Bortezomib-based Regimens Research Articles

Pretreatment Serum Levels of IL-1 Receptor Antagonist and IL-4 Are Predictors of Overall Survival in Multiple Myeloma Patients Treated with Bortezomib.

Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The present study examines the influence on progression-free survival (PFS) and overall survival (OS) by the serum levels of 27 selected cytokines in 61 newly diagnosed MM patients receiving first-line therapy with bortezomib-based regimens. The measurements were performed using a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay and a MAGPIX Multiplex Reader, based on the Bio-Plex® 200 System (Bio-Rad). The following levels were determined: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. Most patients received a VCD chemotherapy regimen (bortezomib, cyclophosphamide, and dexamethasone). In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240–0.8291, p = 0.0302) and ASCT (HR 0.3722, 95% CI: 0.1826–0.7585, p = 0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046–0.438, p = 0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471–9.949, p = 0.0059), and two cytokine levels—IL-1Ra (HR 1.017, 95% CI: 1.004–1.030, p = 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037–0.698, p = 0.0147)—were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.

Partial immunoparesis contributes to risk of early infections in patients with multiple myeloma.

BackgroundPartial immunoparesis, which means at least two suppressed uninvolved immunoglobulins (Igs), had been reported to be associated with poor prognosis in patients with multiple myeloma (MM), but the impact on early infections remains unknown. The purpose of our study was to determine the prognostic implications of partial immunoparesis on early grade ≥3 infections in patients with MM.MethodsHerein we retrospectively analyzed the clinical data of 123 MM patients between 2012 and 2020 at Nanfang Hospital. All patients received bortezomib-based regimens. The relationship between early grade ≥3 infections and partial immunoparesis was investigated using Cox regression analysis.ResultsOur data showed partial immunoapresis was found in 63% MM patients. Partial immunoparesis was significantly related to elevated beta-2-microglobulin (B2M), decreased estimated glomerular filtration rate (eGFR) and progressive international staging system (ISS) stage (P<0.05). Especially, univariate Cox regression analysis showed partial immunoparesis was significantly correlated with early grade ≥3 infections (P=0.003). Moreover, multivariate Cox regression analysis showed partial immunoparesis was an independent significant prognostic factor for early grade ≥3 infections [odds ratio (OR) =3.048; 95% confidence interval (CI): 1.429–6.504; P=0.004]. Furthermore, partial immunoapresis could improve the infection risk model built by Dumontet et al.ConclusionsOur study showed that partial immunoparesis could predict early infections in patients with MM, which may be used to identify the high risk patients for infections and guide strategies for infection prevention.

Recovery of Gonadal Hormone Level Is a Potential Marker for the Response and Prognosis in POEMS Syndrome Patients Treated with Bortezomib Based Combined Chemotherapy

Background：There is no standard treatment recommendation for POMES syndrome, a rare clonal plasm cell disease. Although autologous hematopoietic stem cell transplantation (ASCT) has been considered to have advantage in remission rate and long-term survival, but in most newly diagnosed cases, it is not applicable to conduct ASCT directly because of the severity of patients' conditions. Combined chemotherapy, applied in other plasm cell disorder, is a choice for POEMS syndrome. Both melphalan and lenalidomide have been proved to be effective in POEMS syndrome, but the long-term administration of these agents might damage hematopoietic stem cells and result in failure of stem cell mobilization. Proteasome inhibitor, bortezomib based regimen is also the first-line treatment in other plasm cell dyscrasia. In this study, we investigated and evaluated the effect and safety of the bortezomib-based combined chemotherapy in newly diagnosed POEMS syndrome patients.Method:POEMS syndrome patients newly diagnosed from July 2013 to August 2020 in Xuanwu hospital, Capital Medical University, were enrolled. Informed consent was obtained. Four cycles of Bortezomib-based 28-day BCD regimen (bortezomib 1.3mg/m 2 sc d1,8,15,22, cyclophosphamide iv 0.4g/m 2 d1,15, dexamethasone 40mg iv d1,8,15,22) were used as induction therapy. After the induction, ASCT or another two cycles of BCD therapy were conducted as consolidation therapy. Patients diagnosed in the same period but refusing bortezomib were treated with CD/CTD regimen (the same as BCD without bortezomib), and thalidomide 50-100mg once daily was suggested if it was well-tolerated. (Figure A)Results:There were totally 22 newly diagnosed POEMS syndrome patients accepted BCD regimen, and 16 patients CD/CTD regimen. First of all, the response rate in BCD group was superior to CD/CTD group, no matter the VEGF remission rate or hematologic complete remission rate (Figure B1-B4). The median time to achieve VEGF CR was 133 days in BCD group and 214 days in CD/CTD group. The median time to achieve hematologic remission was 218 days in BCD group and 415 days in CD/CTD group. Secondly, the improvement of neurologic symptoms in BCD group was not inferior to CD/CTD group. Bortezomib was well tolerated and didn't deteriorate the polyneuropathy (Figure C1-C3). Thirdly, during the median 35 months follow-up, the overall 5-year OS of 31 patients was 93.55%, 3-year and 5-year PFS were 83.47% and 76.51% respectively (Figure D1-D2). The 5-year-OS and 3-year and 5-year PFS of BCD group were superior to CD/CTD group (Figure D3-D4). In the consideration of ASCT significantly improve OS and PFS in POEMS syndrome patients, the long-term survival results were analyzed among ASCT group and cheotherapy only groups. The BCD+ASCT group achieved a best 5-year OS and 3-year and 5-year PFS (Figure D5-D6). Fourthly, about 54% of male patients had a subnormal testosterone at diagnosis, with normal or slightly elevated LH. After treatment, testosterone returned to normal level in male patients with the VEGF CR and VEGF PR (Figure E1). And the median remission time of testosterone was 76 days, which was earlier than that of VEGF remission was 143 days. The testosterone returned to normal after two cycle treatment predicted a better PFS. (Figure E2). About 86% of men at diagnosis had elevated estradiol which is the most common gonadal hormone abnormalities. After treatment, patients with better treatment response would have lower estradiol level (Figure E3-E4). Estradiol less than 58pg/ml after two cycle treatment and estradiol less than 48pg/ml after four cycle treatment predicted a better 5-year PFS (FigureE5-E6). After four cycle treatment, slightly elevated estradiol (48-79pg/ml) may be at risk for later recurrence and significant elevated estradiol tended to progress early (Figure E5). In women, low LH was frequently observed. Two patients with persistent low LH died within 1 year of diagnosis. Persistent low LH level in female patients may be an important predictor for poor prognosis.Conclusion:Bortezomib-based BCD regimen in newly diagnosed POEMS syndrome patients seems improve the response rate and survival, especially in patients with sequential ASCT. Recovery of gonadal hormone level might be a potential marker for response and prognosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic Relevance of Cytogenetic Chromosomal Abnormalities on Outcome Among AL Amyloidosis Patients in the Netherlands

