Novel Therapies For Multiple Myeloma Research Articles

Aplidin (Plitidepsin) Regulates Viability and Function of Myeloma Cells and Bone Cells in Combination with Other Anti-MM Drugs

In multiple myeloma (MM) the clonal expansion of malignant plasma cells within the bone marrow results in the development of lytic bone lesions due to exacerbated bone resorption. Despite recent progress in its treatment, MM remains incurable and the associated bone disease persists even after complete remission. Thus, identification of new therapeutic approaches that suppress MM cell growth and protect the bone is an unmet need. Aplidin, a novel anti-cancer compound isolated from the marine tunicate Aplidium albicans, exhibits anti-MM activity even in MM cells resistant to conventional chemotherapy and is currently in phase III clinical trials in Europe. However, the effects of Aplidin on bone cells and MM-induced bone disease are unknown. The goal of the current study was to examine the effect of Aplidin, alone or in combination with other anti-MM drugs, on myeloma cells and bone cells (osteocytes, osteoblasts, and osteoclasts) using in vitro approaches.Aplidin decreased the number of human JJN3 and murine 5TGM1 MM cells with an EC50~10nM, determined by MTT assay, due to decreased cell viability, assessed by Trypan blue exclusion, reaching a 20% increase in MM cell death after 48h. Treatment with glucocorticoids (GC) (10-5M) or Bortezomib (3nM) also decreased MM viability and enhanced the anti-MM activity of Aplidin by 1.6-fold and 2.5-fold, respectively. In addition, Aplidin at >10nM induced MLO-A5 osteocytic dead up to 15% and in combination with GC up to 50%; whereas, in contrast, Bortezomib did not affect osteocyte viability and partially prevented the increase in MLO-A5 cell death induced by Aplidin. Further, 1nM Aplidin increased OB-6 osteoblastic cell death up to 20% and decreased their matrix mineralization capacity, quantified by Alizarin red. These effects were enhanced when Aplidin was combined with GC, but partially prevented by combination of Aplidin with Bortezomib. Cells of the osteoclastic lineage exhibited higher sensitivity to Aplidin in comparison to MM cells or osteoblastic cells, and thus it was tested at lower concentrations. Specifically, 50 pM Aplidin decreased the number of hematopoietic precursors by 15-20%, as quantified by enumerating GM-CSF colonies in cultures established from murine bone marrow. Moreover, Aplidin, at concentrations as low as 0.01 pM, reduced osteoclast precursor commitment and differentiation by 10%, as quantified by enumerating the number of osteoclast precursors maintained in the presence of M-CSF for 3 days with or without Aplidin. In addition, Aplidin decreased by 40% the number of TRAP positive osteoclasts generated after 4 days in the presence of M-CSF and sRANKL; and blunted the rapid (5-15min) increased in ERK phosphorylation induced by Rankl, but did not affect RANKL-induced p38 phosphorylation, suggesting that Aplidin inhibited RANKL-induced differentiation of osteoclast precursors by preventing ERK activation. Lastly, to test the effects of Aplidin on osteoclasts function, mature osteoclasts generated in the presence of M-CSF/sRANKL were detached by trypsinization, replated on bovine dentin slides and exposed to Aplidin for 3 and 7 days. 10pM Aplidin reduced the number of mature osteoclasts by 60% and markedly decreased the number of resorption pits.In summary, Aplidin (1nM and up) decreases MM cell viability and GC or Borteozmib enhances its anti-MM activity. In addition, Aplidin (10nM and up) decreases osteocytic cell viability and this effect is exacerbated by GC but partially prevented by Bortezomib. Moreover, Aplidin (1nM and up) induces osteoblastic cell death and decreases their mineral production, and these effects are increased by GC, but partially prevented by Bortezomib. Furthermore, Aplidin (0.01pM and up) reduces osteoclast precursor commitment and differentiation, and inhibits mature osteoclast resorption activity. Taken together these findings suggest that combining Aplidin with proteosomal inhibitors may be a novel therapy for MM to enhance anti-tumor responses, decrease bone destruction by inhibiting bone resorption, and prevent potential side effects of Aplidin on cells of the osteoblastic lineage. DisclosuresDelgado-Calle:PharmaMar: Research Funding. Galmarini:PharmaMar: Employment. Roodman:PharmaMar: Research Funding. Bellido:PharmaMar: Research Funding.

