First-line Treatment Of Multiple Myeloma Research Articles

An Antibody-Drug Conjugate for Multiple Myeloma Prepared by Multi-Arm Linkers.

First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody-drug conjugate, TE-1146, comprising six lenalidomide drug molecules site-specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE-1146 is prepared using the HighDAR platform, which employs i) a maleimide-containing "multi-arm linker" to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+ -binding cysteine at the C-termini of a reconfigured daratumumab for site-specific drug bundle conjugation. It is shown that TE-1146 remains intact and effectively enters CD38-expressing tumor cells, releasing lenalidomide, leading to enhanced cell-killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE-1146 precisely delivers lenalidomide to target CD38-overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc-dependent effector functions to kill tumor cells.

Observations from Mass-Fix: Prevalence and Characteristics of Therapeutic Monoclonal Antibodies (t-mabs) Detected by Isotyping of Monoclonal Immunoglobulins via MALDI-TOF Mass Spectrometry

Abstract Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (“Mass-Fix”) has replaced serum immunofixation at our institution for detection of monoclonal immunoglobulins. One advantage of Mass-Fix is the ability to differentiate pathogenic endogenous monoclonal antibodies from therapeutic monoclonal antibodies (t-mabs), which are often the first-line treatment for multiple myeloma, by reviewing the light chain signature mass. The objective of this study was to describe the distribution of t-mabs and other key characteristics of clinical serum samples analyzed by Mass-Fix in 2022. Comprehensive results for each sample were extracted retrospectively from the laboratory information system. Of 66,710 total analyzed, 30,701 (46%) samples were reported as “positive” (i.e., contains a monoclonal protein), given the tertiary nature of our institution and reference laboratory services. The positive samples were further subdivided by t-mab (detected by Mass-Fix), with a total of 7,769 (25.3%) t-mabs reported. The top five IgG kappa t-mabs reported include daratumumab (n=6,537), elotuzumab or REGN5458/5459 (n=499), isatuximab (n=348), and rituximab (n=102). Rare observations included monoclonal proteins consistent with tixagevimab/ cilgavimab, for COVID-19 infection (n=7), obinutuzumab, an anti-CD20 t-mab for multiple sclerosis (n=1) and evolocumab, an IgG lambda anti-PCSK9 inhibitor (n=6). Of the 7,769 samples, the t-mab was the only reported clone in 47.7% of cases and was found along with the original disease-associated clone in remaining cases. When the original disease clone was present, it was an IgG kappa isotype 31% of the time and could have confounded the definition of complete therapy response for patients. 69% were non-IgG kappa original clones. Mass-Fix test orders have a multiple-choice prompt to provide any current therapy to aid in the patient’s result interpretation. For those samples where a t-mab was reported, the answer to this question regarding administered therapy was often discrepant from the report: only 38.5% of daratumumab-positive samples had an affirmation of daratumumab administration. The remaining 61.5% of daratumumab-positive samples reported an assortment of therapies, including bone marrow transplant, other t-mabs, no active therapy, or the field was left blank, highlighting poor compliance. Additionally, 154/36,009 samples where the provider affirmed daratumumab administration were reported as negative (i.e., no monoclonal protein observed on Mass-Fix). Often, the send-out laboratory does not have medical record access where treatment information is detailed. In conclusion, we reported the presence of a t-mab in 11.6% of all samples tested with Mass-Fix, suggesting that t-mabs have entered the clinical practice to stay, and accurately determining their presence in the challenging environment of poor compliance to prompt questions and evolving treatment regimens is something that cannot be ignored by clinical laboratories. Mass-Fix allows detection of a t-mab in the same routine run as other testing, without need of a second immunofixation to rule out the IgG kappa finding is not a t-mab.

Trial in Progress: A Phase 2 Study of Linvoseltamab for the Treatment of High-Risk Smoldering Multiple Myeloma (LINKER-SMM1)