Introduction Systemic light chain (AL) amyloidosis is a clonal plasma cell neoplasm, that carries a poor prognosis. Treatment is adapted from protocols as used in MM, and include bortezomib-based (PI) regimens with or without stem cell transplantation (SCT). PI-based regimens have improved treatment responses and outcomes. Cytogenetic analysis has become an important tool in the diagnostic process of plasma cell disorders, and evidence for prognostic significance of specific genetic abnormalities in relation to therapy efficacy is recognized in systemic AL amyloidosis. Thus far, this prognostic significance has been evaluated in single center institutions.Aim This nationwide, population-based study aimed to assess the impact of cytogenetic abnormalities on hematological response and survival among patients with systemic AL amyloidosis treated with PI-based regimens.Methods We identified 349 patients ≥18 years with systemic AL amyloidosis diagnosed between 2017 and 2019 in the Netherlands Cancer Registry, with survival follow-up until February 1, 2021. Data on therapeutic strategy was known for all individual patients. The cytogenetic aberrations studied include gain(1q), hyperdiploidy, del(17p), and IGH rearrangements, i.e. t(11;14), t(4;14), t(14;16), and t(v;14q32) (non-specified IGH rearrangement). Hematological response and overall survival (OS) were evaluated in relation to cytogenetic aberrations. OS was defined as death by any cause post-diagnosis. Uni- and multivariable analysis for establishing independent predictors of OS, i.e. age, sex, cytogenetic assessment and SCT, was performed using Cox regression. Patients diagnosed at autopsy (n=4), patients who did not start first-line therapy (n=64) or received other therapies (n=37), and patients with systemic AL amyloidosis related to Waldenström Macroglobulinemia (n=10) were excluded.Results In our analytic cohort, 234 patients (median age 67 years; 62% males) were treated with PI-based regimens. Of these patients, 153 (65%) were ≤70 years at diagnosis. SCT was performed in 70 (30%) patients following PI-based regimens. For 170 (73%) patients, cytogenetic assessment was performed. IGH rearrangements were observed in 76 patients (45%), comprised of t(11;14) in 27 patients, t(4;14) in 3 patients, t(14;16) in 2 patients and non-specified IGH rearrangements in 44 patients. Furthermore, 26 patients carried a gain(1q), 4 patients a del(17p), and 33 patients were hyperdiploid. Due to the limited patient number with del(17p), response and OS was not evaluated for this subgroup.A complete remission (CR; n=53), very good partial response (VGPR; n=66), or partial remission (PR; n=55) was accomplished for 74% of the patients, ≥VGPR for 51% of the patients. The reached hematological response was irrespective of the detected cytogenetic abnormalities. In detail, ≥VGPR was 56% for patients with a t(11;14), 62% for patients with a gain(1q), 55% for patients with hyperdiploidy, and 50% for patients with an IGH rearrangement and this was not statistical significant different from patients without these cytogenetic abnormalities.The 3-year OS was 61% for patients treated with PI-based regimens. For patients with a cytogenetic assessment (n=170), there was no significant difference in 3-year OS between patients with or without a t(11;14) (69% vs. 66%, respectively; p=0.70), with or without gain(1q) (57% vs. 68%, respectively; p=0.58), with or without hyperdiploidy (72% vs. 65%, respectively; p=0.63), or with or without an IGH rearrangement (59% vs. 72%; p=0.21). Only SCT was an independent predictor for reduced risk of mortality in uni- and multivariable analyses, overall as well as for the specific cytogenetic subgroups.Conclusion In this Dutch ‘real world’ population of AL amyloidosis patients treated with PI-based regimens, 74% had a ≥PR and 51% had ≥VGPR. The 3-year OS was 61%. We evaluated the cytogenetic data of 170 patients, but could not confirm a relation between PI-based regimens and outcome, overall as well as in specific cytogenetic subgroups. Patient numbers of the cytogenetic subgroups were low and we could not determine the partner gene in 44 patients with an IGH rearrangement. To the best of our knowledge, this is the first population-based study to evaluate the prognostic relevance of cytogenetic abnormalities in relation to hematological response and OS among systemic AL amyloidosis patients. DisclosuresMinnema: Alnylam: Consultancy; Kite/Gilead: Consultancy; Jansen-Cilag: Consultancy; BMS: Honoraria; Celgene: Other: Hospitality.

