the occurrence of aneuploidies, the worse the overall survival, illustrating of the impact of cancer genome instability. Disclosures Ye: Janssen: Research Funding; Karyopharm: Research Funding; Portola: Research Funding; MingSight: Research Funding; Sanofi: Research Funding. Talpaz:Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy.

Sequential CD19- and Bcma-Specific Chimeric Antigen Receptor T Cell Treatment for RRMM: Report from a Single Center Study

Background: Relapsed and/or refractory multiple myeloma (RRMM) has a very poor prognosis, especially for chinese patients with limited therapeutic options. Chimeric antigen receptor transduced T cells (CARTs) had been approved to be one of the rescue strategies for malignant B cell hematological tumors. CARTs targeting B-Cell Maturation Antigen (BCMA) were effective against RRMM in recent published clinical studies. CD19 is expressed by B cells before terminal differentiation into plasma cells and is associated with the enhancement of tumor-propagating and drug-resistance properties of myeloma. Thus, CD19 is also a potential therapeutic target. To our knowledge, we firstly designed the clinical study to evaluate the safety and efficacy of sequential infusion of CD19 and BCMA-Specific CARTs for RRMM patients (pts) (NCT 03196414). Our initial results showed this stragety had substantial anti-myeloma activity and well tolerated toxicities, which had been released at the 59th ASH meeting. Here, we will report the latest clinical data of a total of 28 RRMM patients receiving combined autologous CARTs infusion. Methods: Human T cells were collected from autologous peripheral blood mononuclear cells (PBSC). CART production was performed by the Unicar-Therapy Bio-medicine Technology Company (Shanghai, China). In this trial, RRMM pts firstly receive FC regimen as lymphodepleting conditioning , then were infused into CART-19 (1×107/kg on day 0) and CART-BCMA (total dose range: 2-6.8×107/kg) cells as split-dose infusions (40% on day 1 and 60% on day 2). After one month from CARTs infusion, some pts were adminstrated IMiDs for maintence therapy after hematopoietic recovery, including oral thalidomide 50mg/d or lenalidomide 10mg/d. This trial design and observation was seen in Blood,2017,130(Suppl.):506.The median follow-up time was 16 (3-28) months. Results: By January 2019, 28 pts were enrolled in this clinical trial. Among them, 23 (82.1%) pts were males and 5 (17.9%) pts were females. The median age was 57.5 (range: 42-69) years old. All pts were resistant to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), or both. These pts had received an average of 3 (2-8) lines of therapy prior to enrollment. The most common adverse event of CART therapy was acute cytokine release syndrome (CRS), which occurred in 28 pts (100%). 19 pts (67.9%) were evaluated grade 1-2 CRS. 7 pts (25.0%) were evaluated grade 3 CRS, and 2 pts (7.1%) were grade 4. High-grade CRS was associated with elevated levels of IL-6, IFNγ, IL-10 and CRP, especially IL-6 upgradation to thousands of times the baseline. Other toxicities within two weeks of CARTs infusion included fatigue (n=28; 100%), cytopenia (n=28; 100%), anemia (n=28; 100%), prolonged APTT (n=23; 82.1%), elevated creatinine (n=13; 46.4%), gastrointestinal reaction(n=9; 32.1%), elevated transaminase (n=9; 32.1%). Notably, one patient (CRS grade 4) developed grade 4 CRES who exhibited generalized seizure. But this life-threatening complication was quickly relieved after corticosteroids and sodium valproate administration. Two pts (7.1%) had HLH/MAS. No fatal or severe adverse events emerged after two weeks following the infusion. Chronic side effects included chronic diarrhea, hematocytopenia, mild infection, grade ≤2 bilirubin and/or transaminase elevation, hypogammaglobulinemia, etc. No treatment related mortality occurred in this group of pts. Among the 28 pts who completed the CARTs infusion, 27 pts were monitored at predetermined time points and one patient lost follow-up. The overall response rate was 92.6%, and 88.9% of the pts were above PR. 11 pts (40.7%) were CR or sCR, 8 pts (29.6%) were VGPR, 5 pts (18.5%) were PR and one (3.7%) was MR. The remaining 2 pts, one (3.7%) was evaluated as SD and another (3.7%) was PD. 4 pts died from myeloma progression during the follow-up. Of those pts, the median PFS was 8 months. The median OS was 16 months. Conclusions: Combined sequential administration of CART-19 and CART-BCMA cells can be manufactured from heavily-treated MM pts, and could elicit sustained remission for RRMM pts. Toxicities can be well tolerated. CARTs early expansion and persistence in vivo post infusion may be predictive of clinical outcome. How to prolong the survival time of CARTs in vivo is one of the subjects worth studying in the future. Disclosures No relevant conflicts of interest to declare.