Inhibition of PI3K Alpha and PI3K Delta with Copanlisib Shows Preclinical Activity As a Single Agent and in Combination in Multiple Myeloma

Background: The reversible, pan-class I PI3K inhibitor, copanlisib (BAY 80-6946), has preferred activity for the alpha and delta isoforms. This is in contrast to the delta and delta/gamma isoform-selective PI3K inhibitors developed primarily for Non-Hodgkin Lymphoma. We hypothesize that a copanlisib-based combination strategy could provide an effective, novel therapy for multiple myeloma with a pharmacodynamic biomarker to identify patients most likely to benefit from the therapy. Here we demonstrate the preclinical efficacy of copanlisib as a single agent and in combination with carfilzomib, a BET bromodomain inhibitor (BETi) and venetoclax.Methods: A panel of 20 human multiple myeloma (MM) cell lines were evaluated for the effects of copanlisib on cell proliferation after a 5-day exposure to the drug. Sensitive NCI-H929, MM.1S, L-363, and resistant AMO-1, JJN3, COLO-677 MM cell lines were selected for further analysis. All mechanism of action (MOA) studies were performed by treating the MM cells at a dose of 100 nM copanlisib. Cell cycle analysis and induction of apoptosis was performed by FACS after propidium iodide or Annexin V FITC staining respectively on cells treated for 72 hours. Reverse phase protein array (RPPA) was performed at baseline and post treatment for proteomic analysis with confirmatory western blots. Phospho-flow was performed to measure pre- and post-treatment levels of the ribosomal protein phospho-S6 (p-S6). The combination studies utilized serial dilutions of copanlisib with carfilzomib, a BETi, and venetoclax. Excess over highest single agent (EOHSA) was used to evaluate for potentiation. These findings were confirmed in vivo using a SCID mouse model.Results: Following copanlisib exposure, we observed apoptosis in the sensitive cell lines (50-80% AN-V+ cells) but not in resistant cell lines (1-5% AN-V+ cells). We saw an increased cell cycle arrest in G1 in the sensitive cell lines, but not in the resistant cell lines. RPPA performed at baseline revealed a pattern of low p-S6 at the serine positions 235/236 and 240/244 in sensitive compared to resistant cell lines. Western blot analyses validated the RPPA results. We next performed RPPA following exposure to copanlisib, which resulted in a greater decrease in p-S6 in the sensitive cell lines NCI-H929 and L363 (53-83%, 73-93% respectively) compared to resistant cell lines COLO-677 and JJN3 (5-27%, and 38-67%, respectively). The pharmacodynamic p-S6 response was maintained following 24hr and 48hr of drug exposure. These findings were further supported with western blot analysis and phospho-flow. Treatment with copanlisib in combination with carfilzomib or BETi showed potentiation by EOHSA statistics, but this was not seen in with venetoclax. In xenograft models, treatment with copanlisib 10mg/kg by tail vein injection twice daily every 7 days resulted in regression of tumor growth compared to vehicle control. In the L-363 xenograft model, single agent copanlisib resulted in greater tumor regression than single agent carfilzomib.Discussion: Copanlisib demonstrated pre-clinical anti-tumor activity as a single agent and in combination with conventional and novel agents in vitro and in vivo . The low nanomolar range IC50 values correlated with low baseline and post-treatment p-S6, which may allow for the development of a pharmacodynamic FACS based biomarker assay to select patients most likely to benefit from a copanlisib based combination therapy. DisclosuresSlamon:Pfizer: Equity Ownership, Honoraria, Research Funding; Eli Lilly: Consultancy; Bayer: Consultancy; Biomarin: Consultancy, Equity Ownership; Novartis: Honoraria, Research Funding.

The Role of Marrow Microenvironment in the Growth and Development of Malignant Plasma Cells in Multiple Myeloma.

The development and effectiveness of novel therapies in multiple myeloma have been established in large clinical trials. However, multiple myeloma remains an incurable malignancy despite significant therapeutic advances. Accumulating data have elucidated our understanding of the genetic background of the malignant plasma cells along with the role of the bone marrow microenvironment. Currently, the interaction among myeloma cells and the components of the microenvironment are considered crucial in multiple myeloma pathogenesis. Adhesion molecules, cytokines and the extracellular matrix play a critical role in the interplay among genetically transformed clonal plasma cells and stromal cells, leading to the proliferation, progression and survival of myeloma cells. In this review, we provide an overview of the multifaceted role of the bone marrow microenvironment in the growth and development of malignant plasma cells in multiple myeloma.

