Therapy In Myeloma Patients Research Articles

Bendamustine Bridging Versus Standard of Care Chemotherapy on Toxicity Profile for Multiple Myeloma Patients Undergoing CAR T Cell Therapy

Introduction Multiple myeloma (MM) remains an incurable malignancy arising from plasma cells, however great promise has been seen with the use of Chimeric Antigen Receptor (CAR) T cells. Autologous CAR-T products require bridging therapy, however little is known about different agents used in this manner. Some studies indicate decrease in disease burden is crucial, while others note an association with higher rates of toxicity and negative effect on survival. As commercial CAR T cell therapy is indicated after failure of at least 4 prior treatments, careful consideration of bridging therapy is crucial, particularly in patients with aggressive and high-risk disease. This study aims to compare the impact of bendamustine to standard of care (SOC) bridging therapy in MM patients undergoing CAR T cell therapy. Methods A single-center retrospective chart review of 19 adult patients with relapsed/refractory multiple myeloma treated with CAR T cells, who also received bridging therapy with either bendamustine (n=9) or SOC/Other (n=10) was conducted at Mount Sinai Hospital. Patient demographic information (gender, race, MM subtype, history of prior transplant) was collected and toxicity profiles (infection, pancytopenia, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS)) were compared. Descriptive statistics were used to analyze demographic characteristics and toxicity profiles between the two cohorts. Results Comparative analysis of demographics showed that both cohorts were predominantly males with IgG MM subtype, and varied in terms of race ( Figure 1a). The Other cohort had a higher proportion of patients with a history of autologous stem cell transplant (ASCT) (70%) compared to the bendamustine group. In the SOC group, two patients developed infections, whereas none were observed in the bendamustine cohort ( Figure 1b). Pancytopenia was observed in both groups, but interestingly, 100% of patients experienced it in the SOC cohort. CRS and ICANS were comparable between the two groups ( Figure 1b). Comparative statistics demonstrated no significant difference between the two groups ( Figure 1c). Conclusion Our study findings indicate that there was no significant difference in toxicity profiles between the two pre-conditioning therapy groups. Given our limited sample size, future studies with a larger are indicated to validate these results.

Clinical exercise therapy program with multiple myeloma patients: Impacts on feasibility, adherence and efficacy

PurposeMultiple myeloma (MM) is a severe hemato-oncological disease with high mortality and increasing incidence rate. Since evidence on exercise therapy in MM patients remains limited, this study examines feasibility, adherence, and efficacy based on real-life data from an oncologic care structure.MethodsA data evaluation of MM patients who participated in the oncologic exercise and movement therapy (OTT) at the Cologne University Hospital between 2012 and 2019 was conducted. The patient flow was incrementally reduced to four cohorts, intention-to-treat cohort (ITTC), safety cohort (SC), adherence cohort (AC), and efficacy cohort (EC). Cohorts were evaluated descriptively and by means of correlation analysis as well as group and time comparisons.ResultsThirty patients registered at the OTT between 2012 and 2019 (ITTC). The SC (N = 26) attended exercise therapy on average about one session per week over a period of 8 months. One-third dropped out within 3 months. In the AC (N = 15), BMI at baseline exhibited a strong and very significant negative correlation with exercise adherence. In the EC (N = 8), a significant improvement in physical functioning and a tendency towards significance in fatigue reduction between two measurement points was observed. No adverse events were documented.ConclusionsThe present observatory study reveals safety and feasibility while indicating adherence and efficacy of exercising MM patients under real-life therapy circumstances. Found obstacles to exercising as well as improvements in questionnaire scale scores need to be further examined in confirmatory study designs.

CD28: A roadblock to designing long-lasting CARs?

Abstract Multiple myeloma (MM) remains an incurable hematological malignancy by conventional chemotherapeutic approaches. Chimeric antigen receptor T (CAR-T) cells targeting B cell maturation antigen (BCMA) on MM have shown remarkable efficacy in relapsed/refractory patients, leading to their recent FDA approval. However, many MM patients fail to achieve durable remissions leading to relapse in the months following treatment, highlighting the need to better understand mechanisms of CAR-T cell failure. Recent studies demonstrate that reducing CD28 co-stimulatory signals delivered by CARs promote CAR-T cell persistence and reduce exhaustion. Whether endogenous CD28 co-stimulation contributes to in vivo CAR-T cell transience or dysfunction is unknown. Our preliminary data indicate that genetic deletion of the endogenous CD28 receptor does not impair CAR-T cell cytotoxicity but promotes in vivo persistence while targeted mutation of CD28 reduces exhaustion marker expression. These findings suggest that targeting endogenous CD28 on CAR-T cells with CTLA4-Ig (Abatacept) may represent a viable clinical strategy to increase the durability of a potent CAR-T cell design. Importantly, in the context of MM, we have previously shown that CD28 is expressed on and delivers pro-survival signals to MM, contributing to therapy resistance. Moreover, given the abundance of CD28 ligands, CD80 and CD86, within the bone marrow, we hypothesize that CD28 signaling reduces the efficacy of BCMA CAR-T therapy by providing a survival signal to MM cells while simultaneously limiting the durability of CAR-T cells. The combination therapy of BCMA CAR-T cells and Abatacept is expected to enhance the efficacy of adoptive CAR-T cell therapy for MM patients. This work is supported by grants from NIH (R03 CA256122, R01 AI155499).

SBCMA Plasma Level Dynamics and Anti-BCMA CAR-T-Cell Treatment in Relapsed Multiple Myeloma.

