Frontline Therapy For Multiple Myeloma Research Articles

The MODIFY Study Protocol: An Open-Label, Single-Arm, Multicenter, Prospective Pragmatic Study of Ixazomib-Based Triple-Drug Therapy in Chinese Patients with Multiple Myeloma.

Although the bortezomib-based triple-drug therapy is considered as a front-line therapy for multiple myeloma (MM) in Chinese patients, increased level of toxicity leads to treatment dissatisfaction. Treatment with ixazomib, an oral proteasome inhibitor, has demonstrated better efficacy and safety profile without increasing the toxicity. In this study, we investigate the safety and clinical outcomes of Chinese patients with newly diagnosed MM (NDMM) who transitioned from a bortezomib-based triple-drug therapy to an ixazomib-based triple-drug therapy in a real-world clinical setting. This will be an open-label, single-arm, multicenter, prospective, observational study will recruit Chinese patients (aged ≥ 18years) diagnosed with NDMM using International Myeloma Working Group (IMWG) criteria and who have received a bortezomib-based triple-drug therapy for more than two cycles as initial therapy. The previous bortezomib-based triple-drug therapy may include bortezomib, cyclophosphamide, and dexamethasone or lenalidomide, bortezomib, and dexamethasone or bortezomib, doxorubicin, and dexamethasone or bortezomib, thalidomide, and dexamethasone. At the time of enrollment, patients must have achieved at least partial response as defined by IMWG criteria. Approximately 320 eligible patients at 15 top MM hospitals in China will be treated with ixazomib triple-drug therapy and followed up once every 3months for 24months, unless specified. The primary endpoint is to assess progression-free survival at 2years for Chinese patients with NDMM who have transitioned from a bortezomib-based triple-drug therapy to ixazomib-based triple-drug therapy. The clinical effectiveness, safety and tolerability, patient-reported outcomes, and health economic/resource utilization will be evaluated as secondary endpoints. The results from this study may provide evidence to verify the benefits of transitioning from bortezomib-based triple-drug therapy to ixazomib-based triple-drug therapy in Chinese patients with NDMM in a real-world clinical setting. The study has been registered at clinicalTrials.gov (NCT05013190).

A Multiomic Approach to Reversing Therapy Resistance in Multiple Myeloma Using Paired Ex Vivo Drug Sensitivity Measures and RNA Sequencing Data

A key challenge in multiple myeloma (MM) is evolution of resistance to standard-of-care (SOC) therapies such as proteasome inhibitors (PI), monoclonal antibodies, and novel targeted therapies. We developed a computational framework that identifies gene programs associated with SOC therapy resistance by pairing patient RNAseq data with clinical response and ex vivo drug response to find patient-specific targets to overcome therapy resistance. We hypothesize that there are two types of mechanisms of resistance in MM; dynamic (involving cell cycle) and cytostatic (cell-intrinsic, EMDR, complement, etc.). We inferred the dynamic mechanism of resistance by comparing transcriptomic profiles of therapy-naïve vs refractory MM patients, therapy-resistant vs wildtype cell lines, drug perturbation transcriptomics from LINCS-L1000 and activity-based proteomic profiling of MM cell lines. The cytostatic mechanism of resistance was inferred by associating RNAseq data with ex vivo drug response, where CD138+ cells from MM patient samples were co-cultured with human bone marrow stromal cells and patient plasma in an ex vivo reconstruction of the tumor microenvironment and tested with SOC drugs in 399 MM patient samples. The computational framework begins with the construction of a topological map of MM transcriptome using t-SNE and fuzzy c-means clustering on z-normalized expression of 16,738 genes across 844 MM patient samples, which yielded MM-specific gene programs (clusters of co-expressing genes). Using publicly available ChIP-seq databases like ENCODE and ChEA, we identified regulatory proteins (RPs) upstream of these gene programs. Kinases phosphorylating these RPs were identified from proteomic databases like PhosphoSitePlus and PhosphoPoint; generating a cascading GRN of MM gene programs, their RPs, and kinases, described by a biophysical model representing transcription, translation, and post-translational effects. The model estimates expression of each gene as a function of gene expression of its upstream RPs and kinases. The model for transcriptional regulation for each gene is trained using RNAseq data of 422 patients and validated against the rest of the cohort (422). Figure 1 is a graphical representation of gene-wise Pearson's correlation of model-predicted and actual gene expression represented by the color of each point (gene) on the tSNE. The set of genes that have poor correlation in Figure 1 (blue) statistically significantly (hypergeometric test; p-value <1e-48 and representation factor = 7.27) coincide with genes that are epigenetically regulated (identified by their high variability of chromatin accessibility across MM patients). We implement this computational framework to identify gene programs associated with a dynamic mechanism of PI (frontline therapy in MM) resistance, which yielded a GRN comprising of 218 co-expressing genes, 13 upstream RPs, and 45 kinases (17 druggable by kinase inhibitors). Network analysis of this GRN revealed that FOXM1 as a key therapeutic vulnerability (characterized by the highest betweenness centrality - a hub for flow of information) that can be targeted by inhibiting PLK1; a key regulator of cell cycle that phosphorylates FOXM1 that, in turn regulates PLK1 expression. A statistically significant (unpaired t-test) increase in z-normalized expression of PLK1 was observed in MM patients (n = 233) clinically refractory to CFZ (p-value < 0.0001) and BTZ (p-value = 0.0004) compared to PI-naïve. Ex vivo functional validation in a cohort of 61 MM patient samples shows a statistically significant (unpaired t-test) lowering of Volasertib (PLK1 inhibitor) AUC in MM patients that were clinically refractory to CFZ (p-value = 0.03) and BTZ (p-value = 0.02) compared to PI-naïve (Figure 2). Similarly, we infer cytostatic mechanism of resistance to PIs by pairing ex vivo drug response from 399 MM patients with RNAseq data to identify gene programs that are enriched for PI-resistance and PI-sensitivity using gene set enrichment analysis; which identified PRCK, ROCK, and PLK1 inhibitors as therapeutic targets that can either synergize with PIs or exhibit synthetic lethality. Ongoing studies are focused on identifying novel targets to overcome resistance to DARA. The proposed computational approach can identify novel therapeutic strategies to overcome SOC therapy resistance using patient-specific targeted therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