Phase I Study of a Novel Bcl-2 Inhibitor, at-101 in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Background: The development of novel treatment strategies has extended the median survival of MM to nearly a decade but the disease remains incurable and relapse is inevitable. The Bcl-2 pathway is highly relevant to MM cell survival and can be mitigated therapeutically. AT-101 is a novel, orally available pan Bcl-2 inhibitor (Bcl-2, Bcl-xl, Mcl-1, and Bcl-w). Preclinical in vitro and in vivo studies showed that AT-101 enhanced cytotoxicity of lenalidomide-dexamethasone (Rd). We conducted a phase I study in RRMM patients to establish the effective dose of AT-101 with Ld as well as record safety and preliminary efficacy of this combination (NCT02697344). Methods: Key eligibility criteria included: RRMM with measurable disease (serum monoclonal protein ≥1.0 g/dL or urine monoclonal protein &gt;200mg/24 hour or serum immunoglobulin free light chain &gt;10mg/dL AND abnormal serum free light chain ratio). Patients must have received 1-3 prior treatment regimens and have an absolute neutrophil count ≥1.0 x 109, platelets 75 x 109, creatinine clearance ≥50 mL/min, and ECOG performance status ≤2. AT-101 dosing was designed to reach a maximum daily target of 20mg (Cohort 1; 10 mg PO QD, Cohort 2; 20 mg PO QD) utilizing a standard 3 +3 dose escalation design in combination with standard doses of Rd. Treatment was given as outpatient for a maximum of 12, 28-day cycles. For pharmacodynamic studies, AT-101 alone was given in cycle 1, with R (25 mg on days 1-21) and d (40 mg weekly) added cycle 2 onwards. Results: Enrolled patients (n=10) included 60% males with median age 68.5 years (range 55-75) and median time since MM diagnosis 4.5 years (range 0.6-8.3). MM ISS stage was II/III in 7 patients and 8/10 had high-risk cytogenetics with 4 each having del17p and 1q+. Only 1 patient had t(11;14).Patients had received median 2 prior lines of therapy (range 1-3), with 7 having had prior autologous stem cell transplant (ASCT) and the initial induction regimen being bortezomib (V), R and dexamethasone (d) (VRd) in 8, Rd in 1 and cyclophosphamide (C) with Vd (VCd) in 1 patient. At the time of study entry, 3 patients were R refractory while 2 were refractory to both, V and daratumumab (Dara). Median duration of treatment was 7.5 cycles (range 2-12) and 3 patients completed all planned 12 cycles of treatment. Among the evaluable patients, dose limiting toxicities (DLTs) at 20 mg daily dose of AT-101 with 25 mg of R and 40 mg weekly included one patient with grade 4 febrile neutropenia and grade 4 neutropenia lasting 9 days and one patient with grade 4 thrombocytopenia lasting 8 days. G3/4 adverse events (AEs) included atrial flutter (n=1), white blood cell count decrease (n=3), neutropenia (n=5), febrile neutropenia (n=1) and thrombocytopenia (n=2), and back pain (n=1) . No G3/4 non-hematological AEs were noted. Any grade non-hematologic AEs seen in at least 20% (n=2) patients included fatigue (n=9), neuropathy (n=6), nausea (n=3), diarrhea (n=5), constipation (n=3), and creatinine increased (n=2). No patients experienced tumor lysis syndrome. Overall response rate (ORR) was 44% (2 each with very good partial response, VGPR and PR) and clinical benefit rate (CBR) was 89% with 2 additional patients showing minor response (MR) and 2 experiencing stable disease (SD) (Fig 1). Patients with high-risk disease had an ORR of 43% and a CBR of 100%. Median progression-free survival (PFS) for all patients was 8.1 months. Correlative analysis from patients who showed an objective response to treatment revealed a significant increase in bone marrow Th-effector cells, NK cells and cytotoxic CD8+ T-cells along with a significant decrease in immunosuppressive T-regulatory and B-regulatory cells was noted after 1 complete cycle of the combination therapy (p&lt;0.05, Fig 2). Conclusions: This is the first reported clinical trial combining a Bcl-2 inhibitor with immunomodulatory drugs (IMiDs) in MM. AT-101-Rd is a clinically active regimen with an ORR of 40% in predominantly high-risk RRMM patients with an acceptable toxicity profile. Additional patients with MM experienced clinical benefit despite refractory status to prior therapy in this early phase clinical trial. These early findings support the further investigation of AT-101 specifically, and Bcl-2 inhibitors in general, with IMiDs in patients with MM. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Chanan-Khan:Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: AT-101 is not currently FDA-approved for treatment of any condition.