BACKGROUND: Novel chimeric antigen receptor T-cells (CAR-T) target the B-cell maturation antigen (BCMA) expressed on multiple myeloma cells. Assays monitoring CAR-T cell expansion and treatment response are being implemented in clinical routine. METHODS: Plasma levels of soluble BCMA (sBCMA) and anti-BCMA CAR-T cell copy numbers were monitored in the blood, following CAR-T cell infusion in patients with relapsed multiple myeloma. sBCMA peptide concentration was determined in the plasma, applying a human BCMA/TNFRS17 ELISA. ddPCR was performed using probes targeting the intracellular signaling domains 4-1BB und CD3zeta of the anti-BCMA CAR-T construct. RESULTS: We report responses in the first five patients who received anti-BCMA CAR- T cell therapy at our center. Four patients achieved a complete remission (CR) in the bone marrow one month after CAR-T infusion, with three patients achieving stringent CR, determined by flow cytometry techniques. Anti-BCMA CAR-T cells were detectable in the peripheral blood for up to 300 days, with copy numbers peaking 7 to 14 days post-infusion. sBCMA plasma levels started declining one to ten days post infusion, reaching minimal levels 30 to 60 days post infusion, before rebounding to normal levels. CONCLUSIONS: Our data confirm a favorable response to treatment in four of the first five patients receiving anti-BCMA CAR-T at our hospital. Anti-BCMA CAR-T cell expansion seems to peak in the peripheral blood in a similar pattern compared to the CAR-T cell products already approved for lymphoma treatment. sBCMA plasma level may be a valid biomarker in assessing response to BCMA-targeting therapies in myeloma patients.

Phase 1 Study of Elotuzumab and Peripheral Blood Mononuclear Cell Reconstitution in Combination with Autologous Stem Cell Transplantation and Lenalidomide Maintenance for Multiple Myeloma

Phase 1 Study of Elotuzumab and Peripheral Blood Mononuclear Cell Reconstitution in Combination with Autologous Stem Cell Transplantation and Lenalidomide Maintenance for Multiple Myeloma

The Survival Impact of Lenalidomide Maintenance Chemotherapy in Multiple Myeloma Patients Treated with Autologous Stem Cell Transplant and Bortezomib-Based Induction: An Analysis of Real World Data

IntroductionMultiple myeloma (MM) represents an incurable plasma cell malignancy. Success in the management of this disease requires a focus on prolonging disease control to positively impact survival. This is the rationale behind maintenance chemotherapy after frontline autologous stem cell transplant (ASCT). Recent large-scale phase 3 randomized trials have shown daily low dose lenalidomide, an oral immunomodulator (IMID), has led to markedly improved progression free survival (PFS) and an evolving benefit on overall survival (OS). We sought to evaluate the effect of lenalidomide maintenance in patients with MM undergoing bortezomib-based induction chemotherapy and ASCT in a real world setting.MethodsRetrospective review of patients with MM undergoing initial bortezomib-based induction chemotherapy and ASCT was completed in patients at our institution. Patients who began therapy up until June 30th, 2015 were included to ensure a minimum of 2-yrs follow-up. Patients were analyzed on an intention-to-treat basis. Maintenance chemotherapy included those on lenalidomide alone or lenalidomide plus bortezomib, the latter being a treatment option at our centre for high-risk patients. OS was measured from the time induction therapy was started until death or last follow-up. PFS was measured from the time of induction therapy initiation to relapse, death or last follow-up. Maximal response to treatment was assessed according to the IMWG consensus criteria although an additional endpoint of near CR (nCR) was included to account for patients where the monoclonal protein on electrophoresis disappeared and light chains normalized but where CR was not confirmed with immunofixation and a bone marrow biopsy was not done.Results198 patients were included in the analysis. 121 received lenalidomide based maintenance and 77 received no maintenance between December 2004 to June 30th, 2015. Median ISS score was 2 in both groups without significant difference between them (p=0.98) . In the maintenance and no maintenance groups respectively 32% and 36% had ISS stage 3 disease. The mean number of maintenance cycles received was 25 cycles (0.5 - 84). Sixty percent of patients required dose reductions or discontinuation due to adverse effects excluding relapse. Most commonly this was due to cytopenias (29.8%), rash (10.7%), infection (9.1%) and fatigue (5.8%). 15% discontinued therapy before relapse occurred. Though venous thromboembolism and second primary malignancies (SPMs) are a worry in patients treated long term with IMIDs these were only seen in 3.3% and 1.7% of patients respectively. Median follow-up in the maintenance group was 44 months and 60 months in the no maintenance group. Survival data is shown in figure 1. The median OS was not reached in the maintenance cohort and was 89 months in the no maintenance group (p = 0.01). Estimated 3-year OS was superior in the maintenance group at 88.4% versus 80.5% in the no maintenance cohort. A statistically significant difference in median PFS was also noted favouring the lenalidomide maintenance (55.0 months versus 32.9 months, p=0.002). Of patients treated with lenalidomide-based maintenance 95.0% achieved ≥ VGPR (53.7% ≥ nCR) while 77.9% (29.1% ≥ nCR) of those who did not receive maintenance therapy achieved these endpoints (p=0.03). Further characterization of therapy for relapsed disease as well as PFS after 1st relapse (2nd PFS) and time to second relapse (PFS2) will be presented at the meeting.ConclusionsOur retrospective analysis of lenalidomide maintenance therapy in MM patients treated with bortezomib-based induction chemotherapy and ASCT illustrates the positive impact lenalidomide has had on both PFS and OS. Patients treated with lenalidomide at our centre experienced a more prolonged and profound remission of their disease. The treatment was well tolerated with no unexpected adverse effects. Rates of thromboembolic disease and SPMs were low. Most importantly, the superior OS in the maintenance arm suggests that second line therapy for those not receiving maintenance could not overcome the negative impact of an earlier relapse. This data supports our ongoing approach incorporating lenalidomide-based maintenance continued until progression for all patients who have undergone an ASCT. Importantly, these real world results validate the phase 3 trial experience, helping to further establish this approach as a standard of care. [Display omitted] DisclosuresBelch:Amgen, Celgene, Takeda: Honoraria.