307 (PB087) - Targeting the exosome biogenesis pathway to overcome daratumumab resistance in hematological cancers

Background: Daratumumab is a monoclonal antibody that targets CD38, which is highly expressed in lymphoid tumour cells. Daratumumab-based combinations have been incorporated as frontline therapy for multiple myeloma, and is well tolerated in clinical trials for other blood cancers. However, responses are heterogeneous and development of treatment resistance inevitable. Therefore, elucidation and targeting of mechanisms which can overcome daratumumab resistance is essential for the optimization of therapeutic response in patients.

P968: ADDITION OF IXAZOMIB TO POMALIDOMIDE AND DEXAMETHASONE IMPROVES PROGRESSION-FREE SURVIVAL FOR MULTIPLE MYELOMA PATIENTS PROGRESSING ON LENALIDOMIDE AS PART OF 1ST LINE THERAPY: ALLIANCE A061202

Background: Lenalidomide (LEN) maintenance and continuous LEN-based induction therapy until disease progression have become standard of care for frontline therapy of multiple myeloma (MM). As such, an increasing number of patients (pts) in need of 2nd line therapy have LEN-refractory disease. Optimal treatment in this setting has not been rigorously assessed in randomized studies. The phase I portion of Alliance A061202 demonstrated the safety of the ixazomib-pomalidomide-dexamethasone (IXA-POM-DEX) combination for the treatment of pts with LEN and proteasome inhibitor (PI)-refractory MM. Aims: In the randomized phase II portion, we evaluated the addition of IXA to POM-DEX for PI naïve / sensitive pts progressing on LEN as part of 1st line therapy. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), depth of response, survival and safety. Methods: Pts were randomized 1:1 to IXA-POM-DEX or POM-DEX and stratified by prior bortezomib exposure, International Staging System stage (1 and 2 vs 3) and the presence of high-risk cytogenetics. POM was administered at 4 mg on days 1 – 21; IXA 4 mg on days 1, 8 and 15; and DEX 20 mg (>75 years (yrs)) or 40 mg (≤75 yrs) on days 1, 8, 15 and 22 of a 28-day cycle. Treatment was continued until disease progression, the emergence of unacceptable side effects or withdrawal of treatment consent. Results: 38 and 39 eligible pts were assigned to IXA-POM-DEX and POM-DEX, respectively. The median age was 66 yrs (range 41 – 83) and 64 yrs (range 52 – 85). A planned first interim analysis was conducted after 43 out of 57 required events had occurred. PFS favored the IXA-POM-DEX arm (one-sided log rank test value = 4.6345, p=0.03134 [< p-value boundary of 0.058]), yielding a hazard ratio of 0.528 (upper 90% bound = 0.777). A stratified log-rank test found that PFS was superior for the triplet after adjusting for stratification factors (one-sided stratified log rank test value = 5.8371; p=0.0157), adjusted hazard ratio 0.451 (upper 90% bound = 0.694). The ORR favored IXA-POM-DEX (63.2% vs 43.6%, p=0.0853), and the ≥very good partial response was 26.3% vs 5.1%, respectively (p=0.01). The clinical benefit rate (ORR + minimal response rate) was 73.7% and 56.4%. The most common grade 3/4 adverse events included lymphopenia, neutropenia, anemia, and fatigue in 40%, 37%, 16% and 16% of IXA-POM-DEX-treated pts and 26%, 21%, 13%, and 15% of POM-DEX-treated pts. Therapy was discontinued for disease progression in 47.4% of pts on IXA-POM-DEX and 76.9% of pts on POM-DEX and for adverse events in 7.9% and 7.7% of pts, respectively. Summary/Conclusion: The addition of IXA to the POM-DEX backbone improved the depth of response and PFS for pts relapsing on LEN as part of 1st line therapy. Hematologic toxicity was increased with the addition of IXA, but side effects were manageable. The ease of administration of this all-oral combination allowed for safer, uninterrupted treatment during the COVID pandemic. Our results should be confirmed in phase III trials but lend support for this regimen as part of 2nd line therapy for this patient population.