Systemic Light Chain Amyloidosis across Europe: Key Outcomes from a Retrospective Study of 4500 Patients

Systemic Light Chain Amyloidosis across Europe: Key Outcomes from a Retrospective Study of 4500 Patients

Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic

Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic

Randomized Trial Comparing Pomalidomide, Bortezomib, and Dexamethasone (PVd) Versus Bortezomib and Dexamethasone（Vd） in NDMM with Renal Impairment（RI）

Background:RI is one of the most common complications of multiple myeloma (MM). The incidence of RI at diagnosis ranges from 20% to 50%, Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI, and the addition of a third drug to Vd seems to be beneficial，but not for sure. Pomalidomide is extensively metabolized by liver, with only approximately 2% of active substance eliminated in the urine, which suggests that RI may not affect pomalidomide exposure in a clinically relevant manner. The MM013(phase 2, NCT02045017) trial confirmed that Pomalidomide could be safely used in RRMM with RI and achieved good response in MM and Renal function. The OPTIMISMM (phase 3, NCT01734928) trial Subgroup analysis reported efficacy and safety of PVd vs Vd at first relapse by renal function (creatinine clearance [CrCl] < 60 vs ≥ 60 mL/min) before. The ORR significantly improved with PVd vs Vd regardless of renal status (P < .001 for both renal groups): 91.4% vs 53.6% (≥ VGPR,54.3% vs 21.4%) in the CrCl < 60 mL/min group and 89.5% vs 55.2% (≥ VGPR, 64.5% vs 23.0%) in the CrCl ≥ 60 mL/min group. Since RVd is the standard treatment for NDMM patients, We believe that standard dose Pomalidomide plus Vd will be very promising for NDMM patients with RIStudy Design/ Methods:This is a multicenter, prospective, randomized phase 2 study designed to evaluate the efficacy and safety of PVd Versus Vd in Patients With NDMM and Renal Impairment（RI）.Eligible patients were aged ≥18 years and had a diagnosis of multiple myeloma, measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were required to have had no prior antimyeloma regimen. The definition of RI is based on reduced creatinine clearance (15 mL/min≤CrCl＜60 mL/min) without indication for hemodialysis, which have to be the result of myeloma. Key exclusion criteria included previous course of chemotherapy; uncontrolled malignant disorder, infection, or peripheral neuropathy, patients on dialysis will be excluded too.Approximately 79 patients will be randomized 2:1(Figure 1) to Arm A (PVd) or Arm B (Vd), both Arms will have induction therapy for 4 cycles. In Arm A, patients will receive pomalidomide 4 mg on days 1-14 of each cycle. Bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11 of each cycle. Dexamethasone 20mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle (21-day cycles); In Arm B, patients will receive the same bortezomib and dexamethasone as Arm A.The primary endpoint is ≥VGPR, the secondary endpoints are MRD(-) rate,renal response,Immune function,Renal tubular function, and safety. Myeloma response and renal response will be assessed by the International Myeloma Working Group criteria after each cycle. Eficacy analyses will be performed on the intent-to-treat population; Safety analysis will be conducted in the safety population, which are composed of all patients who received ≥1 dose of study medication. The trial is currently enrolling and will be open in 8 sites in China.Disclosure：Research Sponsor : CHIATAI TIANQING PHARMACEUTICAL GROUP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Pomalidomide which was approved in RRMM will be used in NDMM with RI

The infection rate in new diagnosis and relapsed/refractory multiple myeloma patients who had bortezomib-based chemotherapy and relationship between development of infection and lymphocyte/monocyte ratio