The Role of Whole Body STIR MRI in Assessing First Biochemical Relapse in Patients with Myeloma

Background: Myeloma remains an incurable disease and most patients will relapse. The optimal timing of salvage initiation remains uncertain although there is a trend to treating early biochemical relapse. In the current COVID-19 pandemic, delaying therapy of asymptomatic relapsed patients is also desirable, but avoidance of renal failure and symptomatic bony disease is important. Whole body STIR MRI with diffusion weighted imaging (DWI) has the potential to diagnose bone involvement at a very early, pre-symptomatic stage, before cortical destruction occurs. It may be a useful tool to assess the ability to defer therapy in myeloma patients with asymptomatic biochemical relapse.Methods: We performed a retrospective audit of newly diagnosed patients with symptomatic myeloma, diagnosed between April 2012 and Oct 2019. We studied only patients in first relapse who had achieved PR or better to first-line therapy. Patients were typically monitored with monthly serum protein electrophoresis and free light chain assessments. The preferred imaging modality during the study period was whole body STIR MRI with DWI analysis and additional dedicated spinal sequences. Response and relapse criteria were as defined by the IMWG with the exception that regular urine BJP monitoring was not performed. Rapid biochemical relapse was defined as per Sonneveld (ASH Education Book 2017). The decision to initiate therapy for relapse was at the discretion of the treating hematologist.Results: 125 patients with newly diagnosed symptomatic myeloma who achieved PR or better to first line therapy were identified. Median age at diagnosis was 64yrs (range, 32 to 89yrs) and 72% were male. Immunoglobulin type was IgG (54%), IgA (23%), light chain (22%) and IgD (1%). ISS stage was I (19%), II (60%) and III (21%) and 21% were high risk as defined by the presence of t(4;14), t(14;16) or del17p by bone marrow FISH. Half received autologous stem cell transplantation with bortezomib-based therapy being the commonest induction for both transplant- and non-transplant-eligible populations. Amongst this group with responsive disease, haematological response was CR (38%), VGPR (29%) and PR (33%).75 (60%) of patients have relapsed at a median of 32 months. For patients in CR and VGPR, it took a median of 92 days from the first presence or increase in monoclonal immunoglobulin until IMWG defined relapse criteria were met. At the time of IMWG defined relapse, in terms of assessing need for therapy, the patients clinical status was defined as: rapid biochemical relapse (15%), relapse in a patient with high risk FISH (26%), relapse in a patient with renal failure at diagnosis (15%) and meeting CRAB criteria exclusive of MRI findings (7%), leaving 37% (n=27) in slow biochemical relapse without a definite indication for urgent therapy. MRI was performed as the bone imaging modality in 20 of these 27 slow biochemical relapse patients at a median of 42 days (range, -12 days to 210 days) after IMWG defined relapse: 10 demonstrated new focal bone lesions, 3 no lesions, 4 stable lesions and 3 improved bone lesions. Of these 10 patients with no new MRI detected bone disease, two were treated immediately at physician discretion.Thus, only 8 of 75 relapses were asymptomatic with a normal MRI, had no other indication for urgent therapy and were observed. For this group, the median time to treatment was 96 days (range, 34 to 576 days). Of these 5 had therapy initiated at physician discretion in the absence of clinical deterioration at a median of 78 days post biochemical relapse, one had treatment started 38 days after relapse due to renal deterioration and two were observed for 6 months and 1.4 years prior to the development of progressive focal bone lesions on MRI. None of the 10 patients with slow biochemical relapse and no new focal MRI bone lesions developed symptomatic bone disease within 6 months of that normal MRI.Conclusion: Whole body STIR MRI identifies new focal bone lesions in half of patients with slow biochemical relapse and no other treatment indication, justifying early therapy initiation at biochemical progression. In the setting of the COVID-19 pandemic, whole body STIR MRI with DWI may also be a useful tool to identify patients with slow biochemical relapse who are suitable for careful observation rather than salvage chemotherapy. Only a minority (11% in our study) of relapses, however, are potentially suitable for this approach.DisclosuresMollee:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees.

The Exosomal Transfer of Acid Sphingomyelinase Contributes to Drug Resistance in Multiple Myeloma

Introduction Multiple myeloma (MM) is well-known for the development of drug resistance, leading to the need for multiple treatment lines at times of relapse or progression. Even then, most patients ultimately will succumb to this cancer. Therefore, there is a need for new therapeutic strategies to conquer this drug resistance. Lipidomics has recently gained more attention in the search for new cancer therapies. Lipids are mainly found in biological membranes and function as building blocks, but are also important metabolites that can influence energy, structure and signaling cascades. Lipid dysfunction has been correlated to other cancers, like prostate and breast cancer. In this study, we identified changes in lipid content in MM patients and further investigated this altered metabolism in vitro. Methods We performed a lipidomics assay to compare plasma from healthy volunteers to MM patients. For all in vitro experiments, we used four human MM cell lines (JJN3, OPM2, LP1, U266) and primary CD138+ patient samples, isolated by MACS. Differential mRNA expression (SMPD1 = acid sphingomyelinase, ASM) was measured by qRT-PCR and ASM protein levels by western blot. Exosomes were isolated by exoquick, while changes in secretion were measured by nanoparticle tracking analysis. Viability was measured by CellTiter Glo and apoptosis rates for melphalan, bortezomib and ASM inhibitor (amitriptyline) were measured by flow cytometry (annexinV-FITC/7-AAD staining). Drug efficacy of amitriptyline was also confirmed on primary CD138+ samples by CellTiter Glo. Results Lipidomics analysis revealed an increase in ceramides and a decrease in sphingomyelin. Therefore, we believe that the enzyme sphingomyelinase, which converts sphingomyelin into ceramide, is upregulated in MM, which we confirmed on primary CD138+ MM cells for ASM. We also observed an increase in SMPD1 expression by qRT-PCR and ASM levels by western blot after melphalan and bortezomib treatment. Furthermore, we also investigated effects of these drugs on exosome secretion, where we found an increase in the number of exosomes secreted, as well as higher ASM levels in these exosomes. U266-derived exosomes, containing high amounts of ASM, were able to transfer their resistance to ASM-low JJN3 cells as an increase in viability was measured. Inhibition of ASM by amitriptyline, combined with melphalan and bortezomib, increased apoptotic cell death by upregulating cleaved PARP and caspase 3 levels. Combination therapy of amitriptyline with melphalan and bortezomib was also successfully tested on primary CD138+ MM cells. Conclusion This study is the first to identify changes in sphingolipids in plasma of MM patients, where we matched the observed difference to an upregulation of ASM in MM cells. Standard-of-care drugs stimulated ASM expression and production, and cells were able to transfer their resistance to other cells by ASM-rich exosomes. Enzyme inhibition by amitriptyline, a cheap tricyclic antidepressant drug frequently used to combat neuropathic pain in MM, increased drug efficacy of standard-of-care drugs. This study therefore provides a rationale to add ASM-targeting drugs to current combination therapies in MM patients. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Amitriptyline is a tricyclic antidepressant, which is also often used to treat neuropathic pain in Multiple Myeloma patients. Here we describe additive effects of amitriptyline on bortezomib and melphalan treatment in MM.