Background and Significance Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder that precedes the development of multiple myeloma (MM). Traditionally, patients with SMM have undergone observation until progression to MM, but this paradigm can result in poor outcomes for some patients. Phase 3 clinical trials have demonstrated that early treatment with lenalidomide with or without dexamethasone can delay the development of end-organ damage and improve overall survival among SMM patients with high-risk features. Linvoseltamab (REGN5458) is a fully human B-cell maturation antigen (BCMA)×CD3 bispecific antibody that targets BCMA on plasma cells and CD3 on T cells, resulting in targeted T-cell-mediated cytotoxicity. In the Phase 1/2 LINKER-MM1 study, linvoseltamab alone induced deep and durable responses with a generally manageable safety profile in patients with relapsed/refractory MM (Lee et al. EHA. 2023). These data highlight the potential of novel immunotherapies with promising single-agent activity to be attractive therapeutics for early intervention to prevent progression to MM. Study Design and Methods LINKER-SMM1 is an open-label, Phase 2 study (NCT05955508) designed to evaluate the safety and efficacy of linvoseltamab monotherapy in adult participants with SMM who are at a high risk of progression to MM. High-risk criteria include having both ≥95% clonal plasma cells in the bone marrow (BM) and immunoparesis and/or ≥2 of the following: serum M-protein >2 g/dL, free light chain ratio >20, and BM plasma cells >20%. Participants must have a confirmed diagnosis of SMM within 5 years of enrollment, Eastern Cooperative Oncology Group performance status ≤1, and adequate organ function to be eligible. Participants will be excluded from enrollment if they have myeloma-defining events, uncontrolled infection, history of allogeneic stem cell transplantation, or received prior treatment for SMM. The study will take place at approximately 15 sites in Spain and will include two parts: Part 1 (safety run-in) to evaluate the preliminary safety and tolerability of linvoseltamab and Part 2 (expansion) to evaluate the clinical activity of the selected dosing regimen. In Part 1, at least 6 participants will receive linvoseltamab starting with a step-up schedule before reaching the full dose. All subsequent treatment with full-dose linvoseltamab will be given over 28-day cycles until completion of 24 cycles or occurrence of a protocol-defined reason for discontinuation. Assuming that initial safety is shown to be acceptable, an additional 34 participants will be enrolled in Part 2 according to the dosing regimen established in Part 1. Post-treatment safety monitoring will continue for up to 90 days after the last dose of linvoseltamab, and participants with an ongoing response will continue routine efficacy assessments until confirmed biochemical progression, start of non-protocol cancer therapy, or death. Long-term follow-up will continue for up to 5 years after the last dose of linvoseltamab. The primary endpoints in Part 1 are frequency of adverse events (AEs) of special interest, including grade ≥2 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and frequency and severity of treatment-emergent AEs. In Part 2, the primary endpoints are complete response (assessed by International Myeloma Working Group criteria) and minimal residual disease (MRD) negativity (10 -5 sensitivity) after 12 and 24 months of treatment. Secondary endpoints include cumulative safety, overall response rate, duration of response, sustained MRD negativity, biochemical and clinical progression-free survival (PFS), time to myeloma-defining event, time to initiation of first-line treatment for MM, and overall survival as well as immunogenicity and serum concentration of linvoseltamab over time. Exploratory endpoints include PFS after the start of first-line treatment for MM, adequacy of stem cell collection, patient-reported outcomes, and various biomarker changes. As this is a proof-of-concept study, results will be analyzed using descriptive statistics and no formal hypothesis testing is planned. Study accrual is planned to begin in Q4 2023.

Smoldering Multiple Myeloma Progressing to Active Multiple Myeloma Vs De-Novo Active Multiple Myeloma - a Comparison of Disease Characteristics, Organ Involvement and Outcomes in a Real-Life Multicenter Retrospective Cohort Study

Background Smoldering Multiple Myeloma (SMM) is an intermediate precursor phase in Multiple Myeloma (MM) evolution. SMM patients are monitored for progression to active disease, supposing such surveillance will identify myeloma-defining events (MDEs) early and consequently hasten treatment, prevent complications and improve outcomes. To what extent this approach is successful is not well established. We aimed to compare disease characteristics, end organ involvement and outcomes between SMM patients who progressed to active MM vs newly diagnosed MM (NDMM) patients. Methods We performed a two-center real-world case-control retrospective cohort study. Consecutive patients receiving first line treatment for MM after progressing from SMM were identified; each was matched by age and year of diagnosis (±2 years) to a patient first presenting as NDMM. SMM, MM, MDEs and response were defined by the International Myeloma Working Group (IMWG) criteria (2014, 2016); progression-free survival (PFS) and overall survival (OS) were calculated from active MM diagnosis. Data was extracted in 07/2023. Results We identified two cohorts of newly diagnosed MM patients, presented between 09/2008and 02/2023: Post SMM (P-SMM, N=57) and De novo MM patients (D-MM, N=57). Median follow up time was 38.6 months (IQR 23.3 - 72.7). There were no differences in baseline demographics between gender (p=.19), and median age: 73.4 (range 42 - 88) in the P-SMM group and 72.9 (range 42 - 92) in the D-MM (p=.75). Comparing MDEs using SLiM-CRAB criteria between groups, more patients in the D-MM group presented with hypercalcemia (p=.02) and lytic lesions (p=.03). Other domains were similar between groups: anemia (p=.68), renal failure (p=.59), FLC ≥100 (p=.76), % bone marrow plasma cells (BMPC) ≥ 60 (p=.11). D-MM patients had higher ISS/R-ISS at presentation: ISS ≥ II (30 vs 11, p=.004) and R-ISS ≥ II (31 vs 13, p=.002). Additional disease characteristics were balanced at diagnosis of active MM: heavy chain (p=.53), light chain type (p=.69), M-Protein level (p=.23), extra medullary disease (p=.14), Al amyloidosis (p=.13), and high-risk cytogenetics (p=.65). Bone involvement was more frequent in D-MM vs P-SMM patients, with significantly more pathological fractures (p=.006), bone pain (p=.001), and a detrimental bone disease (p=.001) (defined as combination of pathological fracture and/or ≥ 3 lytic lesions) (Figure 1B). Significantly higher rates of hospital admissions for upfront therapy initiation were seen in the D-MM group compared with P-SMM, 18 vs 7 (p=.008), as well as more potentially irreversible MDEs (pathological fractures and/or renal injury): 43 (p=.009) vs 31 (41.9%) respectively. Treatment patterns were balanced excluding bortezomib used more often in the D-MM (p=.009) and daratumumab in the P-SMM group (p=.03). Best response rates to upfront therapy were comparable between groups, (p=.71) as well as ≥ very good partial response (VGPR) rates (p=.88), 52.4% vs 47.6% in P-SMM and D-MM respectively. Frequency of skeletal imaging tests up-to 2-year period prior to active MM diagnosis were associated with lower rates of detrimental bone disease (p=.006). Despite the similar ≥ VGPR rates between cohorts, PFS was longer in the P-SMM group vs D-MM group, 39.6 vs 21.6 months, respectively (log-rank 0.01). A superior PFS in P-SMM group vs D-MM remained after correction for % BMPC at diagnosis (46.2% vs 58.8%, p=.03). OS was also longer, not reached vs 93.7 months (log-rank=.047) (Figure 1A). Conclusions Patients who develop active MM post SMM clinic surveillance presented with a lower disease burden, as well as reduced rates of detrimental bone disease and potentially irreversible MDEs. P-SMM patients had favorable PFS and OS rates. This may reflect effectiveness of SMM monitoring resulting in lower disease burden at time of treatment onset; favorable long-term outcomes may also be affected by variability in treatment patterns between groups. Another possible explanation is that patients with more indolent MM biology may have extended periods of precursor condition, hence increasing their likelihood to be diagnosed by incidental laboratory tests during their SMM phase.