Carfilzomib-Based Combination Regimens Are Highly Effective Frontline Therapies for Multiple Myeloma and Waldenström's Macroglobulinemia

Introduction:Multiple myeloma (MM) and Waldenström's macroglobulinemia (WM) are related plasma cell disorders that respond to treatment with proteasome inhibitors. Several early phase studies have shown that carfilzomib (Cz) is highly effective as the initial treatment of MM and results in deep remissions in most patients. A randomized phase III study is evaluating the efficacy of Cz or bortezomib with lenalidomide and dexamethasone as frontline therapy in MM and could lead to changes in the treatment of choice (NCT01863550). A clinical trial also showed good tolerance and efficacy of Cz in the frontline treatment of WM. In this study we aim to report the efficacy and safety of frontline Cz-based combinations in MM and WM in a standard of care setting.Methods:In this retrospective, single center study, we queried our ambulatory and inpatient (IPATC) database to identify subjects who were diagnosed with MM or WM and received Cz as initial therapy from 4/1/2014 to 11/30/2016. Investigational Cz was excluded. We identified 54 patients with MM (including one with concurrent lambda AL amyloidosis) and 6 patients with WM. Responses were assessed based on guidelines published by the International Myeloma Working Group (Kumar et al. Lancet 2016) and the VI international workshop on WM (Owen et al. BJH 2013). The Kaplan-Meier method was used to estimate time-to-event endpoints including progression free survival (PFS). Statistical software SAS 9.3 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for all the analyses.Results:All MM patients were treated with either KRd (Cz, lenalidomide, dexamethasone) (n=52, 96%) or KCd (Cz, cyclophosphamide and dexamethasone) (n=2, 4%). Median age at diagnosis was 66 years (range 60-70 years). Revised International Staging System (R-ISS) stage I, II or III was present in 20 (37%), 28 (52%) and 6 (11%) patients, respectively. Patients presented with either CRAB criteria (n=48, 89%) or biomarkers of malignancy (n=4, 7%) and 22% had extramedullary disease. Gene expression profiling-70 (GEP-70, Quest Diagnostics) was available for 25 patients (Table 1a). Patients with both high-risk GEP and FISH had early relapse (Table 1b). The maximum doses of Cz used were 36 mg/m2 (n=44), 27 mg/m2 (n=6) and not available (n=4). After a median of 3 cycles, eligible patients underwent autologous stem cell transplant (ASCT) (n= 36, 77%). Fifty-two patients were evaluable for response. After a median of 3 cycles of initial treatment, overall response (ORR) was 98% [complete remission (CR; n=9, 17%), very good partial response (VGPR; n=27, 52%) and partial response (PR; n=15, 29%)]. After ASCT, responses deepened to CR (n=18, 50%), VGPR (n=9, 25%) and PR (n=4, 11%). Eleven patients did not undergo ASCT (comorbidities: 6, insurance issues: 1, patient preference: 3, progression: 1). The median number of cycles received in this group was 4 and best responses were CR (n=3, 30%), VGPR (n=2, 20%), PR (n=5, 50%) while 1 not evaluable. At a median follow up of 7.4 months, overall survival (OS) is 100% while median PFS has not been reached (Figure 1). Five patients discontinued therapy due to toxicity (one of each with pericarditis, shortness of breath, pulmonary toxicity, neuropathy, retroperitoneal bleeding) and 3 due to progressive disease. There were no reported cases of heart failure.Patients with WM, n=6, [MYD88 mutation positive (n=5, 83%), CXCR4 mutation positive (n=0)] were treated with Cz, rituximab and dexamethasone induction followed by maintenance as described by Treon et al. (Blood 2014). Median age was 57 years (range 52-74 years). Patients presented with B symptoms (n=6, 100%) and anemia (n=5, 83%). After a median of 6 cycles of therapy, ORR was 66% [CR: n=1 (17%), PR: n=3 (50%)] while 2 (33%) had minimal response. All patients had resolution of B symptoms and anemia after treatment. One patient (MYD88 positive, CXCR4 negative) relapsed 27 months after starting initial treatment. Only one patient had severe toxicity (debilitating neuropathy attributed to rituximab) prompting therapy discontinuation after 3 cycles (Alfaraj et al, Ann Hematol. 2016). At a median follow up of 33.5 months, OS is 100%. Mutational status did not seem to impact response to therapy.Conclusion:Cz based regimens are generally well tolerated and offer a neuropathy sparing approach with excellent responses in newly diagnosed MM and WM making them a good choice for frontline treatment of these diseases. [Display omitted] DisclosuresLee:Celgene: Consultancy; Eutropics Pharmaceuticals: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Pimera Inc: Consultancy; Daiichi Sankyo: Research Funding; Takeda: Consultancy. Orlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees. Manasanch:quest diagnostics: Research Funding; merck: Research Funding; celgene: Consultancy; takeda: Consultancy; sanofi: Research Funding; adaptive biotechnologies: Consultancy.

Incidence and Management of Therapeutic Monoclonal Antibody Interference in Monoclonal Gammopathy Monitoring.

The treatment of multiple myeloma (MM) has been revolutionized by the introduction of therapeutic monoclonal antibodies (tmAbs). Daratumumab, a human IgG1/κ tmAb against CD38 on plasma cells, has improved overall survival in refractory MM and was recently approved as a frontline therapy for MM. Work on tmAb interference with serum protein electrophoresis (SPE) during MM monitoring has failed to provide information for laboratories on incidence of interference and effective methods of managing the interference at a practicable level. We aimed to evaluate daratumumab and elotuzumab interference in a large academic hospital setting and implement immediate solutions. We identified and chart reviewed all cases of possible daratumumab interference by electrophoretic pattern (120 of 1317 total cases over 3 months). We retrospectively reviewed SPE cases in our laboratory to assess clinical implications of tmAb interference before the laboratory was aware of tmAb treatment. We supplemented samples with daratumumab and elotuzumab to determine the limits of detection and run free light chain analysis. Approximately 9% (120 of 1317) of tested cases have an SPE and/or immunofixation electrophoresis (IFE) pattern consistent with daratumumab, but only approximately 47% (56) of these cases were associated with daratumumab therapy. Presence of daratumumab led to physician misinterpretation of SPE/IFE results. Limits of daratumumab detection varied with total serum gammaglobulin concentrations, but serum free light chain analysis was unaffected. Clinical laboratories currently rely on interference identification by electrophoretic pattern, which may be insufficient and is inefficient. Critical tools in preventing misinterpretation efficiently include physician education, pharmacy notifications, separate order codes, and interpretive comments.