Objectives: Multiple Myeloma (MM) is a disease caused by the clonal proliferation of plasma cells. In recent years, proteozom inhibitors, immunomodulatory agents and monoclonal antibodies have been used in the treatment of MM. In this study, the relation of bortezomib, one of the proteozoma inhibitors used in the treatment of MM, with the development of infection was investigated. Methods: We retrospectively evaluated 56 patients who had MM treated with bortezomib-based regimen. We tried to determine the relationship between infection with immunoglobulin G levels at the time of diagnosis, lymphocyte absolute values at the time of diagnosis, lymphocyte absolute values at the time of chemotherapy, neutrophil absolute value at the time of chemotherapy, lymphocyte absolute values at the time of infection, monocyte absolute value at the time of infection, and the lymphocyte/monocyte (L/M) ratio at the time of infection. The effects of L/M ratio on progression free survival (PFS) and overall survival (OS) were also examined. Results: Thirty (53.6%) of the 56 patients were newly diagnosed, 26 (46.4%) of 56 patients were relapsed/refractory MM. The bortezomib-based regimen was given to all patients. Of the 56 patients included in the study, 21 (37.5%) were female, 35 were male (62.5%). The ages of the patients was 28-79 years (median: 58.5 years). No infection attack was observed in 31 (55.4%) patients. Disease stage (R-ISS) (p = 0.032), presence or absence of co-morbid disease (p = 0.035), disease status during an infection attack (p &amp;lt; 0.01), lymphocytopenia at the time of chemotherapy (p = 0.003), absolute value of lymphocytopenia at the time of infection attack (p &amp;lt; 0.01) and L/M ratio (p &amp;lt; 0.01) had a significant relation with development of infection. Lymphocytopenia at the time of infection attack (p &amp;lt; 0.01, OR&amp;lt;1, 94.6% CI) and L/M ratio (p &amp;lt; 0.01, OR&amp;lt;1, 91.1% CI) had been found significant in univariate logistic regression analysis. Lymphocytopenia at the time of infection attack (p = 0.002, OR&amp;lt;1, 95% CI) and L/M ratio (p = 0.003, OR&amp;lt;1, 95% CI) had been found significant in multivariate logistic regression analysis. L/M ratio had a significant effect on OS (p &amp;lt; 0.017) but not on PFS (p &amp;gt; 0.05). Conclusions: It was determined that L/M ratio has an effect on OS and it is also an independent factor on the development of infection. OS was decreasing and the risk of developing infection was increasing, when the L/M ratio was low.

Prognostic Value of Resistance Proteins in Plasma Cells from Multiple Myeloma Patients Treated with Bortezomib-Based Regimens

While multiple myeloma (MM) treatment with proteasome inhibitors and other agents yields encouraging results, primary and secondary resistance remains an emerging problem. An important factor in such treatment resistance is the overexpression of several proteins. The present study comprehensively evaluates the expression of POMP, PSMB5, NRF2, XBP1, cMAF and MAFb proteins in plasma cells isolated from the bone marrow of 39 MM patients treated with bortezomib-based regimens using an enzyme-linked immunosorbent assay (ELISA). The proteins were selected on the basis of previous laboratory and clinical studies in bortezomib-treated MM patients. It was found that the expression of the investigated proteins did not significantly differ between bortezomib-sensitive and bortezomib-refractory patients. However, the expression of some proteins correlated with overall survival (OS); this was significantly shorter in patients with higher POMP expression (HR 2.8, 95% CI: 1.1–7.0, p = 0.0277) and longer in those with higher MAFB expression (HR 0.32, 95% CI: 0.13–0.80, p = 0.0147). Our results indicate that a high expression of POMP and MAFB in MM plasma cells may serve as predictors of OS in MM patients treated with bortezomib-based regimens. However, further studies are needed to determine the role of these factors in effective strategies for improving anti-myeloma therapy.

P-021: Experience with autologous stem-cell transplant (auto-SCT) in patients with systemic light-chain amyloidosis (LA) at our center

<h3>Background</h3> Auto-SCT is the standard first-line treatment in patients with LA and good personal status. This procedure achieves haematological responses >70% with an average survival rate of more than 8 years. Depending on patient characteristics and hospital guidelines, prior chemotherapy (CT) is administered, usually with Bortezomib-based regimens. The main determinant of survival in LA is cardiac involvement. The subgroup of patients with cardiac involvement and an indication for Auto-SCT is at the highest risk of complications and mortality and should therefore be strictly selected. <h3>Objective</h3> Our objective is to review the experience in our center with Auto-SCT in patients with LA. <h3>Methods</h3> A retrospective descriptive study was conducted at the Son Espases University Hospital between November 2012 and June 2021. Pre- and post-SCT clinical-biological data, complications during transplantation and progression-free survival (PFS) were analyzed. <h3>Results</h3> Eleven patients with a median age of 59 years at the time of Auto-SCT (range 41-69) were included, of whom 7 were male (64%). Ten patients (90.9%) had renal involvement at diagnosis and 6 (54.5%) had cardiac involvement. According to the Mayo Clinic 2013 prognostic staging score, 6 patients (54.5%) had stage I, 3 patients (27.3%) had stage II and 2 patients (18.2%) had stage IIIb (18.2%). All patients received pre Auto-SCT CT with bortezomib-based regimens. The median pre Auto-SCT left ventricular ejection fraction was 58% (41-79 range). Pre Auto-SCT organ-based chemotherapy response was: 8/10 patients (80%) with renal response; 1/6 patients (16.7%) with cardiac response. Pre Auto-SCT haematological response was: 7 patients (63.6%) complete remission, 1 patient (9%) very good partial response, 1 patient (9%) partial response, 1 patient (9%) stable disease and 1 patient (9%) not assessable. The median number of CD34+ cells infused into Auto-SCT was 3.66×10⁶/kg. 10 patients (90.9%) received G-CSF from day +5. 10 patients (90.9%) developed complications during transplantation, 7 of them requiring admission to the Intensive Care Unit (ICU) with a median of 15 days of admission (range 1-24 days), mainly due to acute pulmonary edema - APE (85.7%). 3/7 patients requiring ICU admission passed away, leaving the Auto-SCT-related mortality rate at 27.3%. With a median follow-up of 36 months (range 5-90), a median PFS and an overall survival rate (OS) of 73% (95%CI 46-99) is observed. PFS and OS match because there are no progression events. <h3>Conclusions</h3> Patients with cardiac involvement prior to Auto-SCT have a high risk of morbidity and mortality, with APE being the main complication in our study. Multidisciplinary management of these patients during Auto-SCT is essential to avoid complications.