Initial Safety and Efficacy of Daratumumab (DARA) in Combination with Bortezomib, Lenalidomide, and Dexamethasone in the Treatment of Transplant-Eligible Newly Diagnosed Multiple Myeloma (TE-NDMM) Patients with Standard Risk Who Refused to Accept ASCT As First Line in China

Background: Despite the advent of numerously new drugs, multiple myeloma (MM) remains an incurable plasma cell malignancy. Autologous hematopoietic stem cell transplantation (ASCT) remains an important first line treatment for MM. In China, rate of utility of ASCT in front line was as low as 10%. There are many transplant-eligible (TE) patients who refuse ASCT for a variety of subjective and objective reasons,. Bortezomib, lenalidomide and dexamethasone (VRd) combination has been reported to demonstrate high efficacy in these patients (SWOG S0777), And recently, daratumumab combinations, such as D-VRd (GRIFFIN) and D-VTd (CASSIOPEIA), have shown good results in TE-NDMM patients who received ASCT as initial therapy. The observed benefits of these combination therapies have led us to explore the potential efficacy of D-VRd in standard risk TE-NDMM patients without ASCT. In addition, there were no studies assessing minimal residual disease (MRD) data after treatment with the D-VRd regimen in TE-NDMM patients who are unwilling to undergo ASCT in Chinese population , thus we chose MRD as the primary endpoint. This is the first open-label, single arm study to evaluate the efficacy and safety of D-VRd in TE-NDMM in standard risk without ASCT in China (NCT 05088330). Methods: This is a single-center prospective ongoing clinical study, planning to recruit 76 patients. NDMM patients as documented per IMWG criteria who were evaluated as transplant-eligible, but voluntary not to accept ASCT were enrolled. And t(4;14) or Del(17p) or t(14;16) or R-ISS stage III patients were excluded from this study. D-VRd regimen includes ‘daratumumab’ 16 mg/kg I.V. every week for 2 cycles, 16 mg/kg I.V. every 3 weeks for 6 more cycles, and then 16 mg/kg I.V. for 13 more cycles (Total: 21 cycles); ‘lenalidomide’: 25 mg, P.O., Days 1-14/1-8 cycles; ‘Bortezomib’: 1.3 mg/m2, SC, Days 1, 4, 8, 11/1-8 cycles; dexamethasone: 20 mg, P.O., Days 1, 2, 4, 5, 8, 9, 11, 12/1-8 cycles. The primary endpoint of this study was to evaluate the negativity of NGS MRD at 10-5 after 8 cycles of D-VRd. The secondary objectives of this study were to determine the ORR, sCR, ≥CR ≥VGPR, AE, TTR and DOR of treatment. Patients were recommended to have stem cells collection after 4 cycles of D-VRd treatment. Result: As of 30 June 2023, 24 patients including 6 safety-run-in patients were enrolled. The median (range) age of these 24 patients was 65 (50-74) years. 54.2% (13/24) were male. 62.5% of patients had a 1q gain. 16.7% (4/24) of patients had renal insufficiency with 30mL/min <CCR <60mL/min (Table 1). The median follow-up time was 3 (1-11) months, 8 patients completed 4 cycles and 2 patients completed 2 cycles. Among the 17 patients who had response evaluation, the ORR was 94.1%, 87.5% (7/8) of patients had VGPR or better after 4 cycles (Figure 1). All patients (6/6) above VGPR and CR had NGS MRD negativity. Both 2 patients who have completed the 8 cycles treatment achieved CR and MRD negativity. All patients had bone pain relief. The main treatment-related adverse events were hematological toxicity, which occurred in 22 patients including neutropenia (n=14, Grade 1-2 for 10 patients and Grade 3-4 for 4 patients), lymphopenia (n=13, Grade 1-2 for 10 patients and Grade 3-4 for 3 patients) and thrombocytopenia (n=19, Grade 1-2 for 15 patients and Grade 3-4 for 4 patients). One patient had to discontinue lenalidomide due to serious adverse event (SAE) of pulmonary embolism. Other toxicities to date include pneumonia (n=3, Grade 1 for 2 patients and Grade 2 for 1 patient), ALT/AST increase (n=10, all Grade 1), and rash (n=3). The infusion related reactions were reported in 25% of patients (n=6, Grade 1 for 4 patients and Grade 2 for 2 patients). Conclusion: In the safety-run-in phase, D-VRd induction therapy was well tolerated in the Chinese population in 6 patients. This preliminary study of D-VRd demonstrated excellent efficacy with rapid response even in a population with high 1q gain. The most common adverse events were hematological toxicities that were manageable after 2 cycles. The updated results will be presented in the following phase.