Inferior Survival with Use of Autologous Stem Cell Transplant As Second-Line Therapy in Multiple Myeloma

Background: Multiple myeloma (MM) remains incurable with eventual relapse and death occurring despite multiple lines of chemotherapy. Standard frontline therapy for MM has traditionally consisted of combinations of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and dexamethasone followed by consolidation with high-dose melphalan and autologous stem cell transplantation (ASCT). A randomized trial using IMiD and PI-based induction demonstrated significant progression-free survival (PFS) benefit with upfront ASCT in consolidation compared to ASCT in second-line at relapse, but no OS benefit (Attal et al, NEJM, 2017). Delay of ASCT to second-line or beyond may in part be due to the aforementioned lack of OS benefit shown with upfront ASCT and increase of sustained deep responses, including MRD negativity, to novel frontline 3 and 4-drug regimens and continuation of therapy in the frontline. We performed a chart review comparing PFS1, PFS2, and overall survival (OS) of patients who underwent upfront ASCT as consolidation to those who received ASCT in the second-line after one relapse ('delayed ASCT'). The study was approved by the Institutional Review Board at Weill Cornell Medical College. Methods: 124 MM patients who underwent ASCT either as consolidation in first-line or delayed ASCT after relapsing on one prior treatment between 2010-2016 were included. Demographics and clinical parameters were extracted from the electronic medical record. PFS1, PFS2, and OS were calculated from date of diagnosis to first relapse, second relapse, and death, respectively. Patients were censored if lost to follow-up prior to experiencing the relevant event. PFS1, PFS2, and OS of patients receiving upfront ASCT were compared to those of patients receiving delayed ASCT. Log-rank tests were used to statistically evaluate differences between Kaplan-Meier PFS/OS curves. Cox proportional hazards models were used to calculate hazard ratios (HR) using upfront ASCT as the reference treatment. Results: Among the 124 patients, 93 underwent upfront ASCT as consolidation and 31 underwent delayed ASCT after relapsing on one prior line of therapy (Table 1). Induction regimens and pre-transplant therapies received are detailed in Table 1. Of the delayed group patients, 6 underwent ASCT directly without second-line induction and 25 as consolidation after second-line therapy. Patients receiving upfront ASCT had significantly longer median PFS1 compared to patients who received delayed ASCT (6.45 vs 1.25 years; P&lt;0.001), with a HR of 0.18 (95% CI, 0.11-0.29) (Figure 1A). Median PFS2 in the upfront ASCT group was likewise significantly longer than in the delayed group (9.19 vs 3.69 years; P&lt;0.001), with a HR of 0.31 (95% CI, 0.18-0.55) (Figure 1B). With a median follow-up of 6.0 and 5.8 years in the upfront and delayed groups, respectively, median OS was not reached in either group but trended towards prolonged survival with upfront ASCT (P=0.052), with a HR of 0.46 (95% CI, 0.20 to 1.03) (Figure 1C). Conclusions: In this cohort of 124 MM patients undergoing ASCT as consolidation in the upfront setting or delayed ASCT in second-line after relapse, upfront ASCT was associated with significantly improved PFS1 and PFS2, similar to findings by Attal et al. However, in that study, no difference in OS was seen between upfront and delayed groups, while our data, with longer follow-up, showed median OS trending towards significance. This has important implications as with use of novel induction regimens and maintenance therapy, ASCT is more commonly being delayed to early relapse in second-line or beyond. If transplant is intended to be used in the first few lines of therapy, our data show that delaying ASCT even to second-line has a significant negative impact on PFS. In addition, a shorter OS with delayed transplant was suggested although did not reach statistical significance, possibly due to small numbers or more patients with high-risk MM in the delayed group. It is also important to note the lack of daratumumab-based regimens which may have improved PFS/OS in either or both arms. Thus, our findings should be prospectively validated in a larger trial of ASCT as consolidation in first-line vs second-line or beyond using novel, monoclonal antibody-based regimens. Disclosures Rosenbaum: Janssen: Research Funding; Honoraria Akcea: Other: Accordant Health. Coleman:Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau. Van Besien:Miltenyi Biotec: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.

Frontline therapy in multiple myeloma: fast start for a long game

Frontline therapy in multiple myeloma: fast start for a long game

Venous Thromboembolism with Contemporary Lenalidomide-Based Regimens and Adequate Thromboprophylaxis in Newly Diagnosed Multiple Myeloma: A Systemic Review and Meta-Analysis