Ectopic expression of BIRC5-targeting miR-101-3p overcomes bone marrow stroma-mediated drug resistance in multiple myeloma cells

BackgroundMultiple myeloma (MM) cells gain protection against drugs through interaction with bone marrow stromal cells (BMSCs). This form of resistance largely accounts for resistance to therapy in MM patients which warrants further exploration to identify more potential therapeutic targets.MethodsWe performed miRNA/mRNA qPCR arrays and western blotting to analyze transcriptional and translational changes in MM cells co-cultured with BMSCs. Drug cytotoxicity and apoptosis in MMGFP-BMSC co-cultures were measured using fluorescence plate reader and flowcytometry, respectively. miRNA was overexpressed in MM cell lines using Lentiviral transduction, miRNA-3’UTR binding was examined using luciferase assay.ResultsWe found that BMSCs downregulated miR-101-3p and upregulated survivin (BIRC5) in MM cells. Survivin was downregulated by miR-101-3p overexpression and found to be a direct target of miR-101-3p using 3’UTR luciferase assay. Overexpression of survivin increased viability of MM cells in the presence of anti-myeloma drugs, and miR-101-3p inhibition by anti-miR against miR-101-3p upregulated survivin. Furthermore, overexpression of miR-101-3p or silencing of survivin triggered apoptosis in MM cells and sensitized them to anti-myeloma drugs in the presence of BMSCs overcoming the stroma-induced drug resistance.ConclusionsOur study demonstrates that BMSC-induced resistance to drugs is associated with survivin upregulation which is a direct target of miR-101-3p. This study also identifies miR-101-3p-survivin interaction as a druggable target involved in stroma-mediated drug resistance in MM and suggests it for developing more efficient therapeutic strategies.

Clodronate-Liposome Mediated Macrophage Depletion Abrogates Multiple Myeloma Tumor Establishment In Vivo

Multiple myeloma is a fatal plasma cell malignancy that is reliant on the bone marrow microenvironment. The bone marrow is comprised of numerous cells of mesenchymal and hemopoietic origin. Of these, macrophages have been implicated to play a role in myeloma disease progression, angiogenesis, and drug resistance; however, the role of macrophages in myeloma disease establishment remains unknown. In this study, the antimyeloma efficacy of clodronate-liposome treatment, which globally and transiently depletes macrophages, was evaluated in the well-established C57BL/KaLwRijHsd murine model of myeloma. Our studies show, for the first time, that clodronate-liposome pretreatment abrogates myeloma tumor development in vivo. Clodronate-liposome administration resulted in depletion of CD169+ bone marrow–resident macrophages. Flow cytometric analysis revealed that clodronate-liposome pretreatment impaired myeloma plasma cell homing and retention within the bone marrow 24 hours postmyeloma plasma cell inoculation. This was attributed in part to decreased levels of macrophage-derived insulin-like growth factor 1. Moreover, a single dose of clodronate-liposome led to a significant reduction in myeloma tumor burden in KaLwRij mice with established disease. Collectively, these findings support a role for CD169-expressing bone marrow–resident macrophages in myeloma disease establishment and progression and demonstrate the potential of targeting macrophages as a therapy for myeloma patients.

Phase 1 study of elotuzumab in combination with autologous stem cell transplantation and lenalidomide maintenance for multiple myeloma.

8021 Background: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma. We initiated a single-center, open label, phase 1 trial based on the hypothesis that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (auto-SCT) and lenalidomide maintenance for consolidation therapy in myeloma patients will be safe and feasible. Methods: This is a Phase 1b, open-label, trial investigating elotuzumab and autologous PBMC reconstitution with auto-SCT consolidation therapy and lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability of elotuzumab and autologous PBMC reconstitution in the setting of auto-SCT and lenalidomide maintenance. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must be eligible for auto-SCT, and meet inclusion/exclusion criteria. Fifteen subjects participated in this study. The treatment plan is: In addition to PBSC harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily begins with cycle 4 of elotuzumab. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab. Results: 15 subjects have been enrolled in the study. All of these subjects are included in the safety population, having received at least 1 dose of elotuzumab. Nine of 15 subjects have completed 4 of the first 5 planned elotuzumab infusions.. The majority of adverse events, including infusion reactions attributable to elotuzumab, have been grade 2 or lower. There were no delays in hematopoietic reconstitution. No AEs were attributed to PBMC reconstitution. Conclusions: The combination of elotuzumab and PBMC reconstitution with standard auto-SCT and lenalidomide maintenance for consolidation therapy appears to be safe and feasible. The trial is ongoing and has completed accrual. The clinical results will be updated for presentation.