Multidirectional pattern of hair growth with carflizomib use for multiple myeloma

Extensive use of novel therapies for multiple myeloma has been accompanied by intriguing toxic side effects affecting various organs and organ systems. Although skin effects with some of these medications have been well-documented, hair changes are fairly rare. We report herein a unique case of a patient with myeloma who developed multidirectional pattern of scalp hair growth starting at 14 months into treatment with cafilzomib. This pattern of hair growth had not previously been described in the literature.Management and outcome: The patient had a near-complete response to caflizomib, and continues on this maintenance treatment regimen to the present day. There has not been any change in the unusual hair appearance and texture. A score of 5 on the Naranjo nomogram makes the causality relationship between carfilzomib use and the multidirectional hair growth probable. The mechanism by which carfilzomib causes this hair change remains to be elucidated.

Proteasome inhibition: the dawn of novel therapies in multiple myeloma.

Proteasome inhibition: the dawn of novel therapies in multiple myeloma.

US Cost Burden of Relapsed Refractory Multiple Myeloma during Third and Later Lines of Treatment

Background: Several novel therapies for multiple myeloma (MM) have been approved in recent years. While these therapies have demonstrated improvement in real-world tumor responses and progression-free survival, the cost burden of late-line relapsed refractory MM is not well understood. The objective of this retrospective cohort analysis of US claims data was to examine total, MM-related, and adverse event (AE)-related healthcare costs for patients with MM at different lines of treatment (LOTs), with a focus on patients at third (3L) or later (4L+) LOT. Methods: The study identified an incident cohort of treatment-naïve patients with MM aged ≥18 years from the PharMetrics Plus (IQVIA™, Durham, NC) database of US commercial claims and included patients had a first diagnosis of MM (Index date) between January 1, 2012 and December 31, 2016 and received ≥1 MM therapy during the ≥1-year follow-up period. Endpoints included all-cause and MM-related costs per patient per month (PPPM), common AEs, AE-related costs per episode, and proportion of patients requiring AE-related hospitalization. Descriptive analyses were conducted based on LOT (first-line [1L], second-line [2L], 3L and 4L+) which was defined using all MM drugs of interest observed within 28 days of use of the first MM drug, whereas end of a LOT was identified using a 90-day gap in the therapy regimen or use of a new agent outside the 28-day window. All-cause and MM-related costs were compared between patients indexed from 2012-2014 and 2015-2017 (ranges based on the availability of new MM drugs) using a univariate generalized model with log link and gamma distribution. Results: Of the 2,120 patients in the incident cohort, 799 (37.7%) and 390 (18.4%) patients received 3L and 4L+ treatments, respectively. Mean (standard deviation) age at initial MM diagnosis was 58.9 (8.9) and 58.8 (8.6) years for patients progressing to 3L and 4L+. Patients at 3L or 4L+ had greater use of novel therapies (29.2% and 66.9%, respectively) vs patients at 1L (1.4%) and 2L (12.0%). Mean all-cause and MM-related total costs PPPM were higher in 3L and 4L+ vs the mean costs for the entire cohort (Table 1). Costs were significantly greater in patients indexed later (2015-2017) vs earlier (2012-2014) during the study (before inflation adjustments). The most frequent AEs after initial MM diagnosis included hematologic AEs (anemia [79.3%], neutropenia [40.9%], and thrombocytopenia [38.2%]), pneumonia (32.6%), and bone pain (72.9%). The median duration of most AEs was short (1.0-5.0 days). The AE-related cost per episode of these AEs was high and increased during later lines of therapy, largely driven by increased inpatient and outpatient costs (Table 2). Costs were highest across lines of therapy for anemia, neutropenia and pneumonia. Conclusion: Patients in 3L and 4L+ of MM treatment incurred high healthcare costs that followed a typical cost distribution ranging from $18,000 to $22,000 PPPM (median values), with several patients incurring much higher costs that swung mean values substantially upward ($89,000 and $40,000 PPPM, respectively). Costs of managing AEs followed a similar distribution but were somewhat similar across LOTs, with median values ranging from $2,000 to $4,500 per episode and mean values exceeding $30,000 per episode. Additional research should focus on better understanding patients with high cost values, and other costs of managing MM and associated AEs that were not addressed in this analysis. Acknowledgments: Medical writing assistance was provided by Mary E. Morgan PhD at Fishawack Indicia Ltd UK and funded by GlaxoSmithKline. Programming was provided by Kainan Sun, an employee of IQVIA. This study (HO-18-18615) was funded by GlaxoSmithKline. Disclosures Felber: GlaxoSmithKline: Employment, Equity Ownership. Chen:IQVIA: Employment; GSK: Research Funding. Willson:GSK: Equity Ownership; GSK: Employment. Bell:GlaxoSmithKline: Equity Ownership; GlaxoSmithKline: Employment. Simard:GlaxoSmithKline (former employee): Employment; Medtronic (current employee): Employment. Nunna:GSK: Research Funding; IQVIA: Employment. Dharmani:GSK: Employment. Stirnadel-Farrant:GSK: Employment, Equity Ownership. Wang:GSK: Employment; BMS: Equity Ownership. Bruno:GSK: Employment; BMS: Equity Ownership.