Background: Lenalidomide (Len) and low-dose dexamethasone (dex) in combination with proteasome inhibitor (PI) or cytotoxic agent is an integral part of front-line therapy in multiple myeloma (MM). Use of Lenalidomide (Len) in MM had demonstrated an increased risk of venous thromboembolism (VTE) in initial studies which led to the incorporation of routine thromboprophylaxis with Len-based regimens. Existing estimate of VTE incidence from a prior analysis on Len-based regimens in newly diagnosed MM is 0.8 per 100 patient-cycles [Carrier et al. 2011]. However, there is a gap in literature on the incidence of VTE in patients receiving contemporary Len-based combination regimens along with adequate thromboprophylaxis. Hence, we conducted a systematic review and meta-analysis of clinical trials to assess the incidence of VTE with Len-based regimens in newly diagnosed MM patients.Method: We queried Ovid Medline, Ovid Embase and Cochrane Library databases to obtain relevant studies until March 2018. We included all phase I-III clinical trials testing a Len-based combination regimen for induction +/- consolidation therapy along with protocol-mandated thromboprophylaxis. VTE was defined as deep vein thrombosis or pulmonary embolism (CTCAE Grade 2 or above). Our primary outcome was pooled incidence of VTE events per patient-cycle, which was subsequently converted to VTE events per 100 patient-cycle for ease of comparison with existing literature in MM. We performed meta-analyses with random-effects model using a comprehensive meta-analysis software. Heterogeneity was calculated using I2 statistic and a value <25% was considered negligible, up to 50% moderate, and ≥70% was considered substantial heterogeneity. The protocol for this systematic review is registered with PROSPERO [CRD42018102971].Results: Initial search generated 1069 citations. After screening, 15 clinical trials with 3381 patients were included. Among 15 trials, 4 were phase I/II, 6 were phase II and 5 were phase III. All but one trial used low-dose dex. The pooled incidence of VTE events was 0.4 per 100 patient-cycles [95% CI. 0.3-0.5; I2: 70%]. Incidence rate of VTE in individual studies are summarized in Table I. The Forest Plot is shown in Figure I.Subsequently, we performed pre-specified subgroup analyses on trials with Len-dex, Len-dex + PI, Len-dex + doxorubicin and Len with Melphalan-Prednisone (MPR). The pooled incidence of VTE per 100-patient cycle with Len-dex was 0.3 [95% CI. 0.1-0.4; I2:92%], Len-dex with PI was 0.9 [95% CI. 0.3-1.6; I2: 69%], Len-dex with doxorubicin was1.5 [95% CI. 0.7-2.2; I2: 0%] and MPR was 0.3 [95% CI. 0.2-0.4; I2: 0%]. Notably, the incidence of VTE was higher with Carfilzomib-Len-dex when compared to Bortezomib-Len-dex regimens. Two trials with Len-dex + Doxorubicin had a higher rate of VTE irrespective of the dex dose. The most common modes of thromboprophylaxis used were ASA (range, 70-325 mg) and low molecular weight heparin.Conclusion: Patients with newly diagnosed MM receiving contemporary Len-based regimens have a significant incidence of VTE despite adequate thromboprophylaxis. However, the incidence rate compares favorably with prior estimate. The rate of VTE was highest with the use of Len-dex + Doxorubicin triplet regimen. In the Len-dex+PI subgroup, the incidence of VTE was higher in trials using Carfilzomib-Len-dex compared to Bortezomib-Len-dex regimen. These findings can be clinically applied at an individual level to choose a Len-based combination regimen based on the risk of thrombosis. New prophylactic agents like direct oral anticoagulants should be tested to further decrease the rate of VTE with Len-based combination regimens. DisclosuresKhorana:Janssen: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Bayer: Consultancy. Majhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Atara: Honoraria.

Carfilzomib-containing combinations as frontline therapy for multiple myeloma: A meta-analysis of 13 trials.

To investigate the activity and safety of carfilzomib-containing combinations as frontline therapy for multiple myeloma. We searched published carfilzomib reports for newly diagnosed multiple myeloma. Thirteen trials were identified, covering 704 subjects. Pooled analysis showed that carfilzomib combinations as frontline therapy for multiple myeloma attained an impressive at least complete response (≥CR) rate of 21%, at least very good partial response (≥VGPR) rate of 68%, overall response rate (ORR) of 94%. The ≥CR rates of 18% pre-SCT were increased to 43% of post-ASCT, and 64% of postconsolidation (P<.001). For those patients receiving carfilzomib therapy, response quality improved further over time (≥CR rates of 10% after 2nd cycle, 20% after 4th cycle, 43% after 8th cycle; ≥VGPR of 29% after 2nd cycle, 68% after 4th cycle, 88% after 8th cycle). ≥CR rates of 49% from CFZ-LEN-DEX triplet regimen were higher than 18% from CFZ-CYC-DEX triplet regimen and 21% from CFZ-THA-DEX triplet regimen (P=.03). Carfilzomib combinations could produce clinical benefits in newly diagnosed patients with multiple myeloma. High-quality response rate could be further improved through ASCT, consolidation therapy, and more cycles of chemotherapy even in the era of carfilzomib. CFZ-LEN-DEX could be a good combination regimen.

A Pilot Study of Peripheral Blood Hematopoietic Stem Cells Mobilization with the Combination of Bortezomib and G-CSF in Multiple Myeloma and Non-Hodgkin's Lymphoma Patients.