Duloxetine prevents bortezomib and paclitaxel large-fiber chemotherapy-induced peripheral neuropathy (LF-CIPN) in sprague dawley rats.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating, treatment-limiting, side-effect of several classes of chemotherapy drugs. While negatively impacting oncology patients' quality of life, chemotherapy-induced large-fiber (LF) neuropathy is amongst the least well understood components of CIPN, and one for which there is currently no established therapy. Preliminary clinical observations have led to the suggestion that Duloxetine, which is used for the treatment of pain associated with small-fiber CIPN (SF-CIPN), may be effective against LF-CIPN. In the present experiments we developed a model of LF-CIPN and studied the effect of Duloxetine on LF-CIPN induced by two neurotoxic chemotherapy agents: the proteasome inhibitor, Bortezomib, a first-line treatment of multiple myeloma; and, the anti-microtubule taxane, Paclitaxel, used in the treatment of solid tumors. Since there are currently no models for selective the study of LF-CIPN, our first aim was to establish a pre-clinical model in the rat. LF-CIPN was evaluated with the Current Perception Threshold (CPT) assay, which uses a high frequency (1000Hz) electrical stimulus protocol that selectively activates large-fiber myelinated afferents. Our second aim was to use this model to test the hypothesis that Duloxetine can prevent LF-CIPN. We report that Bortezomib and Paclitaxel induce elevation of CPT, compatible with loss of large-fiber function, which are prevented by Duloxetine. Our findings support the clinical observation that Duloxetine may be an effective treatment for the large-fiber CIPN. We also suggest that CPT could be used as a biomarker for LF-CIPN in patients receiving neurotoxic chemotherapy.

Ixazomib, Oral Metronomic Cyclophosphamide, and Dexamethasone for First-Line Treatment of Multiple Myeloma: A Phase II Brown University Oncology Group Study.

Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228).

Ixazomib combined with lenalidomide and dexamethasone chemotherapy for newly diagnosed multiple myeloma in China-Compared with bortezomib/lenalidomide/dexamethasone.

To compare the response and safety of Ixazomib/Lenalidomide/Dexamethasone (IRd) and Bortezomib/Lenalidomide/Dexamethasone (VRd) treatment in newly diagnosed multiple myeloma (MM). This was a single-center retrospective analysis in Xiangtan Central Hospital. A total of 52 newly diagnosed MM patients from June 2019 to June 2021 were enrolled and divided into the IRd (n=21) and VRd (n=31) groups. After 4cycles of chemotherapy, the best response and adverse events were recorded. Moreover, the progression-free survival (PFS) and overall survival (OS) were calculated. Patients in IRd group and VRd group showed similar PFS (Log-rank p=0.70), OS (Log-rank p=0.61) and overall response rate (83.87% vs 90.48%, p=0.803). In addition, patients in VRd group showed lower Eastern Cooperative Oncology Group scores (p=0.047), and higher incidence of peripheral sensory neuropathy (0.00% vs 19.35%, p=0.032) than that of patients in IRd group. Compared to VRd regimen, IRd had the similar efficacy, better safety, and may be more convenient for patients with poor basic condition for newly diagnosed MM. This study provides an insight for physicians to use IRd as first-line treatment in MM.

Subcutaneous daratumumab (DARA SC) versus active monitoring in patients (pts) with high-risk smoldering multiple myeloma (SMM): Randomized, open-label, phase 3 AQUILA study.

TPS8075 Background: Standard of care for SMM includes active monitoring until progression to multiple myeloma (MM); however, recent evidence suggests pts with high-risk features may benefit from early treatment. DARA is a human IgGκ monoclonal antibody targeting CD38 that is approved as monotherapy for relapsed/refractory MM (RRMM) or in combination with standard of care for RRMM or newly diagnosed MM. Results from the phase 3 COLUMBA study showed that DARA SC demonstrated similar efficacy to intravenous (IV) DARA but with a lower rate of infusion-related reactions and shorter administration time. Based on the promising single-agent activity observed with IV DARA in intermediate- or high-risk SMM pts during the phase 2 CENTAURUS study, we hypothesized that DARA SC may delay progression to MM versus active monitoring in pts with high-risk SMM. Methods: AQUILA is an ongoing, randomized, open-label, multicenter phase 3 study of DARA SC versus active monitoring in pts with high-risk SMM. DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) is administered by manual injection over approximately 5 minutes at alternating locations on the abdomen weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter until 39 cycles (28 days/cycle), up to 36 months, or until disease progression. Eligibility criteria include confirmed diagnosis of SMM for ≤5 years, factors indicating high risk of progression to MM (clonal bone marrow plasma cells [BMPCs] ≥10% and ≥1 of the following: serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 to < 100, or clonal BMPCs > 50% to < 60% with measurable disease), and ECOG performance status ≤1. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee, with disease progression defined according to International Myeloma Working Group diagnostic criteria for MM. Secondary endpoints include time to biochemical or diagnostic (SLiM-CRAB) progression, overall response rate, complete response rate, duration of response, time to response, time to first-line treatment for MM, PFS on first-line treatment for MM (PFS2), overall survival, and incidence of MM with adverse prognostic features. The study completed enrollment on May 6, 2019; 390 pts have been randomly assigned to DARA SC or active monitoring. The primary efficacy analysis will be performed after approximately 165 PFS events have been observed. Clinical trial information: NCT03301220.