Fixed Dose Carfilzomib Triplets in Lenalidomide Refractory Myeloma

BackgroundMyeloma outcomes have improved due to the use of novel agents. However, patients who have failed bortezomib and lenalidomide represent a significant challenge. In New Zealand, myeloma patients are initially treated with CyBorD, transplant (if eligible) and VTD consolidation. Lenalidomide/dexamethasone is approved as third line therapy, or as second-line in patients with neuropathy. Compassionate access of carfilzomib became available in May 2016 for patients who have progressed after bortezomib and lenalidomide.MethodsPatients with myeloma treated with a carfilzomib triplet were identified from our database. After two initial doses of carfilzomib at 20mg/m2 patients were given a fixed dose of 60mg as a 30 minute infusion. Carfilzomib was given on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. To streamline administration, carfilzomib was infused via a Portacath in most patients. Patients received dexamethasone 20mg PO on days of carfilzomib (1, 2, 8, 9, 15 and 16), and cyclophosphamide 300mg/m2 PO Days 1, 8, and 15, thalidomide 100mg daily, lenalidomide 25mg Days 1-21 or venetoclax 800mg daily. Routine support care was valaciclovir, cotrimoxazole and allopurinol. Aspirin 100mg was given daily to reduce cardiovascular events. A baseline echocardiogram was obtained in all patients. Treatments were continued for 9 cycles, followed by maintenance (reducing carfilzomib to only Days 1 and 2 of a 28-day cycle, but continuing oral therapy) until treatment failure. Patients who progressed by IMWG criteria continued treatment if they continued to derive benefit. Patients were followed with monthly myeloma blood monitoring but did not routinely have bone marrow assessments to assess CR status. All statistical analysis was done using IBM SPSS version 20.ResultsBetween 18/5/16 and 21/5/18, 38 patients with RRMM were treated with a triplet containing carfilzomib, dexamethasone and cyclophosphamide( KCd n=33), lenalidomide (KRd n=3) thalidomide (KTd n=1), or venetoclax (KVd n=1). All patients except one, received at least 2 cycles of treatment and 19 currently continue therapy. The median number of cycles given is 10 (range 2-27). The median age at treatment initiation was 68yrs (range 51yrs to 91yrs); there were 17 patients >70yrs and three >80yrs. Patients had a median of 3 prior therapies and 18pts had received a ABMT, Prior treatment included bortezomib (100%), thalidomide (92%), lenalidomide (95%), and pomalidomide (18%). Carfilzomib triplets were generally well tolerated. One patient discontinued due to shortness of breath after two cycles. One patient had a non-STEMI cardiac event prior to routine use of aspirin, but continued on KCd. The best response was ≥CR 8% (n=3), ≥VGPR 32% (n=12), ≥PR 74% (n=28) ≥ MR 84% (n=32), four patients had SD and two progressed without benefit.Of the 38 patients, 21 have progressed with a median PFS of 9 ± 2.4 months. PFS was better in patients aged <70yrs, 53% at 18 months vs 0% for those aged >70 (median 4 months)(p=0.008). So far 15pts have died with a median OS of 18 ± 3 months. All deaths were in patients who had progressed. Outcomes were superior in those aged <70 yrs, OS 68% at 18 months (median OS not reached), versus those aged >70 yrs, OS 17% at 18 months (Median OS 11±6 months)(p=0.008) The median survival from relapse was poor at 2 months. However, of the 6 patients alive after progression, 3 received an anti-CD38 antibody as salvage and 3 remain on treatment with KCd, the longest continues on treatment at 15 months.SummaryFixed dose carfilzomib triplets are effective salvage therapy in myeloma patients who fail bortezomib and lenalidomide therapy. Treatment is well tolerated, even in elderly patients, albeit with inferior outcomes. [Display omitted] DisclosuresSimpson:Abbvie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Chan:Amgen: Honoraria; Karyopharm: Research Funding.

Retrospective Analysis of Modified Hyper-CVAD Therapy Combined with Proteasome Inhibition for Patients with Multiple Myeloma and Renal Insufficiency or Renal Failure

Background: While novel agents have allowed for successful outpatient treatment of patients with multiple myeloma (MM), multi-agent infusional chemotherapy regimens continue to have a role, particularly in high burden disease states. However, the use of platinum-based regimens is limited in patients with renal insufficiency and renal failure. We have been using a modified hyperCVAD regimen, termed HyperCD (Table 1), with omission of vincristine, and inclusion of a proteasome inhibitor (PI, either bortezomib or carfilzomib) in these aggressive clinical presentations for rapid tumor reduction. Here we present our experience with this treatment modality, with analysis of treatment outcomes and toxicities in the renal insufficiency subset.Methods:We performed a single-center chart review of all MM patients at our institution with available electronic medical records who received at least one HyperCD cycle in the setting of concurrent renal insufficiency (defined by estimated eGFR <50mL/min by CKD-EPI at treatment start) between 01/2012 and 12/2016. Data on demographics and disease characteristics were collected. Response was determined by IMWG criteria. Progression free survival (PFS) and overall survival (OS) were calculated by Kaplan Meier method, with PFS including progression or death from any cause and censoring at last known follow-up for live patients.Results:Baseline characteristics: Sixty-seven patients were included in this analysis (Table 2), including 46 non-dialysis dependent and 21 dialysis dependent patients. Median age was 62 years (range 29 - 85). 19% had known prior high-risk cytogenetics defined by t(4;14), t(14;16) and/or 17p(del). Median number of prior lines of therapy was 2 (range 0-14). 34% had prior autologous transplantation. Prior therapies included alkylator therapy in 67%, immunomodulator in 64%, anti-CD38 antibody therapy in 13%, and PI in 87%. Reasons for HyperCD administration included rapidly progressive disease (63%), hypercalcemia (30%), extensive bony (16%) or soft tissue disease (9%), primary (4%) or secondary plasma cell leukemia (7%), and stem cell mobilization (22%). Disease status at time of treatment included new diagnosis (13%), insufficient prior response (18%), and relapsed/refractory or relapsed disease (69%). The median number of cycles administered per patient was 1 (range 1-4), with 55% receiving 1 cycle and 45% receiving 2 or more cycles. The median creatinine at therapy start was 2.93 (range 1.15-8.98).Responses: Of 23 patients on dialysis, 8 (35%) were able to discontinue either during or sometime after therapy. Median percent improvement in creatinine after therapy among non-dialysis patients was 24% (p=0.0001 by wilcoxon signed rank). The overall response rate (ORR) was 69% (46/67), with 1% complete responses (CR), 28% very good partial responses (VGPR), and 39% partial responses (PR). The median time to PR or better was 1.1 months, with a median PFS of 5.1 months, and median OS of 21 months. 87% of patients were able to bridge to other therapy including autologous transplantation (22%). 81% of patients have progressed or died at last follow-up, with disease being the most common cause of death (29/34, 85%).Therapy related toxicities: Median duration of severe neutropenia (ANC</=500/µl) was 4 days (range 0-17) and severe thrombocytopenia (platelets </= 50,000/µl) 7 days (range 0-29), per cycle. 24% of patients had neutropenic fever with documented infections in 37%. Other toxicities included severe bleeding (4%), deep vein thrombosis (7%), and cardiac events (25%), including tachyarrhythmia (9%), demand ischemia (3%), heart failure (2%), pulmonary hypertension (3%), and volume overload (9%). One patient (2%) had potential treatment related mortality (TRM) approximately 3 months after therapy and 1 patient (2%) died within 30 days from progressive disease.Conclusion: HyperCD-based regimens yielded relatively high response rates in MM patients with renal insufficiency, including renal failure. Several patients discontinued dialysis, with improvement in renal function also seen in non-dialysis patients. While TRM was low, hematologic, infectious, and cardiac toxicities were common. The majority of patients were able to successfully bridge to other therapy. HyperCD-based regimens may thus be a potential alternative to platinum based therapies in myeloma patients requiring intensive infusional chemotherapy. [Display omitted] DisclosuresShah:Nekktar: Consultancy; Teneobio: Consultancy; Amgen: Consultancy; Sutro Biopharma: Research Funding; Janssen: Research Funding; Nkarta: Consultancy; Indapta Therapeutics: Equity Ownership; Takeda: Consultancy; Celgene: Research Funding; Indapta Therapeutics: Consultancy; Bluebird: Research Funding; University of California San Francisco: Employment; Kite: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy. Wong:Janssen: Research Funding; Roche: Research Funding. Martin:Sanofi: Research Funding; Amgen: Research Funding; Roche: Consultancy. Wolf:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy.