Background: Bortezomib has become an integral part of front-line therapy of multiple myeloma in a large majority of patients. There are preliminary reports which show that addition of bortezomib can augment the peripheral blood CD34 count during stem cell mobilization. In this single center prospective trial we added bortezomib to G-CSF to evaluate the effects of bortezomib on peripheral CD34 counts and collection.Methods: Patients aged 18-70 years with diagnosis of multiple myeloma (MM) or non-hodgkin's lymphoma (NHL) who were eligible for autologous stem cell transplantation (ASCT) and had received no more than three prior chemotherapeutic regimens were eligible for the study. Patients were enrolled in two groups. Group A (N=3) received G-CSF 16mcg/kg for 5 days and proceeded to stem cell collection on D5 and then received bortezomib 1.3mg/m2 on D5 after stem cell collection and G-CSF 16mcg/kg on D6, 7, 8 and repeat stem cell collection on D6, 7, 8 till the goal was achieved. Group B (N=17) received G-CSF 16mg/kg on D1-5 and received bortezomib 1.3mg/m2 on D4 and proceeded to stem cell collection on D5. If the patient was not able to collect the predefined goal CD34, G-CSF was continued on D 6, 7, 8 and a second dose of bortezomib 1.3mg/m2 was given on D7. Mobilization procedure was stopped once the predefined goal CD34 collection (4 x 106/kg for MM and 2 x 106/kg for NHL) had been collected.Primary objectives of the study was to determine if addition of bortezomib to G-CSF will result in an increase in PBSCs by > 2-fold and to achieve median neutrophil engraftment 12 days post ASCT. Secondary objectiveswere to evaluate the collected product for co-mobilization of lymphoma or myeloma cells and to determine if the use of bortezomib increases the mobilization of immune-stimulatory Dendritic cell (DC) -1 subsets.Results: A total of 23 patients were enrolled and 20 were evaluable for the results. Only one patient with NHL was enrolled and rest had MM. Median age of pts was 57 years, M/F 8/12, median number of previous chemotherapy regimens was 1 (range 1-3).The median peripheral blood CD34 count pre and post bortezomib in all patients were 28.8 x 106/kg and 37 x 106/kg respectively. All three patients in group A had drop in peripheral blood CD34 counts on D6 post bortezomib as they had undergone stem cell collection on day 5. In part B (N=17), 15 patients had increase in peripheral blood CD 34+ve cell counts with 4 patients achieved doubling while 11 pts had less than doubling of peripheral blood CD34 count after receiving bortezomib. Two patients had minimal drop in the peripheral blood CD34 counts post bortezomib. Median number of CD34 cells collected in15 patients (part B) were 5.06 x 106 CD34 cells/kg (range 4-15.1). 18 patients proceeded to ASCT and median time to neutrophil engraftment (ANC ≥500/cumm) post transplant was 12 days (range 11-16) and platelet engraftment (Plt count ≥ 20,000/cumm) was 18 days (range 15-27). There was no significant change in DC1/DC2 ratio in both groups following treatment with bortezomib and G-CSF (Figure 1).In group A all three patients collected goal CD34 count on day 5 and 2/3 patients collected >4 x106 CD34 cells/kg on D6 post bortezomib and1/3 patients collected 2.6 x 106 on D6 post bortezomib. In group B (n=17), 2 patients were unable to collect because of low CD34 counts on D4 and D5, 11 pts collected the goal in one day (D 5) and 4 pts required two days of apheresis (D 5 and 6). None of the patients received D7 bortezomib.Conclusion: Use of bortezomib during autologous stem cell collection was safe and well tolerated. Majority of patients had increase in peripheral blood CD34 counts post bortezomib administration on D4. Future trials should explore bortezomib as an alternate strategy to chemo-mobilization in combination with growth factors. [Display omitted] [Display omitted] DisclosuresOff Label Use: Bortezomib for stem cell mobilization. Lum:Karyopharm Therapeutics Inc: Equity Ownership; Transtarget.Inc: Equity Ownership. Deol:Bristol meyer squibb: Research Funding. Abidi:celgene: Speakers Bureau; Millenium: Research Funding.

Frontline therapy for multiple myeloma (MM) in real-world clinical practice: Results from the third interim analysis of the multinational, non-interventional, observational EMMOS study

patients, serum lactic dehydrogenase was elevated (>300 U/L) in eight patients and found to correlate with the serum concentrations of 2-microglobuline, hemoglobin and creatinine. Patients with values below 300 U/L had a median survival time of 88 months (Mean: 87.8, SD: 43.8, CV: 0.5) compared to 90 months (Mean: 87 months, SD: 42.3, CV: 0.5) for those with levels above 300 U/L. Conclusion: Serum lactic dehydrogenase at diagnosis, thus, had no prognostic information in multiple myeloma when related to overall survival. 2. Multiple Myeloma Therapy in Newly Diagnosed Patients including Transplantation