Survival Analysis of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients in Czech Republic

Introduction: Although highly effective agents and novel therapeutic strategies are being developed, high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) has not been overcome in the first-line treatment for fit patients (pts) with multiple myeloma. The objective of this work is to retrospectively analyze the use of this procedure in newly diagnosed Czech patients.Methods: Data were derived using the Czech Myeloma Group Registry of Monoclonal Gammopathies. By February 2 nd 2021, a total of 2154 newly diagnosed multiple myeloma patients who underwent HDT/ASCT were identified.Results: At the time of multiple myeloma diagnosis, the median age was 59 years; 24%/56%/14%/5%/1% pts were ECOG 0/1/2/3/4; 44%/32%/24% pts were ISS stage I/II/III; 14.5%/17.5%/68% and 84%/16% pts were Durie-Salmon stage I/II/III and subclassification A/B, respectively. The combinations of agents used in the induction regimen were proteasome inhibitor (PI), immunomodulatory drug (IMiD) and glucocorticoid (GC) in 28.5% (613/2154) pts; PI, GC and chemotherapy (CHT) in 24.8% (534/2154) pts; GC and CHT in 22,5% and IMiD, GC and CHT in 16.1% (346/2154). Other combination of drugs was used in 8.2% (177/2154) pts. It was registered that 3.7% (79/2154) induction regimens were switched to a different combination because of toxicity, patient's choice, poor peripheral venous access or other reasons. Single HDT/ASCT was performed in 77.3% (1665/2154) cases whereas tandem HDT/ASCT was given to 11.8% (254/2154) patients. In 10% (215/2154) cases, the transplantation technique was not specified. Nine percent (193/2154) patients were treated within a clinical study. The median progression free survival (mPFS) and the median overall survival (mOS) of the whole cohort was 28.9 and 92.1 months, respectively. Information about response to treatment before and after the high-dose therapy were available for 75.7% (1627/2154) and 92.2% (1987/2154) patients, respectively. Disease status at the time of HDT/ASCT was defined as stringent complete response (sCR) at 2.2% (36/1627), complete response (CR) at 11.9% (194/1627), very good partial response (VGPR) at 38.2% (621/1627), partial response (PR) at 40.9% (666/1627), minimal response (MR) at 3.6%, (58/1627), stable disease (SD) at 2.2% (36/1627), progressive disease (PD) at 1% (16/1627) patients. The overall response rate (ORR) on day 100 was 92.8% (sCR: 10.5% [209/1987], CR: 22.4% [446/1987], VGPR: 35% [696/1987], PR: 24.8% [493/1987], MR: 2.7% [54/1987], SD: 1.4% [27/1987], PD: 3.1% [62/1987]). We also performed a survival analysis of patients progressing up to 18 months after HDT/ASCT (n=1219) versus patients progressing in more than 18 months (n=935). The median OS was 41.5 versus 124.9 months, respectively. An analysis of the role of tandem HDT/ASCT in this real-world cohort will be presented at the conference.Conclusion: Globally as well as in the Czech Republic, HDT/ASCT is an important therapeutic approach in the first-line treatment of multiple myeloma. Our analysis of 2154 newly diagnosed transplant-eligible patients confirms high effectiveness - ORR of 92.8%, mPFS of 28.9 months, and long-term survival reaching mOS of 92.1 months. DisclosuresMinarik: Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Comparison of the renal response of bortezomib-based induction and conventional regimen in multiple myeloma patients with renal failure

Aim: Vincristine-doxorubicin-dexamethasone (VAD) was the commonly used first-line treatment for multiple myeloma (MM) patients with renal failure before bortezomib entered clinical practice. In this trial, we aimed to compare the effect of VAD and bortezomib-cyclophosphamide-dexamethasone (VCD) chemotherapy regimens on improving kidney function in MM patients with renal failure. Materials and Methods: The records of MM patients in our center between January 2010 and February 2020 were retrospectively analyzed. Patients who received VAD or VCD as a first treatment chemotherapy protocol and whose initially estimated glomerular filtration rate (eGFR) was 50 mL/min/1.73 m2 and below were included in the study. Patients were divided into two groups according to the chemotherapy regimens they received. Results: Sixty one MM patients (VAD: 26, VCD: 35) were included in the study. No significant difference was found between the VAD and VCD groups when the baseline, 1st and 2nd month eGFRs were compared (p>0.05). Overall renal response rate (at least minor response) in the VCD group at the end of the 1st month were higher than in the VAD group (p=0.002). Also, renal response rate in the VCD group at the end of the 2nd month were higher than in the VAD group (p=0.033). Conclusion: In MM patients with renal insufficiency, overall renal response rates have increased with the use of VCD instead of VAD as a standard induction regimen.

Melphalan and Exportin 1 Inhibitors Exert Synergistic Antitumor Effects in Preclinical Models of Human Multiple Myeloma.