PS1547 LONG‐ACTING G‐CSF (LIPEGFILGRASTIM, “LONQUEX”) FOR STEM CELL MOBILIZATION IN MULTIPLE MYELOMA PATIENTS UNDERGOING AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT)

Background:Autologous stem cell transplantation (ASCT) is a standard of care in eligible newly‐diagnosed patients with multiple myeloma (MM), many of whom will require a second ASCT in their disease course. Therefore, successful, high‐yield mobilization of hematopoietic stem cells (PBSCs) is of particular importance in these patients. Pegfilgrastim, a pegylated GCSF with extended serum half‐life, maintains therapeutic levels over 2 weeks following single‐dose subcutaneous (SC) injection. Several studies have shown pegfilgrastim to be successful in adequately mobilizing PBSCs for ASCT in MM patients, however these studies were mostly performed prior to the introduction of novel therapies in MM. Lipegfilgrastim (“Lonquex”, Teva) is a novel long‐acting r‐metHu GCSF produced by the conjugation of a single 20‐kDa polyethelene glycol to the natural O‐glycosylation site of GCSF. Lonquex has been shown to shorten the time of neutropenia in patients undergoing conventional chemotherapy. Lonquex has not previously been studied for stem cell mobilization in MM patients undergoing ASCT.Aims:Evaluate the efficacy and tolerability of a single SC injection of Lonquex in mobilizing cells for ASCT in 24 patients with MM (ClinicalTrials.gov ID: NCT02488382).Methods:12 Males and 12 Females were enrolled after Bortezomib (13 pts) or Lenalidomide (11 pts)‐ baseline induction therapy. Lonquex was given as a single, 6 mg SC injection. PBSCs were collected using the COBE Spectra Apheresis System (Caridian BCT, Lakewood, CO, USA, vv. 6.1 or 7.0.) A 4‐fold estimated blood volume was processed daily in 4–5 hours. CD34+ cells were enumerated using flow cytometry, and apheresis was initiated at a PBSC count > 106 cells/L. 1–3 leukapheresis procedures were performed, with mobilization failure defined as a yield of <2 x 106 cells/kg body weight over 3 procedures. Target CD34 number was 6 x 106 CD34+ cells/kg.Results:Mobilization was started at 3 (range: 2–5) days after Lonquex injection with a median CD34+ count of 22.65 (range: 3.36–105) x 106 cells/L. Efficiency per collection and total yield are depicted in Figure 1. The median total CD34+ cells mobilized was 7.26 (range: 0.77–12.4) x 106/kg. One patient failed to mobilize, and two patients mobilized <6 x 106 cells/kg; these patients underwent successful mobilization with plerixafor. Toxicity associated with Lonquex was mild and transient; adverse effects included myalgia (13%), arthralgia (13%), bone pain (13%), headache (8%) and vomiting (4%). Twenty‐one patients underwent ASCT following high‐dose melphalan. The median CD34+ dose infused at ASCT was 3.9 (range: 3.0–6.0) x 106 cells/kg. Outcomes did not differ from historical controls. 16 patients developed mucositis (11 gr. I‐II, 5 gr. III) and 19 experienced neutropenic fever. Three patients received PRBCs and 17 patients received platelet transfusions. All patients engrafted; median neutrophil engraftment occurred on day 11 (range: 11–13) and platelet counts > 20 x 109 cells/L were achieved on day 13 (range: 11–15).Summary/Conclusion:A single, 6 mg SC injection of Lonquex in patients with MM resulted in efficient and safe PBSC mobilization, with adequate CD34+ cell yield, mild transient side effects and successful engraftment following ASCT. Results were not different from historical controls using GCSF or recombinant pegfilgrastim. Lonquex is administered only once, rather than over multiple days, increasing convenience and potentially improving both compliance and quality‐of‐life (QoL). Our findings may serve the basis for a well design 2‐arm comparative study.image

Common Adverse Effects of Novel Therapies for Multiple Myeloma (MM) and Their Management Strategies.