P-174: Clinical study of bortezomib-based regimens of BCD, PAD and VDD for newly diagnosed multiple myeloma – an analysis of 400 cases in a single center of China

<h3>Background</h3> Objective To investigate the clinical efficacy and safety of bortezomib-based regimens of BCD (bortezomib, cyclophosphamide and dexamethasone), PAD (bortezomib, doxorubicin and dexamethasone) and VDD (bortezomib, pegylated liposomal doxorubicin and dexamethasone). <h3>Methods</h3> 400 newly diagnosed multiple myeloma (MM) patients enrolled in two prospective non-randomized cohort studies in a single center were retrospectively analyzed from April 2008 to August 2017. <h3>Results</h3> Among all the patients, 194 cases (48.5%) received BCD, 84 cases (21.0%) received PAD, and 122 cases (30.5%) received VDD. 1) Analysis of clinical features: Serum albumin (ALB) level was lower in the BCD group than the other two (P<0.001), and the proportion of patients in the International Stage System (ISS) stage III was higher in the BCD and VDD groups than the PAD group (P=0.002). Patients younger than 65 years were much more in the PAD group than the other two. Correspondingly, the proportion of patients receiving autologous hematopoietic stem cell transplantation (ASCT) was significantly higher in the PAD group. 2) The overall response rates (ORR) of the patients in BCD, PAD and VDD groups were 87.5%, 83.6% and 83.0% respectively, and there was no significant difference between the three groups. More patients attained complete response (CR) in the VDD group than the other two (P=0.049).The rate of minimal residual disease (MRD) negativity was slightly higher (60%) in PAD group which may be related to the higher ASCT proportion in this group, but the difference was not statistically significant (P=0.272). 3) Whether combined with alkylating agents (BCD) or combined with anthracyclines (PAD and VDD), there was no significant difference of the median progression-free survival (PFS) and the median overall survival (OS). Also there was no significant difference in PFS and OS between BCD, PAD and VDD groups. 4) In the safety aspect, there was no significant difference in non-hematologic toxicities such as peripheral neuropathies, cardiac events, gastrointestinal reactions, thrombus and bleeding events between the three groups. The incidence of hand-foot syndrome in VDD group was 5.8%, all of which were grade 1/2. In terms of hematologic toxicity, the incidence of grade 3/4 neutropenia and thrombocytopenia was significantly higher in the PAD group than the other two groups. There was no significant difference between the BCD and VDD group. <h3>Conclusion</h3> As the bortezomib-based three-drug regimens combined with traditional chemotherapeutic agents, BCD, PAD and VDD can all achieve remission in more than 80% newly diagnosed MM patients as induction therapy. The efficacy and long-term outcomes are comparable between the three regimens. In the aspects of safety, the BCD and VDD groups had a lower risk of grade 3/4 hematological toxicity.

Assessment of Minimal Residual Disease in Multiple Myeloma patients undergoing Autologous Stem Cell Transplant using Multiparameter Flow Cytometry

Abstract BACKGROUND Multiple Myeloma (MM) is still considered an incurable relapsing disease, despite major advances in multidrug combinations, incorporation of autologous transplant and achieving higher rates of CR. This suggests persistent presence of residual disease, not detected by current techniques. Minimal residual disease (MRD) monitoring by multiparameter flow cytometry (MFC) is a powerful tool to quantitatively measure residual disease and allow tailoring of the management plan on individual basis. AIM To assess the value of MRD by MFC in determining the efficacy of treatment, monitoring depth of remission and predicting impending relapse. PATIENTS AND METHODS We included 33MM patients, who were candidates for ASCT in this prospective study. MFC (with a 0.01% limit of detection) on a BM aspirate obtained before transplant and at day 100 post-transplant, was used to measure MRD for all patients. Patients were then later assessed for progression 1-year post-transplant. RESULTS MRD status at 100 days post-transplant was strongly related to the risk of 1-year post-transplant progression (p-value 0.001), and by using a ROC curve, we found that MRD (%) at 100 days post-transplant can predict progression after 1 year with a best cutoff value ≥ 0.04 achieving a 75% sensitivity and 81.2% specificity. On dividing the patients according to their MRD status before and after transplant, group 3 who were MRD positive pre- and post-transplant, had a high risk of progression 1year post-transplant (p-value 0.003). The use of bortezomib-based regimens resulted in a deeper response and a more negative MRD pre-transplant (p-value 0.01), that was maintained post-transplant. Also, ASCT resulted in the development of deeper remission (p-value 0.004) and more MRD negativity (p-value 0.02). CONCLUSION we recommend the use of MRD by MFC as a powerful prognostic tool that should be incorporated in routine myeloma workup.