Results of an Upfront Myeloma Carepath Pilot with Response-Adapted Therapy

Background: VRD (bortezomib, lenalidomide, dexamethasone) and Rd (lenalidomide, dexamethasone) are standard regimens for upfront treatment of multiple myeloma (MM). VRD is preferred by many centers due to higher response rates although no survival difference has been shown so far. Higher risk for side effects, especially peripheral neuropathy, higher cost, and the retrospective observation of inferior survival in genetically high risk myeloma with use of 3- compared to 2-drug regimens containing novel agents (Baz R et al. ASH 2011, abstract # 1878) puts this practice into question. Since no test predicts who may experience harm from insufficient or excessive therapy we designed a carepath that starts with 2 drugs but adapts therapy early to achieve uniform MM control.Methods: Newly diagnosed symptomatic MM patients (pts) with measurable disease who are not eligible for or elect against a clinical trial are advised to begin a 2-drug regimen of lenalidomide (R) and weekly dexamethasone (d) or, if cast nephropathy suspected or R copay too high, bortezomib (V) and dexamethasone (D). Depending on response assessment per IMWG 2011 criteria after each cycle, treatment intensity is increased with sequential addition of agents (R or V, cyclophosphamide, and then liposomal doxorubicin) when there is not at least minor response (MR) after the first, or at least partial response (PR) after the second cycle of an administered combination. Once PR is reached pts are evaluated for high dose melphalan (HDM) and ASCT or consolidation with their induction regimen followed in either case by lenalidomide maintenance. The carepath includes supportive care recommendations for use of bisphosphonates, shingles prophylaxis, and thromboembolism prophylaxis. After IRB approval, pts treated by two physicians who piloted the carepath were identified through our registry and electronic medical records were reviewed.Results: From Oct 2012 to March 2014 the carepath was used in 24 pts. Their median age was 61 (42-82), SD stage was IIIA in 17, IIIB in 4, and IIA in 3; median ISS stage was II (III, II, and I in 9,5,10 pts, respectively), and of 18 pts with informative MyPRS® and/or FISH, 3 (17%) had high risk features (del17p, t4:14, MyPRS® score 76.04). Fifteen pts (62.5%) received 2 drugs, seven (29%) 3 drugs, and four (12.5%) were treated with 4 drugs (fig.1). Three pts underwent HDM and ASCT. Since bone marrow examinations to diagnose complete remission were not required, the best response so far is very good partial response (VGPR) in 14 pts (58%), PR in 7 pts (29%), MR in 2 pts (8%), and stable disease (SD) in 1 pt (4%) (fig.1). After median follow up of 10.7 months (5.3-20.3) one pt experienced progression after initial PR on 2 drugs and no pt has died. Bisphosphonates, shingles and DVT prophylaxis were used according to carepath in all pts. Hospital admission for a MM or treatment related complication was required in one pt (vertebral compression fracture while in PR on IV bisphosphonates); DVT (below-the-knee) on aspirin prophylaxis occurred in 2 pts (8%), and 2 pts (8%) developed peripheral neuropathy (grade 2 in one; transient grade 3 while on twice a week bortezomib in the other).Conclusions: Starting myeloma induction with Rd or VD, with use of additional agents only in patients who do not respond early, achieved uniform disease control that required 2 drugs in about 60%, 3 drugs in about 30%, and 4 drugs in about 10% of pts in this carepath pilot. Compared to VRD for all pts, response-adapted therapy reduces neuropathy risk and cost (savings for drug alone in this cohort > $4000 / cycle). Overall survival will be the ultimate assessment of the utility of this approach, but response assessments to date support ongoing utilization of the carepath. [Display omitted] DisclosuresOff Label Use: Lenalidomide as frontline therapy for multiple myeloma. Faiman:Celgene: Speakers Bureau; Millennium / Takeda: Speakers Bureau; Onyx / Amgen: Speakers Bureau. Reu:Celgene: Research Funding; Novartis: Research Funding; Millennium / Takeda: Consultancy, Research Funding; Onyx : Speakers Bureau.

Proteasome Inhibition Increases Recruitment of IκB Kinase β (IKKβ), S536P-p65, and Transcription Factor EGR1 to Interleukin-8 (IL-8) Promoter, Resulting in Increased IL-8 Production in Ovarian Cancer Cells

Proinflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) contributes to ovarian cancer progression through its induction of tumor cell proliferation, survival, angiogenesis, and metastasis. Proteasome inhibition by bortezomib, which has been used as a frontline therapy in multiple myeloma, has shown only limited effectiveness in ovarian cancer and other solid tumors. However, the responsible mechanisms remain elusive. Here, we show that proteasome inhibition dramatically increases the IL-8 expression and release in ovarian cancer cells. The responsible mechanism involves an increased nuclear accumulation of IκB kinase β (IKKβ) and an increased recruitment of the nuclear IKKβ, p65-phosphorylated at Ser-536, and the transcription factor early growth response-1 (EGR-1) to the endogenous IL-8 promoter. Coimmunoprecipitation studies identified the nuclear EGR-1 associated with IKKβ and with p65, with preferential binding to S536P-p65. Both IKKβ activity and EGR-1 expression are required for the increased IL-8 expression induced by proteasome inhibition in ovarian cancer cells. Interestingly, in multiple myeloma cells the IL-8 release is not increased by bortezomib. Together, these data indicate that the increased IL-8 release may represent one of the underlying mechanisms responsible for the decreased effectiveness of proteasome inhibition in ovarian cancer treatment and identify IKKβ and EGR-1 as potential new targets in ovarian cancer combination therapies.

Chromatin immunoprecipitation analysis of bortezomib-mediated inhibition of NFκB recruitment to IL-1β and TNFα gene promoters in human macrophages.

Interleukin-1β (IL-1) and tumor necrosis factor-α (TNF) are important pro-inflammatory cytokines involved in the mediation of the immune response, inflammation, tissue repair, and tumor progression. Regulation of IL-1 and TNF expression is mediated at the level of transcription by the transcription factor NFκB. Inhibition of NFκB activity by the proteasome inhibitor bortezomib (BZ) has been used as a frontline therapy in multiple myeloma and other hematological malignancies. In this chapter, we describe a protocol that uses chromatin immunoprecipitation (ChIP) to analyze the NFκB recruitment to endogenous IL-1 and TNF promoters in BZ-treated human macrophages. Corresponding to the BZ-suppressed mRNA levels of IL-1 and TNF, we show that BZ inhibits p65 NFκB recruitment to IL-1 and TNF promoters. This study specifically uses U937 macrophages, but the protocol could be easily modified to analyze the regulation of NFκB recruitment in other cell types.