The purpose of this review was to evaluate management strategies for common adverse effects of novel therapies in multiple myeloma (MM), including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and a histone deacetylase inhibitor. There are several adverse effects that occur across multiple classes of antimyeloma drugs, including rash, peripheral neuropathy, infusion reactions, and cardiotoxicity, but most can be managed without complete discontinuation of the agent or abandonment of the class. Additionally, several agents have critically important drug-drug interactions or dose-modification implications in hepatic or renal insufficiency that can be easily overlooked, and exacerbate adverse effects. As treatment of MM moves from fixed-duration traditional chemotherapy to novel agent-based regimens, commonly administered continuously until disease progression or intolerable toxicities, providers must adopt their management strategies for both acute and long-term adverse effects. Early and frequent monitoring for therapy-related complications, dose adjustments when needed, and timely treatment for toxicities are all important steps toward ensuring longevity of treatment from a limited array of therapeutic options that currently exist for a disease with a relapsing and remitting course.

A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells.

Novel therapies for multiple myeloma (MM) can target mechanism(s) in the host-MM bone marrow (BM) microenvironment mediating MM progression and chemoresistance. Our studies showed increased numbers of tumor-promoting, immunosuppressive and drug-resistant plasmacytoid dendritic cells (pDCs) in the MM BM microenvironment. pDC-MM cell interactions upregulate interleukin-3 (IL-3), which stimulates both pDC survival and MM cell growth. Since IL-3 R is highly expressed on pDCs in the MM BM milieu, we here targeted pDCs using a novel IL-3 R-targeted therapeutic SL-401. In both in vitro and in vivo models of MM in its BM milieu, SL-401 decreases viability of pDCs, blocks pDC-induced MM cell growth, and synergistically enhances anti-MM activity of bortezomib and pomalidomide. Besides promoting pDC survival and MM cell growth, IL-3 also mediates progression of osteolytic bone disease in MM. Osteoclast (OCL) progenitor cells express IL-3 R, and we show that SL-401 abrogates monocyte-derived OCL formation and bone resorption. Finally, we show that SL-401 also decreases the viability of IL-3 R-expressing cancer stem-like cells in MM. Overall, our study provides the preclinical basis for clinical trials of SL-401 to block pDC-induced MM cell growth, inhibit osteoclastogenesis and target MM stem-like cell subpopulations to improve patient outcome in MM.

Common Adverse Effects of Novel Therapies for Multiple Myeloma (MM) and their Management Strategies: A Need for Clinical Research Priority

Common Adverse Effects of Novel Therapies for Multiple Myeloma (MM) and their Management Strategies: A Need for Clinical Research Priority

Characterization of Lineage Vs. Context-Dependent Essential Genes in Multiple Myeloma Using Crispr/Cas9 Genome Editing