Abstract 2300: CDK4/6 inhibition triggers dissociation of MEIS2 from CRL4CRBN E3 ligase to induce interferon response and reprogram myeloma for IMiD vulnerability

Abstract Inhibition of CDK4/6 has emerged as an effective therapy in human cancer. Palbociclib, the first selective CDK4/6 inhibitor (CDK4/6i), is FDA-approved for treatment of metastatic breast cancer, and abemaciclib has been fast tracked for approval as a front line breast cancer treatment. Recent evidence in mouse models of breast cancer further indicates that CDK4/6 inhibition triggers anti-tumor immunity, but the precise tumor intrinsic mechanism that mediates CDK4/6 inhibition for a clinical response remains to be defined. To address this, we inhibited CDK4/6 with palbociclib in sequential combination with immunomodulary drugs (IMiD)s in primary bone marrow myeloma cells (BMMCs), using normal bone marrow plasma cells as a control. IMiDs, lenalidomide (Len) and pomalidomide (Pom), are standard of care for multiple myeloma (MM) and lymphoma. Each rarely achieves complete remission despite a high overall response rate and durability. However, each markedly potentiates the clinical efficacy of diverse partners by unknown mechanisms. Cereblon (CRBN), a substrate receptor of the CUL4-ROC1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase, is requited for IMiD's anti-tumor activity. Binding of Len or Pom to CRBN accelerates the recruitment of transcription factors IKZF1/3 to CRL4CRBN for ubiquitination and degradation in MM cells. One of the targets of IKZF1/3 is IRF4, which is required for survival of MM cells and reduced after exposure to Len or Pom. Moreover, MEIS2, a homeobox transcription factor was identified to be an substrate of CRBN in crystal structure and by biochemical screen, implicating a role for MEIS2 in modulates IMiD's anti-tumor activity. However, evidence for MEIS2 expression in myeloma cells is lacking. Previously, we have shown that prolonged early G1 arrest (pG1) induced by sustained CDK4/6 inhibition reprogrammed cancer cells for vulnerability to diverse clinically relevant agents ex vivo and in animal models. To address if CDK4 inhibition reprograms MM cells for IMiD vulnerability, first we show that the intrinsic IMiD sensitivity in primary BMMCs ex vivo is a major determinant for the clinical response to IMiD therapy in myeloma patients. Second, we discovered that MEIS2 is aberrantly expressed and associated with CRBN in BMMCs. Third, MEIS2 is regulated by the cell cycle in primary MM cells and required for the survival of MM cells in part by maintaining IRF4 expression. Finally, CDK4/6 inhibition liberates CRBN from association with MEIS2 in pG1. This rapidly accelerates Len-mediated ubiquitination and degradation of IKZF1/3, loss of IRF4, de-repression of IRF7 and induction of interferon (IFN) responsive genes that culminated in TRAIL-mediated apoptosis. Dissociation of MEIS2 from CRBN thus represents a noel mechanism by which CDK4/6 inhibition reprograms myeloma for vulnerability to IMiDs through induction anti-tumor IFN response. Citation Format: Xiangao Huang, David Jayabalan, Maurizio Di Liberto, Zhengming Chen, Anna Schinzel, Scott A. Ely, Adriana Rossi, Morton Coleman, Joseph M. Lane, William C. Hahn, Tomer M. Mark, Ruben Niesvizky, Selina Chen-Kiang. CDK4/6 inhibition triggers dissociation of MEIS2 from CRL4CRBN E3 ligase to induce interferon response and reprogram myeloma for IMiD vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2300.

26 - Phase 1 Study of Elotuzumab in Combination with Autologous Stem Cell Transplantation and Lenalidomide Maintenance for Multiple Myeloma

Background: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma patients in combination with lenalidomide and dexamethasone. We hypothesized that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (ASCT) and lenalidomide maintenance for consolidation therapy in myeloma patients will be safe and feasible. Methods: This is a Phase 1b, open-label, trial investigating safety of administration of elotuzumab and autologous PBMC in conjuction with high-dose melphalan and stem cell transplantation followed by lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. The treatment plan is as follows: In addition to standard peripheral blood stem cell mobilization and harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan conditioning (day −1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 post-stem cell infusion and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive subsequent cycles of elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily days 1-21 of every 28-day cycle begins with cycle 4 of elotuzumab, and may continue off study beyond cycle 12 at the investigator's discretion. Results: The study completed accrual of the planned 15 subjects. All 15 subjects are included in the safety population, completed the treatment protocol or came off study, and are evaluable. The majority of adverse events, including infusion reactions attributable to elotuzumab, were grade 2 or lower. Grade 3 or higher hematologic AEs, including anemia, neutropenia, lymphopenia, thrombocytopenia, and non-hematologic AEs including nausea, vomiting, and dehydration, were attributable to the ASCT procedure. Two subjects came off study before study completion; one for personal choice (VGPR at time of study withdrawal) and one for early progression. Thirteen subjects completed the study protocol. At the one-year post-ASCT time point, subjects were re-staged and the results are as follows: 1 PR, 6 VGPR, and 7 sCR. ORR was 93% (14/15) and one-year PFS was 93% (14/15). Correlative studies including tumor microenvironment immunophenotyping, MRD assessment, and T cell receptor sequencing are ongoing. These results will be available for presentation.