High-dose chemotherapy with melphalan followed by autologous transplantation is a first-line treatment for multiple myeloma. Here, we present preclinical evidence that this treatment may be significantly improved by the addition of exportin 1 inhibitors (XPO1i). The XPO1i selinexor, eltanexor, and KOS-2464 sensitized human multiple myeloma cells to melphalan. Human 8226 and U266 multiple myeloma cell lines and melphalan-resistant cell lines (8226-LR5 and U266-LR6) were highly sensitized to melphalan by XPO1i. Multiple myeloma cells from newly diagnosed and relapsed/refractory multiple myeloma patients were also sensitized by XPO1i to melphalan. In NOD/SCIDγ mice challenged with either parental 8226 or U266 multiple myeloma and melphalan-resistant multiple myeloma tumors, XPO1i/melphalan combination treatments demonstrated stronger synergistic antitumor effects than single-agent melphalan with minimal toxicity. Synergistic cell death resulted from increased XPO1i/melphalan-induced DNA damage in a dose-dependent manner and decreased DNA repair. In addition, repair of melphalan-induced DNA damage was inhibited by selinexor, which decreased melphalan-induced monoubiquitination of FANCD2 in multiple myeloma cells. Knockdown of FANCD2 was found to replicate the effect of selinexor when used with melphalan, increasing DNA damage (γH2AX) by inhibiting DNA repair. Thus, combination therapies that include selinexor or eltanexor with melphalan may have the potential to improve treatment outcomes of multiple myeloma in melphalan-resistant and newly diagnosed patients. The combination of selinexor and melphalan is currently being investigated in the context of high-dose chemotherapy and autologous transplant (NCT02780609). SIGNIFICANCE: Inhibition of exportin 1 with selinexor synergistically sensitizes human multiple myeloma to melphalan by inhibiting Fanconi anemia pathway-mediated DNA repair.

Comparison of Different Upfront Transplant Strategies in Multiple Myeloma - a Large Registry Study from Chronic Malignancies Working Party of EBMT

Comparison of Different Upfront Transplant Strategies in Multiple Myeloma - a Large Registry Study from Chronic Malignancies Working Party of EBMT

The disease journey for patients with multiple myeloma treated with novel agents: a retrospective cohort study in Taiwan

Novel agents have been available for first-line treatment of multiple myeloma (MM) in Taiwan since 2009. At present, little is known about the disease journey of patients treated with novel agents in Taiwan. We constructed a disease-progression model to describe the disease journey in patients aged ≥18 years with newly diagnosed MM in Taiwan who received first-line treatment with novel agents (thalidomide or bortezomib).

FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma.

MYCN amplification in neuroblastoma predicts poor prognosis and resistance to therapy. Yet pharmacological strategies of direct MYC inhibition remain unsuccessful due to its "undruggable" protein structure. We herein developed a synthetic lethal screen against MYCN-amplified neuroblastomas using clinically approved therapeutic reagents. We performed a high-throughput screen, from a library of 938 FDA-approved drugs, for candidates that elicit synthetic lethal effects in MYC-driven neuroblastoma cells. The proteasome inhibitors, which are FDA approved for the first-line treatment of multiple myeloma, emerge as top hits to elicit MYC-mediated synthetic lethality. Proteasome inhibition activates the PERK-eIF2α-ATF4 axis in MYC-transformed cells and induces BAX-mediated apoptosis through ATF4-dependent NOXA and TRIB3 induction. A combination screen reveals the proteasome inhibitor bortezomib (BTZ) and the histone deacetylase (HDAC) inhibitor vorinostat (SAHA) concertedly induce dramatic cell death in part through synergistic activation of BAX. This combination causes marked tumor suppression in vivo, supporting dual proteasome/HDAC inhibition as a potential therapeutic approach for MYC-driven cancers. This FDA-approved drug screen with in vivo validation thus provides a rationale for clinical evaluation of bortezomib, alone or in combination with vorinostat, in MYC-driven neuroblastoma patients.

First-line treatment of multiple myeloma

Within the last two decades the therapeutic options for newly diagnosed multiple myeloma have changed dramatically. The implementation of high-dose chemotherapy with melphalan and subsequent autologous blood stem cell transplantation initially led to prolonged survival in younger, fit patients. Furthermore, recent data suggest that patients with high-risk disease seem to benefit most from tandem transplantation approaches. Therefore, risk stratification at initiation of first-line treatment is of great importance. With the advent and integration of the so-called novel agents, such as thalidomide, lenalidomide and bortezomib into first-line treatment, both transplant eligible and ineligble patients gained new therapeutic perspectives. In Germany, the combination of bortezomib with cyclophosphamide and dexamethasone is currently considered the standard of care as induction regimen before high-dose treatment and transplantation; however, the combination of lenalidomide, bortezomib and dexamethasone is increasingly being used, but is still not yet approved in Germany. For patients where high-dose therapy and stem cell transplantation are not feasible, bortezomib and lenalidomide are available as backbone agents of various combination regimens. Recently, the anti-CD38 antibody daratumumab has been approved in combination with bortezomib, melphalan and prednisone as primary treatment for newly diagnosed patients. An allogeneic stem cell transplantation can be considered for younger patients without relevant comorbidities and with high-risk disease or early relapse after autologous blood stem cell transplantation but should only be performed within controlled clinical trials and in specialized centers.