Multiple Myeloma (MM) remains an incurable malignancy in part because of an incomplete understanding of which genes are critically responsible for MM cell survival and proliferation. To address this unmet need, and building on our recent functional genomics studies with the CRISPR/Cas9 gene editing platform (ASH 2015; Int. MM Workshop, Rome 2015), we reasoned that quantification of sgRNA depletion in the absence of any treatment could identify genes essential for the survival or proliferation of MM cells and better define their role as candidate therapeutic targets. To this end, we transduced Cas9-expressing RPMI-8226 and MM.1S cells with the lentiviral genome-scale GeCKO pooled library of sgRNAs. After culture of these cell lines for 2, 6, 8 or 12 weeks without any treatment, we identified, based on next generation sequencing for the sgRNA sequences, genes with significantly depleted sgRNAs (4-6 sgRNAs/gene, >2-fold average depletion, FDR=0.05, based on MAGECK algorithm) in Cas9+ cells compared to their initial sgRNA plasmid pools, baseline cultures, or isogenic parental Cas9-negative cells. These results were confirmed for each cell line with a 2nd independent genome-wide analysis and with a focused sgRNA library containing a subset of candidates defined by the genome-wide analyses. We compared these results with data from our in-house or publicly available CRISPR/Cas9 gene editing studies, involving a total of 50 cell lines from other hematologic malignancies (leukemia, lymphoma) and from 8 different types of solid tumors. We identified 3 broad categories of essential genes in MM cells: a) core essential genes, with sgRNA depletion across the majority of MM and non-MM lines of our study, representing cellular processes critical for practically all lineages (e.g. genes involved in regulation of basic transcription factor complexes, ribosomal function, proteasome, spliceosome, structural proteins for mitochondria and other key organelles, et.c.); b) genes selectively essential for MM cell lines, but not for the overwhelming majority of leukemia, lymphoma or solid tumor cell lines; c) genes with a role in small subset(s) of cell lines, across diseases, which harbor defined genetic features correlating with this dependency. We integrated our CRISPR/Cas9-based data on MM-selective essential genes with a reanalysis of the Achilles Heel shRNA screen in MM and non-MM cell lines (10 and 493, respectively) of the Cell Line Encyclopedia Program (CCLE) program. We applied a series of statistical tests (e.g. Wilcoxon rank test or marker selection feature of GENE-E algorithm with 1000 permutation tests) to identify genes with a significantly lower rank in sgRNA or shRNA depletion in MM vs. non-MM cell lines, across different specific thresholds for fold change and statistical significance. We identified more than 50 high-value candidate target genes with preferential essentiality in MM, compared to non-MM cell lines of diverse lineages. Prominent examples of such MM-selective, essential genes included: transcription factors (e.g. IRF4, CCND2, MAF, NFKB1, NFKB2, RELA, RELB); otherNF-kB-related genes (e.g. IKBKB); PIM2 (but not PIM1 or PIM3 in this cell line panel); regulators of protein homeostasis, including diverse E2 and E3 ubiquitin ligases; and several other known or biologically-plausible dependencies which are under further evaluation. Many of these MM-selective dependencies exhibited significantly higher expression in MM, compared to non-MM cells, both in cell lines (based on the CCLE dataset) and patient-derived samples (comparison of Broad/MMRF vs. TCGA datasets, respectively). Notable observations of context-dependent essential genes include ARID1A in MM.1S cells (plausibly due to deficiency in its paralog ARID1B); and cases of both MM and non-MM cells with RAS mutations but lack of dependency on that gene. Targeting of lineage-specific dependencies (e.g. ER or AR in breast or prostate Ca, respectively) has provided major clinical benefit in some tumors; while context-specific dependencies are a cornerstone of molecularly-guided individualized treatments. Therefore, by identifying lineage- and context-dependent essential genes for MM, our integrated genome-wide CRISPR/Cas9 and shRNA analyses in molecularly annotated panels of MM vs. non-MM cell lines provide an attractive framework towards designing novel therapies for MM. DisclosuresNo relevant conflicts of interest to declare.

Patterns and Determinants of Cancer-Directed Drug Therapy in Medicare Beneficiaries with Multiple Myeloma