MM-301: Plasma Cell Leukemia, PCL

Context PCL is a rare entity and a very aggressive disease. The diagnosis is based on the presence of more than 20% of PCL in peripheral blood or an absolute plasma cell count of more than 20×109. It is classified as primary PCL when it occurs in a patient with no previous history of MM and as a secondary PCL when it is observed as the leukemic transformation of relapsed or refractory recognized MM. Objective Diagnostic challenges and treatment of PCL. Case Report A 34-year-old female was accepted in clinic in 2019. She has spleen: 161 mm; liver: 148 mm. High levels of beta-2M and LDH. More than 30% of plasma cells in peripheral blood. Severe anemia, leukocytosis, and thrombocytopenia. Flow cytometry showed clonality for plasma cells. Results We treated our patient with VTD-PACE regimen (a combination of bortezomib 1 mg/m2, s.c, D1, D5, D8, and D11; dexamethasone 40 mg D1–D4 i.v.; thalidomide 200 mg/d, D7–D28, p.o.; cisplatin 10 mg/m2 D1–D4, i.v.; adriamycin 10 mg/m2 D1–D4,i.v.; cyclophosphamide 400 mg/m2 D1–D4, and etoposide 40 mg/m2 D1–D4, i.v.). We recommended HSCT, and she went abroad because this procedure cannot be performed in our country yet. Conclusions PCL is a rare entity, very aggressive, with a poor prognosis. Early diagnosis and early treatment are very important prognostic factors. Treatment with immunomodulatory drugs such as bortezomib-based regimens, followed by stem cell transplant, is recommended. References Harousseau JL, Atal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in phase II clinical trial. Leukemia. 2009;23:1337-1341. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma; changes in early mortality and outcomes in older patients. Leukemia. 2013;28(5):1122-1128.

MM-066: Primary Plasma Cell Leukemia: A Rare Entity with Four Cases

Context Primary plasma cell leukemia (PPCL) is a rare hematological malignancy with an incomprehensible pathogenesis and a very aggressive course. Objectives Determining the risk factors that can cause the development of PPCL and affect its course was aimed. Design Four PPCL patients diagnosed at Gulhane Training and Research Hospital between March 2019 and June 2020 were evaluated in terms of laboratory and clinical course retrospectively. Patients or Other Participants The mean age of the patients at the time of diagnosis was 66 years (44–76), and males/females:1/1. None of the patients had a history of multiple myeloma (MM). Results Two patients presented with leukocytosis. Mean WBC was 59.625x103/mL (3800–197,000), average plasma cell in smear was 54.5% (20–100), mean plasma cell was 55,500x103/mL (600–188,000). Leukapheresis was applied to one patient. Anemia was detected in all, mean Hb was 9.9 g/dL. Thrombocytopenia was detected in 3 patients and mean platelet was 101x103m/L. Immunofixation results were IgG lambda in two, free lambda in one, and free kappa in 1 patient. Genetic results could not be reached. One patient was lost to follow-up and 3 patients were given bortezomib-cyclophosphamide-dexamethasone (VCD) in first-line treatment. Two patients died during follow-up, and mean survival was 77 days. One patient who was given 1 cycle VCD and 1 cycle lenalidomide-dexamethasone was lost to follow-up. ASCT could not be planned due to the short life span of the patients. Conclusion Incidence of PPCL is 0.4–1.2/million, progression from MM is seen in 0.5% cases. There is no difference between MM and PPHL in terms of CD38 and CD138 positivity, but CD56 is more frequently positive in MM and CD20 in PCL. CD27 positivity in PCL indicates increased anti-apoptotic activity. Discussion Approximately 150 multiple myeloma patients were followed up in our clinic between the same dates. Secondary PCL cases were not detected, and the fact that all of the diagnosed cases were PPCL created a picture incompatible with the incidence rates reported in the literature. Lambda monoclonality was shown in three of our patients, so it constitutes a feature for PPCL, unlike myeloma. Absence of genetic results is an important lack of our patients. More patients are needed for determination of risk factors in PPCL. It is necessary to identify poor prognostic indicators and urgently undergo transplantation in eligible patients using bortezomib-based treatment regimens.

The Clinical Characteristics and Prognosis of Chinese Patients with Light-Chain Amyloidosis: A Retrospective Multicenter Analysis

To retrospectively identify the critical characteristics and prognostic factors of light-chain amyloidosis. Patients and Methods: Data were collected and compared from 91 patients who were diagnosed with light-chain amyloidosis at four hospitals between January 2010 and November 2018. We analyzed the clinical characteristics and performed an overall survival (OS) analysis. Results: Patients (median age, 60 years) were diagnosed with organ involvement of the kidney (91.2%), heart (56%), liver (14.3%), soft tissue (18.7%), or gastrointestinal tract (15.4%), and 68.1% of patients had more than two organs involved. Patients were most treated with bortezomib-based regimens (56%), and only one patient had autologous stem cell transplantation (auto-ASCT). The median OS was 36.33 months and was influenced by the ECOG score, renal involvement, cardiac involvement, hepatic involvement, and persistence of positive immunofixation. Patients who received bortezomib-based treatment had a trend of favorable OS compared to those who received non-bortezomib-based treatments, but the difference was not statistically significant. Although the overall number of organs involved was not related to OS, the number of organs involved in the heart, liver and kidney was related. Multivariate analysis indicated that cardiac involvement and negative hematologic response with persistence of positive immunofixation were independent prognostic factors for OS. Conclusion: Cardiac involvement and the hematologic response to treatment were independent prognostic factors for OS in light-chain amyloidosis patients.