Bortezomib and lenalidomide as front-line therapy for multiple myeloma

The objective of the study was to investigate the effects and safety of novel agents such as bortezomib and lenalidomide in the treatment of newly diagnosed patients with multiple myeloma. We performed a comprehensive meta-analysis of randomized controlled trials (RCTs). An initial search yielded 627 citations, of which 10 RCTs enrolling 4534 patients met the inclusion criteria. The addition of bortezomib to first-line therapy significantly prolonged overall survival (OS) (hazard ratio [HR], 0.75 [0.65, 0.87], p < 0.001). On the other hand, the addition of lenalidomide had no impact on survival (HR, 0.88 [0.65, 1.20], p = 0.42). Both lenalidomide and bortezomib consistently improved progression-free survival (PFS) compared with conventional therapy alone. The corresponding HRs were 0.65, 95% confidence interval (CI) [0.55, 0.77] (p < 0.001) for bortezomib and 0.48, 95% CI [0.42, 0.55]; (p < 0.001) for lenalidomide, respectively. Some of the increased adverse events reported were herpes zoster (relative risk [RR], 3.64 [2.23, 5.94], p < 0.001), peripheral neuropathy (RR, 3.59 [1.89, 6.83], p < 0.001) and gastrointestinal effects (RR, 2.19 [1.37, 3.50], p = 0.001) among patients receiving bortezomib, and gastrointestinal effects (RR, 2.36 [1.33, 4.17], p = 0.003) and thromboembolic events (RR, 2.55 [1.48, 4.38], p < 0.001) among patients receiving lenalidomide. Interestingly, treatment with bortezomib seemed to be associated with a lower rate of treatment related mortality (RR, 0.39 [0.18, 0.85], p = 0.02). An increased incidence of second primary cancers was observed in the lenalidomide group (RR 2.61 [1.60, 4.27], p < 0.001). In summary, bortezomib improved OS, and both lenalidomide and bortezomib consistently improved PFS of patients with newly diagnosed myeloma when it was added to standard therapy.

Frontline Therapy for Multiple Myeloma: A Concise Review of the Evidence Based on Randomized Clinical Trials

The past decade has seen significant progress in the development of new and effective therapies for multiple myeloma. Stem cell transplantation and the introduction of novel agents, such as thalidomide, lenalidomide, and bortezomib, have significantly improved outcomes of myeloma patients. In the current review, we analyzed the available data provided by published randomized clinical trials for the frontline therapy of myeloma patients. We attempted to assess the relative contribution and impact of these new therapies in the setting of both, transplant eligible and transplant ineligible patients.

Second autologous transplant as salvage therapy in multiple myeloma

High-dose chemotherapy followed by autologous haematopoetic stem cell transplantation (ASCT) is a standard frontline therapy for multiple myeloma (MM). Unfortunately, there are no randomized clinical studies examining the role of a second ASCT in patients who relapse after the initial autotransplant. Analysing all available retrospective studies, it seems that salvage ASCT can safely be performed in most patients with an overall treatment-related mortality rate <5%. Approximately 65% of patients will achieve an objective response and progression-free and overall survival will be around 12months and 32months, respectively. Retrospective data suggest that patients with a progression-free survival of ≥18months after initial ASCT are most likely to benefit from a salvage autotransplant. However, patients with a <12-month duration of response after initial ASCT should not be considered for a second autograft in the relapsed setting because this group will probably only experience ASCT-related toxicity without any clinical benefit. Quality of response after initial ASCT and number of therapies preceding salvage ASCT may also have a predictive value. Importantly, these findings need to be verified by randomized clinical trials in order to firmly integrate salvage ASCT into a global therapeutic concept for myeloma patients including optimized induction, consolidation, and maintenance approaches.

Bortezomib for the Treatment of Previously Untreated Multiple Myeloma

Management of multiple myeloma (MM) has been drastically changed in the last 10 years thanks to the introduction of novel agents, which, combined with the backbone of classical chemotherapy, have led to a significant improvement in disease control. Bortezomib is the first reversible proteasome inhibitor approved for the treatment of MM, with wide synergism in vitro and in vivo with a plethora of drugs active for MM. In patients eligible for autologous stem cell transplantation (ASCT), the achievement of complete response or very good partial response before ASCT is associated with prolonged progression-free and overall survival. Thus, the goal of induction regimens should include, at least for younger patients, a continued improvement of the quality and depth of the achieved response. This article is focused on reviewing the major efforts in frontline therapy for MM, including bortezomib-containing induction regimens in patients either eligible or ineligible for ASCT.

How to select among available options for the treatment of multiple myeloma

The introduction of novel agents (thalidomide, bortezomib and lenalidomide) in the frontline therapy of multiple myeloma has markedly improved the outcome both in younger patients who are candidates for high-dose therapy plus autologous stem-cell transplantation (HDT/ASCT) and in elderly patients. In the HDT/ASCT paradigm, novel agents may be used as induction therapy or after HDT/ASCT as consolidation and/or maintenance therapy. It is now possible to achieve up to 70% complete plus very good partial remission after HDT/ASCT and 70% 3-year progression-free survival (PFS). However long-term non-intensive therapy may also yield high response rates and prolonged PFS. Randomized trials comparing these two strategies are underway. In elderly patients, six randomized studies show the benefit of adding thalidomide to melphalan-prednisone (MP). a large randomized trial has also shown that the combination of bortezomib-MP is superior to MP for all parameters measuring the response and outcome. Finally, the role of maintenance is currently evaluated and a randomized trial shows that low-dose lenalidomide maintenance prolongs PFS.