Introduction: The introduction of novel therapies for multiple myeloma (MM) such as immunomodulatory drugs and proteasome inhibitors has led to considerable improvements in clinical outcomes, but the disease remains incurable. Both conventional and to a lesser extent novel therapies come with toxicity and treatment decisions need to be individualized based on factors such as age and comorbidities. Little is known about the frequency of drug therapy use in MM in real-world clinical practice.Objective: This study aimed to assess the prevalence of, and determinants associated with cancer-directed drug therapy among newly diagnosed symptomatic MM (NDMM) Medicare beneficiaries.Methods: This retrospective cohort study used Surveillance, Epidemiology, and End Results (SEER) registry and linked Medicare Claims (SEER-Medicare) data. We identified patients (>65 years) with an incident diagnosis of MM from 2007-2011 and associated claims from 2006-2012. Eligible patients had continuous enrollment in Medicare Parts A and B (12 months prior to) and in Part D (two months prior to) through six months post-diagnosis, or death (among patients who died within 6 months post diagnosis). Patients were required to have evidence of CRAB symptoms (hypercalcemia, renal insufficiency, anemia and bone disease) based on intravenous bisphosphonate utilization and ICD-9 diagnosis codes found in claims from six months pre- to one month post-MM diagnosis. Patients were followed until death; or censoring due to non-continuous Parts A, B and D enrollment after six months post diagnosis. We identified receipt of MM-directed therapies from Medicare claims during the follow up period using NDC and HCPCS codes for the following agents: bendamustine, bortezomib, cyclophosphamide, (liposomal) doxorubicin, interferon alfa-2b, etoposide, lenalidomide, melphalan, thalidomide, vincristine, and vorinostat, excluding dexamethasone monotherapy. The distribution of frontline therapies received within 90 days of diagnosis was characterized descriptively. Charlson Comorbidity Index (CCI) was derived based on claims within one year pre-diagnosis using a validated algorithm. Baseline characteristics among those who received any MM-directed treatment were compared to those who did not using t-tests and Chi-square tests for continuous and categorical variables, respectively. We also compared treatment rates in those diagnosed in an early (2007-2009) versus late period (2010-2011).Results: Of 3,391 patients with NDMM who met our inclusion criteria, 2,599 (76.6%) received MM-directed therapy during follow up. The median time until treatment initiation was 49 days (range: 0-2156). The treatment rate using a landmark analysis of patients who survived at least 6 months produced congruent results (77% treated patients). Those who initiated therapy were younger (mean age: 75.6 years) compared to untreated patients (mean age: 78.7 years, p<.001) and had a lower comorbidity burden based on the CCI (p<.001) (Table 1). Among those with CCI=0, 81.7% received treatment, while 79.0% of those with CCI=1 and 69.0% of those with CCI>1 received treatment (p<0.001). African American patients were less likely to receive therapy (68.6%) compared to Caucasians (77.7%) and those who were of another race/ethnicity (79.7%, p<0.001). The proportion of patients initiating treatment was highest in the West (78.8%) and Midwest (78.7%) versus the South (75.1%) and Northeast (72.6%) (p<0.001). Among patients receiving treatment, the following drug therapies were observed within three months of diagnosis: bortezomib (n=937 patients, 36.1%), lenalidomide (n=633,25.5%), melphalan (n=398, 15.9%), thalidomide (n=404, 15.5%) and cyclophosphomide (n=75, 2.8%). Of patients diagnosed in 2007-2009, 75.6% received MM-directed drug treatment compared to 78.0% of those diagnosed in 2010-2011 (p=0.12).Conclusion: Among NDMM patients, 23% did not receive MM-directed therapy. Treatment was associated with younger age and a lower comorbidity burden. Racial disparities, with a lower proportion of African American treated patients, and geographic variation in treatment rates were also observed. Future research is needed to assess the extent to which these determinants reflect patient preferences versus other factors, such as barriers to treatment access. [Display omitted] DisclosuresSlejko:PhRMA: Research Funding; Takeda: Research Funding; National Pharmaceutical Council: Research Funding. Romanus:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Goto:Novartis AG: Research Funding. Onukwugha:IMPAQ International: Honoraria; Bayer Healthcare: Research Funding; Takeda: Research Funding. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Yong:Takeda: Employment.

Management of Multiple Myeloma and Usage of Bortezomib: Perspective from India and Ukraine.

Novel treatment strategies have remarkably improved the multiple myeloma (MM) patients’ survival, with associated increased costs. A joint panel meet of international experts from India and Ukraine was held in New Delhi on May 19, 2016 focusing on MM management, bortezomib role, unmet medical needs, and current challenges. The health-care system for oncology in India is majorly private vs. government-based in Ukraine. In India, electrophoresis, serum-free light chain assays, bone marrow tests, and X-rays are available modes of diagnosis. Despite of the numerous cancer centers and stem cell transplant centers, most patients do not prefer transplant owing to its high-cost and social stigma. Majority of the patients are treated with bortezomib or lenalidomide-based regimens. Most patients buy drug themselves. The expanding generic drugs market is a ray of hope for the affordable drugs. In Ukraine, immuno-fixation, bone marrow analysis, and magnetic resonance imaging are common diagnostic modalities. Due to high cost, only few patients undergo transplant. Bortezomib-based regimens are preferred in most of the patients; however, usage is limited due to high costs and lack of funds. Thalidomide-based regimens are used for maintenance therapy due to affordability. In case of relapsed MM, bortezomib is preferred in triple therapy; however, more affordable option is cyclophosphamide, thalidomide, and dexamethasone (CTD). Issues, such as cost containment, common treatment strategies, enhanced collaboration, and improved health-care access, need immediate attention. High-quality generics access will improve outcomes and support health-care cost containment. Pharmacoeconomic studies and head-to-head trials are warranted to determine the cost-effectiveness and benefit of novel therapies in MM.

The Rapid Evolution of Novel Therapies in Multiple Myeloma.

The Rapid Evolution of Novel Therapies in Multiple Myeloma.