Bortezomib‐based therapy for newly diagnosed multiple myeloma patients ineligible for autologous stem cell transplantation: Czech Registry Data

This study compared the use of bortezomib in different combination regimens in newly diagnosed multiple myeloma (NDMM) patients who were transplant ineligible. We analyzed data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group (CMG) to provide real-world evidence of outcome for 794 newly diagnosed MM transplant ineligible patients. The most frequently used regimen was VCd (bortezomib-cyclophosphamide-dexamethasone) (47.5%) over VMP (bortezomib-melphalan-prednisone) (21.7%), BDd (bortezomib-doxorubicin-dexamethasone) (9.8%), and VTd (bortezomib-thalidomide-dexamethasone) (2.9%). The overall response rate (ORR) was 69.2% (478/691), including 12.6% (≥ CR); 34.7% very good partial responses (VGPR); and 21.9% partial responses (PR). Among triplet regimens, VMP was the most effective regimen compared to VCd, BDd, and VTd. Median PFS was 22.3 vs. 18.5 vs. 13.7 vs. 13.8 mo, (P=.275), respectively, and median OS was 49 vs. 41.7 vs. 37.9 vs. 32.2mo (P=.004), respectively. The most common grade 3-4 toxicities were anemia in 17.4% and infections in 18% of patients. Our study confirmed that bortezomib-based treatment is effective and safe in NDMM transplant ineligible patients, especially VMP, which was identified as superior between bortezomib-based induction regimens not only in clinical trials, but also in real clinical practice.

Multiple Extramedullary-Bone Related and/or Extramedullary Extraosseous Are Independent Poor Prognostic Factors in Patients With Newly Diagnosed Multiple Myeloma.

BackgroundExtramedullary (EM) lesions are common in multiple myeloma (MM) and are often related to the poor prognosis of MM but are scarcely understood.MethodsIn this retrospective study, the baseline characteristics of 357 newly diagnosed patients with extramedullary multiple myeloma (EMM) and their impact on the prognosis were analyzed. All patients received first-line treatment with bortezomib-based regimen.ResultsThe overall incidence rate of EM was 22.4%, and the detection rate of PET/CT was significantly higher than other imaging methods (P = 0.015). The cohorts consisted of 10 cases of extramedullary extraosseous (EME) and 70 cases of extramedullary-bone related (EMB), including 53 cases with single site involvement (one case with EME) and 27 cases with multiple sites (>1 site) involvement (nine cases with EME). EMM patients had high levels of hemoglobin (Hgb, ≥10 g/dl) and serum lactate dehydrogenase (LDH, >245u/L) and are inclined to early-stage revised international staging system (R-ISS). Compared to patients without EM, those with EMM had worse progression-free survival (PFS) (P = 0.014) and overall survival (OS) (P = 0.032). In addition, patients without EM and those with a single site of EMB had similar PFS and OS, while patients with multiple sites of EMB or EME and multiple sites of EMB with EME had poor PFS and OS. Multivariate analysis confirmed that multiple sites of EMB and/or EME were independent prognostic predictors affecting PFS and OS in newly diagnosed MM patients.ConclusionsThis study suggested that among patients treated with bortezomib-based regimens, multiple sites of EMB and/or EME are independent poor prognostic factors for newly diagnosed MM patients, while a single site of EMB does not affect the survival of newly diagnosed MM patients. Thus, these findings could be used as a reference for the study of EMM patients in the new drug era, but prospective clinical studies are needed to provide evidence-based data for the diagnosis and treatment of EMM.

Efficacy of Bortezomib-Based Regimens for Patients with Newly Diagnosed AL Amyloidosis Not Receiving ASCT Compared with Alkylators and Dexamethasone-Based Regimens

BackgroundFor patients not receiving autologous stem cell transplantation (ASCT), bortezomib-based regimens such as CyBorD (bortezomib with cyclophosphamide and dexamethasone), BMDex (bortezomib with melphalan and dexamethasone), VD have been first-line treatment in AL amyloidosis over the last few years. Changing trends in first-line treatment (MDex to bortezomib-based regimens) significantly improved responses over time. However, several studies showed early death (<6 months) rate have been unchanged or rather higher in bortezomib-based group. The purpose of this study is to investigate the efficacy of bortezomib-based regimens for patients with newly diagnosed AL amyloidosisPatients and methodsA total 115 patients with newly diagnosed AL amyloidosis who did not receive ASCT were analyzed. They were registered from two cohorts; retrospective cohort (April 1995 - November 2011, n=27) and prospective cohort (March 2012 - February 2017, n=88). Patients were classified into two groups according to first-line treatment; bortezomib-based regimens (VMP, n=39; Bortezomib and dexamethasone, n=12; CyBorD, n=8; BMDex, n=2; Bortezomib with thalidomide and dexamethasone, n=1) and alkylator and dexamethasone-based regimens (MDex, n=35; Cyclophosphamide and dexamethasone, n=18). The primary endpoint was early death rate and secondary endpoints were overall response rate, overall survival, and progression free survival.ResultsAt baseline characteristics, bortezomib-based group showed significantly higher risk of cardiac involvement and more advanced stage. Although bortezomib-based group was in higher risk, there were no significant differences in early death rate (22.5% vs 18.8%, p=0.790). The rate of ≥ VGPR (very good partial response) and overall response rate were significantly higher in bortezomib-based group (50% vs 22.3% and 63.2% vs 28.9%, respectively). However overall survival and progression free survival represented no significant differences by two groups (p=0.916 and p=0.798).ConclusionIn this retrospective analysis bortezomib-based regimens in newly diagnosed AL amyloidosis showed higher efficacy and similar early death rate and survival in spite of higher cardiac risks in comparison with alkylating agents with dexamethasone. [Display omitted] DisclosuresKim:J&J: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Celltrion, Inc: Consultancy, Honoraria; Roche: Research Funding; Takeda: Research Funding; Donga: Research Funding.