Lenalidomide Is a Highly Effective Maintenance Therapy in Myeloma Patients of All Ages; Results of the Phase III Myeloma XI Study

Lenalidomide Is a Highly Effective Maintenance Therapy in Myeloma Patients of All Ages; Results of the Phase III Myeloma XI Study

Phase 1 Study of Elotuzumab in Combination with Autologous Stem Cell Transplantation and Lenalidomide Maintenance for Multiple Myeloma

Introduction: Elotuzumab is a humanized monoclonal antibody directed against SLAMF7 that is approved for use in relapsed multiple myeloma patients in combination with lenalidomide and dexamethasone. This agent appears to have several modes of action, including facilitation of antibody-dependent, cell-mediated cytotoxicity (ADCC) through binding to SLAMF7 on myeloma cells and activation of natural killer (NK) cells to kill tumor cells through ligation of the target. We initiated a single-center, open label, phase 1 trial based on the hypothesis that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) reconstitution to standard-of-care autologous hematopoietic stem cell transplantation (auto-SCT) and lenalidomide maintenance for consolidation therapy in myeloma patients after induction therapy will be safe and feasible. We hypothesize that early PBMC reconstitution post-auto-SCT will restore a viable NK cell population for activation by elotuzumab, which may target residual myeloma cells and promote tumor-specific humoral and cellular immune responses against myeloma cells. Subsequent maintenance therapy with elotuzumab and lenalidomide may amplify this response, resulting in long-term maintenance of the minimal residual disease state.Methods. This is a Phase 1b, open-label, trial investigating elotuzumab and autologous PBMC reconstitution with auto-SCT consolidation therapy and lenalidomide maintenance. The primary objective of this study is to assess the safety and tolerability of elotuzumab and autologous PBMC reconstitution in the setting of auto-SCT and lenalidomide maintenance in multiple myeloma patients. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must achieve partial response or better by IMWG criteria with induction chemotherapy, be eligible for auto-SCT by institutional standards, and meet inclusion/exclusion criteria. Fifteen subjects are planned in this pilot study. The treatment plan is as follows: In addition to standard peripheral blood stem cell mobilization and harvest, subjects undergo steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan conditioning (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 post-stem cell infusion and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive subsequent cycles of elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily days 1-21 of every 28-day cycle begins with cycle 4 of elotuzumab, and may continue off study beyond cycle 12 at the investigator's discretion. Bone marrow aspirates and peripheral blood are collected for correlative studies at screening, cycle 2, cycle 4, and at the end of study after cycle 12. For the primary endpoint analysis, the safety population includes all subjects who received at least one dose of study treatment. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab.Results: Fourteen of the planned 15 subjects have been enrolled in the study. Demographic and staging data reflect the general transplant-eligible myeloma patient population at our institution. All 14 of these subjects are included in the safety population, having received at least 1 dose of elotuzumab. Nine of 14 subjects have completed at least 4 of the first 5 planned elotuzumab infusions and are evaluable. The majority of adverse events, including infusion reactions attributable to elotuzumab, have been grade 2 or lower. Grade 3 or higher hematologic AEs, including anemia, neutropenia, lymphopenia, thrombocytopenia, and non-hematologic AEs including nausea, vomiting, and dehydration, were attributable to the auto-SCT procedure. There were no delays in hematopoietic reconstitution observed. One episode of grade 3 hypertension was attributed to elotuzumab infusion and resolved with supportive care. No AEs were attributed to PBMC reconstitution.Conclusions: The combination of elotuzumab and PBMC reconstitution with standard auto-SCT and lenalidomide maintenance for consolidation therapy of multiple myeloma appears to be safe and feasible. One subject withdrew for personal reasons. The trial is ongoing and is expected to complete accrual and the clinical results will be updated for presentation. DisclosuresChari:Celgene: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Geerlof:Bristol-Myers Squibb: Employment. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Cho:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus, Inc.: Research Funding; Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees.

Autologous Stem Cell Transplant in Multiple Myeloma: Excellent Safety and Efficacy Possible in a Non University Hospital of Developing Country

Background: There have been major advances in past decade in the continuum of therapy for transplantation-eligible multiple myeloma patients. For patients requiring therapy, recommended induction treatment consists of triple drug regimens followed by the collection of hematopoietic stem cells. For transplantation-eligible patients, highdose melphalan followed by autologous stem cell transplant (HSCT) remains the standard regimen as it helps in increasing both the frequency and depth of responses leading to improved outcomes [1-3]. Autologous HSCT has thus become the standard approach after induction therapy for myeloma patients

Immunoglobulin Heavy/Light Chain Measurements During Monitoring Provide Prognostic Information of Relapse After Therapy in Myeloma Patients