The Current Situation of Multiple Myeloma Treatment in Japan: A Cross-Sectional Analysis Based on Health Insurance Claims Data

Introduction: Multiple myeloma (MM) is a rare disease with an estimated annual prevalence of 5.3 per 100,000 persons in Japan (Center for Cancer Control and Information Services, 2017). The median age of Japanese patients at the time of diagnosis is 66 years (Japanese Society of Myeloma, 2016). Bortezomib, thalidomide, lenalidomide, pomalidomide, panobinostat, carfilzomib, elotuzumab, ixazomib, and daratumumab have been approved for MM treatment in Japan. Despite a systematic review on treatment costs for relapsed/refractory MM patients in Japan (Yamabe et al. 2015) and a study identifying factors influencing drug choice for first-line treatment of MM (Bolt et al., 2018), comprehensive data on the current situation with MM treatment costs in Japan are lacking. We analyzed health insurance claims data to demonstrate the current status of MM treatment patterns and associated costs in Japan.Methods: We used a health insurance claims database containing records of 19.8 million individuals from 314 acute care hospitals. Diagnostic information was based on the 10th revision of the International Classification of Diseases (ICD10). Drugs were coded based on the Anatomical Therapeutic Chemical Classification System. The monthly medical cost per patient (MMCP) was analyzed from April 2008 to December 2016 as follows: total MMCP, MMCP for MM drugs, and MMCP for other costs (hospitalization, surgery and tests, etc.). The share of each agent in the medical cost of MM drugs was also analyzed throughout the same period. We selected patients with ≥ 1 diagnosis of MM (ICD10 code C90.0). The observation period for each patient started at the latter date of first medical care day for any disease or the first MM diagnosis and ended at the last medical care day for any disease.Results: We identified 19,137 MM patients. Total MMCP showed an increasing trend until lenalidomide was launched in Japan in 2010, at which point MMCP began to stabilize (Figure 1). MMCP per MM drug showed an increasing trend during the entire study period, but other medical costs showed a decreasing trend after the launch of lenalidomide (Figure 2). Detailed analysis of other costs showed that oral medication cost ratio increased just after the launch of lenalidomide and further increased gradually from 2015, while the basic hospitalization cost ratio gradually decreased after the launch of lenalidomide (Figure 3). Analysis of the contribution of each drug to the medical cost of MM drugs showed that the lenalidomide cost reached almost 40% of the share immediately after its launch and remained stable thereafter (Figure 4). Lenalidomide maintained its stable share even after the launch of newer drugs (eg, pomalidomide and carfilzomib) (Figure 4).Discussion: Although a significantly better prognosis has been reported in MM patients treated after 2010 (Shibayama et al. 2013), our data show that lenalidomide addition to MM treatment in Japan did not increase total MMCP for approximately 5 years following lenalidomide launch. This may be due to the prescription of lenalidomide leading to improved MM management in clinical practice, as indicated by changes in the medical cost share of each drug. Such interpretation is also corroborated by a decrease in injection cost and an increase in oral medication cost. It can be argued that as lenalidomide is orally administered, hospitalization and the use of other materials are reduced, resulting in treatment cost reduction. The hospitalization costs for patients receiving lenalidomide maintenance therapy were lower than those for patients not receiving any maintenance therapy (Ashcroft et al. 2018). The Guidelines for the Treatment of Multiple Myeloma (Japanese Society of Myeloma, 2016) present the regimen lenalidomide + low-dose dexamethasone (Rd) for newly diagnosed MM patients and the induction regimen Rd + bortezomib (RVd) for transplant-eligible MM patients as a grade A treatment recommendation and specify a lenalidomide-based triplet regimen as a salvage treatment option for relapsed and/or refractory MM patients. Such a recommendation may explain the relatively stable share of lenalidomide medical care costs despite the launch of new drugs (pomalidomide and carfilzomib) in Japan. DisclosuresUno:Celgene K.K.: Employment. Saito:Celgene K.K.: Employment. Janune:Milliman: Employment. Iwasaki:Milliman: Employment. Ohtsu:Celgene K.K.: Employment.

The Prognostic Impact of t(14;16) in Multiple Myeloma: A Multicenter Retrospective Study of 213 Patients. Is It Time to Revise the Revised ISS?

The Prognostic Impact of t(14;16) in Multiple Myeloma: A Multicenter Retrospective Study of 213 Patients. Is It Time to Revise the Revised ISS?

The Prognostic Impact of t(14;20) in Multiple Myeloma - a Multicenter Retrospective Study of 26 Patients