Tourmaline US-MM6, an Open-Label, Single-Arm, Multicenter Study Evaluating the Effectiveness and Safety of Ixazomib in Combination with Lenalidomide and Dexamethasone (IRd) in Patients (pts) with Newly Diagnosed Multiple Myeloma (NDMM) Switching from a Bortezomib-Based Triplet Induction Regimen

Tourmaline US-MM6, an Open-Label, Single-Arm, Multicenter Study Evaluating the Effectiveness and Safety of Ixazomib in Combination with Lenalidomide and Dexamethasone (IRd) in Patients (pts) with Newly Diagnosed Multiple Myeloma (NDMM) Switching from a Bortezomib-Based Triplet Induction Regimen

Bortezomib-Based Induction Regimen Followed By Autologous Stem Cell Transplantation (ASCT) after Conditioning with MEL200 Is Highly Effective and Well Tolerated in Elderly Multiple Myeloma (MM) Patients up to the Age of 75 Years

Introduction: The age limit of 65 for performing Autologous stem cell transplantation (ASCT) in elderly patients with Multiple Myeloma (MM) is currently debated, since efficacy and safety have been recently improved but no conclusive data are still available. Over the last years the policy of our Center was to treat fit patients up to the age of 75 with the same program adopted for younger patients, i.e. bortezomib-based induction followed by ASCT. Herein we report the outcome of the series of consecutive patients aged >65 undergoing first-line ASCT at our center together with an analysis of potential prognostic parameters.Patients and Methods: From January 2009 to December 2016 86 of 270 (31,8%) newly diagnosed symptomatic MM patients aged 65-75 years (M/F: 46/40 , median age 68, 35% aged ≥ 70) received bortezomib-based induction (VTD 91%, VD 7%, VCD 2%) followed by ASCT as first-line treatment. Standard conditioning was melphalan 200 mg/sqm (MEL200) and patients not achieving CR after ASCT were to receive a second ASCT 3-6 months after the first if grade IV non hematological toxicities were not observed with first transplant. According to physician judgement based on age, comorbidities and fitness, MEL dose could be reduced to 140 or to 100mg/sqm. Overall 38% of patients received a single and 62% a double transplant and MEL200 was given to 63%, MEL140 to 9% and MEL100 to 28% of patients, respectively. ECOG PS at diagnosis was ≥2 in 21% of patients. The impact of age, ECOG PS and MEL dosage on progression-free (PFS) and overall survival (OS) was analyzed. Results: Complete remission (CR) after the first ASCT was 34% and very good partial response (VGPR) was 39%. Rate of grade 4 non-hematologic toxicity was 16% (5% mucositis, 10% infections; one Idiopathic Pneumonia Syndrome 60 days after ASCT was also observed). Median hospital stay was similar between patients aged 65-69 years and ≥ 70 years (18 vs 18 days). Transplant related mortality (TRM) was 0%; death rate was 13% and was due to progressive disease in 91% of cases (the latter 9% concerns a cardiac arrest secondary to aspiration pneumonia in a patient in VGPR 3 months after first ASCT). After a median follow-up of 2.5 years, 2-year PFS was 75% and OS 91%. No significant survival difference was seen between patients aged 65-69 and ≥ 70 years (2-year PFS 75% vs 70% and OS 92% vs 91%, respectively). PS 0-1 vs ≥ 2 at diagnosis significantly impacted on OS (2-year PFS 74% vs 60%, p=0.65; OS 97% vs 69%, p 0.01, respectively). A significantly better outcome was seen in patients receiving MEL200 conditioning, compared to lower MEL doses (2-year PFS 86% vs 57%, p 0.036; 2-year OS 100% vs 82%, p 0.005; Figure 1). In the subgroup of 51 patients receiving VTD and MEL200 median OS was not reached. Of note, 44% of patients in the PS ≥ 2 subgroup received MEL200, suggesting that impaired long term survival is only partially influenced by a less intensive treatment. Conclusion: According to our single center experience a significant proportion of newly diagnosed MM patients aged up to 75 years can successfully receive a bortezomib-based (VTD) induction regimen followed by ASCT. Efficacy is highest with MEL200 as conditioning before ASCT and survival Is better in patients with PS <2. Objective methods are warranted to assess transplant eligibility and the optimal dosage of the conditioning regimen in the single patient in order to optimize the use and the efficacy of ASCT in elderly MM.Figure 1: outcome according to MEL dosage [Display omitted] DisclosuresRossi:Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.