AbstractAbstract ▪3964▪This icon denotes a clinically relevant abstract Introduction:Monitoring multiple myeloma (MM) patients is required to help guide therapy and assess response. Currently the most commonly employed tests to monitor MM patients include serum protein electrophoresis (SPEP), immunofixation (IFE), 24hr urine and serum free light chain (FLC) analysis. Whilst electrophoretic tests are adequate for IgG MM, they may be inadequate for IgA MM where the monoclonal immunoglobulin co-migrates with other serum proteins (∼60% of cases). Recently the inclusion of FLC testing to identify patients in stringent complete response (sCR) has been recommended. Novel nephelometric reagents have become available that can quantify IgA kappa and IgA lambda immunoglobulins (HLC) in serum. Here we assess the use of these tests at maximum response to detect residual disease and comment on the prognostic value of sCR.Patients, materials and methods:196 IgA MM patient samples recruited from the MRC IX trial were assessed at maximum response. Briefly, patients were randomised on to intensive (I: induction therapy with CVAD or CTD followed by high-dose melphalan and ASCT) and non-intensive (NI: clodronate or zoledronic with MP or CTDa) arms. Median age was 59 years (range: 37–71) and 74 years (range: 65–89) for patients in the I and NI arms, respectively. 31% patients in the I arm and 39% in the NI arm presented with stage III disease. Samples were taken 3 months after autologous stem cell transplant or maximum response and analysed nephelometrically using serum FLC and HLC immunoassays. Ratios for both FLC and HLC were compared to normal ranges (FLC normal ratio= 0.256–1.65, IgAkappa/IgAlambda normal ratio=0.8–2.04). Additionally, isotype-matched immunoparesis was described as <0.48 g/L IgAkappa and <0.36g/L IgAlambda. Results were compared to SPEP, IFE and total immunoglobulin assays (where immunoparesis was described as <6g/L IgG and <0.4g/L IgM). 2-year progression free survival (PFS) was determined using Kaplan Meier analysis (SPSS v 19.0). Results:3 months post-therapy, patient responses were: I arm: progressive disease (PD): n=1(<1%); minimal response (MR): n=1(<1%); partial response (PR): n=10(8%); very good partial response (VGPR): n=35(29%); complete response (CR): n=13(11%); sCR: n=58(48%); for two patients no data was available; NI arm: progressive disease (PD): n=3(4%); stable disease (SD): n=5(7%); MR: n=10(13%); PR: n=31(41%); VGPR: n=16(21%); CR: n=11(15%). Within the 2-year follow up, 41% patients in the I arm and 46% in the NI arm relapsed. Median PFS was not significantly different between the two arms (not reached v 7 months, p=0.65).Response (3VGPR) was not associated with PFS in either arm (I, p=0.717; NI, p=0.236). By contrast, achievement of a sCR (p=0.013) was significantly associated with longer PFS in the I arm and tended towards significance in the NI arm (p=0.063). An abnormal HLC ratio was associated with shorter PFS in both arms (I, p=0.002; NI, p=0.032). In all patients achieving a 3VGPR, an abnormal HLC ratio was associated with shorter PFS (p>0.0001). Similarly, in patients achieving a 3CR an abnormal HLC ratio was also associated with shorter PFS (p=0.04). Furthermore, patients achieving a CR where both FLC and HLC ratios were normal had a significantly longer PFS than those with an abnormal FLC or HLC ratio (median PFS not reached v 18 months, p=0.007). Isotype-matched immunoparesis was associated with shorter PFS in all patients achieving a CR (p=0.061). By contrast, systemic immunoparesis of either IgG or IgM immunoglobulins were not associated with PFS (p=0.525 and p=0.964, respectively). Discussion:Novel therapies have dramatically improved MM patient outcomes, however improvements in the assessment of those outcomes has not followed a similar trajectory. Here we present data suggesting immunoglobulin HLC ratios may be better markers of residual disease than electrophoretic methods. In addition a response category based on normalisation of both FLC and HLC ratios may be more valuable than sCR. Finally, the identification of isotype matched immune reconstitution as a marker of outcome suggests a preferential suppression of immunoglobulin production not previously reported. Conclusion:Normalisation of the FLC and HLC ratio at maximum response is a better assessment of disease than IFE. Further work is required to validate these results and to assess FLC and HLC ratios against multi-parametric flow cytometry. Disclosures:Young:Binding Site: Employment.

Do Elderly Myeloma Patients Benefit From High Dose Therapy (HDT) and Autologous Stem Cell Transplant (ASCT)?: A Comparative Survival Analysis using SEER Registry

AbstractAbstract 2072 Introduction:Many randomized control trials demonstrated that HDT-ASCT is superior to conventional therapies in myeloma patients and prolongs progression free survival (PFS) and overall survival (OS) (Attal M, 1996, Childs JA, 2003). However, in treating a malignancy with a median age of diagnosis of 69 years, the majority of the patients will not be eligible for this beneficial approach if a nominal numerical age cut-off (<65 years) is followed based on the assumption that elderly patients cannot tolerate HDT-ASCT; nor will they be eligible for clinical trials involving HDT-ASCT if stringent age-restricted inclusion criteria are incorporated. Therefore, we have evaluated if the elderly patients benefit from HDT-ASCT. Methods:We used the Surveillance, Epidemiology, and End Results (SEER) 18 registry data (www.seer.cancer.gov) as our comparator (reflects 28% of the US population);to provide information on incidence, prevalence and survival from 1973–2009. The data from an institutional cohort (IC) is obtained from the records of patients that underwent HDT-ASCT from January 2000 to January 2012. We used IBM SPSS version 20 to generate the Kaplan-Meier survival curves. Results:Of the 6,571,117 malignant cases listed in SEER registry, a total of 74,826 cases (1.1%) of multiple myeloma (ICD-03 code 9732) were identified (39735 males and 35091 females). Median age of the patients is 70 years. Among these patients 48,988 patients (65%) are over the age of 65. A total of 901 myeloma patients underwent HDT-ASCT from IC during the evaluable period and 167 patients (19%) were over the age of 65. The median survival for each subset is listed in Table 1. Both male and female WCI-ASCT myeloma patientshad prolonged OS compared to the SEER myeloma patients, despite the difference in magnitude of advantage in IC-ASCT male patients vs. female patients. Both white and black patients, as well as patients undergoing HDT-ASCT across all age subgroups had a significant survival advantage. Conclusions:In each subgroup, by the decade of diagnosis, gender, race, age subsets we have consistently demonstrated a significant survival benefit for IC transplant patients ≥age 65 compared to SEER myeloma patients ≥age 65 if offered HDT-ASCT. Selection-bias prevails in the groups showing improved overall survival. Hence, a careful selection process considering physiologic age as a determinant for transplant eligibility would result in better outcomes, and not preclude the elderly from the survival benefits of HDT-ASCT.Table 1Median OS in myeloma patients ≥65 years; across subsetsMedian OS (95% CI)SEER patients (95% CI) (N)Emory transplant patients (95% CI) (N)Patients ≥65 years20 months (19.624–20.376) (48988)62 months (55.732–68.268) (167)Year of diagnosis1993-200219 months (18.382–19.618) (16596)57 months (27.523–86.477) (16)2003+22 months (21.279–22.721) (19487)62 months (57.478–66.522) (151)SexMale19 months (18.481–19.519) (25185)63 months (57.330–68.670) (103)Female20 months (19.453–20.547) (23803)53 months (40.370–65.630) (64)RaceWhite19 months (18.580–19.420) (39047)59 months (47.579–70.421) (119)Black21 months (20.079–21.921) (7254)62 months (54.637–69.363) (40)Age stratification65-6932 months (30.965–33.035) (10480)62 months (40.737–83.263) (114)70-7426 months (25.122–26.878) (11448)56 months (44.307–67.693) (45)75+14 months (13.601–14.399) (27060)42 months* (8)Comparison for all subsets p-value=0.000; * p-value 0.021. Disclosures:Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Research Funding, Unpaid consultancy, Unpaid consultancy Other; Genentech: Unpaid consultancy, Unpaid consultancy Other; Gilead: Research Funding; Spectrum: Research Funding; Janssen lymphoma research foundation: Membership on an entity's Board of Directors or advisory committees. Waller:Outsuka: Research Funding.