IntroductionThe prognosis in multiple myeloma (MM) is based upon complex biological and clinical features. One of the strongest predictors of outcome are the intrinsic genetic abnormalities in the malignant plasma cells. t(14;20), as other chromosome 14 abnormalities, deregulates the c-musculoaponeurotic fibrosarcoma (c-MAF) oncogene. Due to the relative rarity of t(14;20) [<1.5% of newly diagnosed MM; slightly higher in monoclonal gammopathies of unknown significance- about 5%], there are no large databases which provide the natural history of this abnormality. Its meaning remains controversial due to the small sample sizes in previously published reports in contrast to t(4;14) and 17p- abnormalities which have been described independently in the literature.MethodsWe retrospectively analyzed the clinical features and outcomes of patients t(14;20) from 5 clinical centers in Germany, Italy and the United States. Newly diagnosed MM patients according to the International Myeloma Working Group (IMWG) criteria were enrolled. The t(14;20) was detected by double color fluorescence in situ hybridization (FISH) using bone marrow samples. Baseline characteristics at diagnosis, comorbidities, patient treatment regimens and clinical outcomes were collected using unified case report forms. Clinical responses were assessed according to the IMWG uniform response criteria. Overall survival (OS) was defined as the period between the date of initial diagnosis and the date of death or the date of the last observation. Progression-free survival (PFS) was defined as the period between the date of initial diagnosis and either the date of the first relapse or death of any causes or the date of the last observation. Cox proportional hazard regression analysis was applied to assess risk factors of death. Survival curves were plotted by the Kaplan-Meier method and compared using log-rank and Breslow-Gehan-Wilcoxon tests.Results26 patients were included in analysis including 11 males (42.3%). Median age at MM diagnosis was 68.5 years (range 56-71). Immunoglobulin isotype included: IgG (n=14, 53.8%), IgA (n=9, 34.6%), light chain (n=3, 11.5%). R-ISS stage at diagnosis included: stage III (n=8, 30.8%); stage II (n=9, 34.6%) and stage I (n=1, 3.8%)- the staging for remaining 8 patients is unknown. Anemia (<10g/dl) was observed in 13 (50%), impaired renal function (creatinine clearance <40 mL per minute or serum creatinine >2 mg/dl) in 3 (11.5%). In 14 (53.8%) cases osteolytic lesions were present. In 15 patients (57.7%) the t(14;20) was associated with other cytogenetic aberrations, including del17p in 2 patients (7.7%), t(4;14) in 5 patients (19.2%) and t(14;16) in 4 patients (15.4%). First line treatment for MM included mostly PIs + IMIDs in 8 patients (30.8%), PIs + IMIDs + chemotherapy in 7 patients (26.9%) or PIs alone in 3 cases (11.5%). Auto-PBSCT was performed in 8 cases (30.7%).Median PFS was 30 months (CI 95% 17.8 months; Figure 1, panel A). Median OS was not reached (Figure 1, panel B). 5-year OS from MM diagnosis was 77.5% (±10.6%).ConclusionIn this study of 26 patients with t(14;20) the median PFS and 5-year OS were 30 months and not reached, respectively. Historically, the presence of a t(14;20) is considered to be a very poor prognostic factor-this was not observed in this multi-institutional retrospective analysis. In comparison to the recent studies (Ross et al, Haematologica, 2010; n=27; median survival 14.4 months), the PFS and OS of patients with t(14;20) in our analysis are better than expected. It should be highlighted that most probably in the Ross et al. study patients were not treated with novel drug therapies. Nonetheless, this controversy remains to be elucidated in the future studies. DisclosuresCastillo:Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding. Hari:Celgene: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria. Goldberg:COTA Inc.: Employment, Equity Ownership.

Abstract 1847: The ubiquitin proteasome system controls cell cycle gene expression through regulation of histone acetylation in multiple myeloma

Abstract Transcription factors (TFs) are generally short-lived proteins that undergo active turnover. The dynamic interaction of TFs and co-regulators with promoters and enhancers allows cells to continuously adjust gene expression. Whereas the composition and binding of TFs at genomic sites is the focus of a widespread research effort, relatively little is known about how these complexes are removed by the ubiquitin-proteasome system (UPS). Multiple myeloma (MM), the second most common hematopoietic malignancy, has become a model disease for drugs that interfere with the UPS through either blocking or facilitating protein elimination. The proteasome inhibitor Bortezomib, for instance, is used as first-line treatment in MM. Since TFs are prime targets of proteasomal degradation, our research is focused on defining how nuclear proteolysis regulates transcriptional dynamics in this disease. This is of particular relevance since the therapeutic mechanisms of action of proteasome inhibitors are still ill-defined. Following proteasome inhibition in multiple myeloma cell lines, we performed chromatin-immunoprecipitation for histone H3 acetylation (K27) and multiple histone deacetylases (HDACs) and used next generation sequencing (ChIP-seq) to identify unique gene clusters that are actively regulated by the proteasome and quantify epigenetic changes in dependence of protein turnover. Our findings reveal that cell cycle and mitosis-related genes, particularly subsets of genes involved in centromere formation and sister chromatid segregation, are associated with nuclear protein turnover and transcriptionally repressed by proteasome inhibition. Among the main transcriptional co-repressor complexes, we found NCoR1 to play a key role in controlling MM growth by adjusting cell cycle gene expression. Following proteasome inhibition, stabilization of NCoR1 at the promoters of these genes favors the recruitment of histone deacetylases to further inhibit gene activity. Concordantly, analysis of a panel of MM patients shows that the expression levels of certain histone deacetylases correlate with patient survival, specifically when treated with proteasome inhibitors. We are currently examining how NCoR1 is degraded, with a particular emphasis on the impact on histone acetylation at cell cycle gene promoters. Exploring how histone modifications and proteasome activity crosstalk in a therapeutically relevant manner in MM will help us to better understand how this degradation pathway impacts myeloma proliferation. This research project will contribute to our understanding of epigenetic and transcriptional dynamics in MM. With our focus on the continuously changing abundance of TFs and co-regulators at promoters of cell cycle genes, we seek to unlock new therapeutical pathways and more specific targets for MM treatment compared to blunt proteasome inhibition. Citation Format: Laure Maneix, Polina Iakova, Shannon Moree, Luke Fletcher, Premal Lulla, Sarvari V. Yellapragada, Andre Catic. The ubiquitin proteasome system controls cell cycle gene expression through regulation of histone acetylation in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1847.