Stem Cell Mobilization after Various Induction Regimens in Patients with Multiple Myeloma

Stem cell mobilization after various induction regimens in patients with multiple myelomaIntroduction: Rapid development of novel therapies for multiple myeloma has led to a significant improvement in response to the treatment. Stem cell mobilization before autologous stem cell transplantation is a source of considerable costs of transplant procedure. Whether modern induction regimens affect outcome of stem cell mobilization has not been extensively studied.Aim: The goal of this study was to compare efficacy of stem cell mobilization after different induction regimens in patients with multiple myeloma. The primary goal was to compare CTD (cyclophosphamide, thalidomide, dexamethasone), CVD (cyclophosphamide, bortezomib, dexamethasone) and VTD (bortezomib, thalidomide, dexamethasone) and regimens in terms of succesful stem cell collection.Methods: All patients with multiple myeloma who have been planned for stem cell collection and were treated with one of the above mentioned regimens were included in this retrospective analysis. The demographic data, amount of stem cells collected, number of days needed to reach the target collection were recorded. All patients received high dose cyclophosphamide 2,5 g/m2 prior to stem cell collection and were primed with G-CSF twice daily from day 5. The collection was started at day 10. Collection goal was 8x106/kg CD34+ cells.Results: 15 patients received CTD, 25 patients CVD and 16 patients VTD regimen before stem cell collection. Groups were comparable according to age, gender and myeloma stages. Mean collected cells at the end of collection were 9.2 (SD 2.8) for CTD, 12.3 (SD 5.6) for CVD and 10.1 (SD 2.1) for VTD (p=0.066). Mean daily harvest was 3.4, 8.0 and 7.6 x106/kg respectively (p=0.01). Mean days needed to reach desired harvest were 3, 2.25 and 1.6 days (p=0.001). No collection failure was observed.Conclusion: The best collection results were seen in patients after induction with CVD or VTD regimen. VTD regimen also required the least days for collection and seems to be most beneficial for cost of collection. CTD regimen shows the least efficacy in stem cell collection before autologous transplantation. All patients managed to harvest for at least one stem cell transplant. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

International Validation of a Dithiothreitol (DTT)-Based Method to Resolve the Daratumumab Interference with Blood Compatibility Testing

IntroductionDaratumumab (DARA), an IgG1k human monoclonal antibody (Ab) against CD38, is a promising novel therapy for multiple myeloma. However, direct binding of DARA to endogenous CD38 on reagent red blood cells (RBCs) interferes with routine blood bank serologic testing. We recently showed that treating reagent RBCs with DTT eliminates the DARA interference by denaturing cell surface CD38, allowing the safe transfusion of patients on DARA.1 This multicenter international study was aimed at validating the DTT method for use by blood banks worldwide.MethodsParticipating blood banks received two plasma sample unknowns. Sample 1 was spiked with DARA alone (5 mcg/mL). Sample 2 was spiked with DARA plus a clinically significant RBC Ab (anti-D (Rh immune globulin) or monoclonal anti-Fya or anti-s). Sites were instructed to first perform an Ab screen using their usual method (tube, gel, or solid phase), then to repeat the Ab screen using DTT-treated RBCs (gel or tube). If the Ab screen remained positive with DTT-treated RBCs (Sample 2), sites were to identify the unknown Ab using a DTT-treated RBC panel (gel or tube.) The primary outcome measure was the proportion of sites able to successfully identify the unknown Ab in the presence of DARA. Qualitative data were collected by online survey.ResultsPaired plasma sample unknowns were shipped to 25 study sites in North America, South America, Europe, Asia, and Australia/New Zealand. Data were received from 23 sites to date (Table). For the initial Ab screen, 10 sites used tube testing, 7 sites used gel, and 6 sites used solid phase. All sites observed DARA interference with the Ab screen (false positive agglutination reactions). All sites reported no DARA interference using DTT-treated RBCs. For Ab identification (Sample 2), 13 sites used tube testing and 10 sites used gel. 23/23 sites (100%) were able to correctly identify the unknown Ab using the DTT method. The Abs identified were: anti-Fya (9/9), anti-s (8/8), and anti-D (6/6). Feedback on the DTT method was mainly positive, with 86% of sites that responded to the survey indicating that they planned to use the DTT method to manage clinical samples from DARA-treated patients.ConclusionDARA consistently interferes with all three Ab screening methods currently used by blood banks (tube, gel, and solid phase.) Using DTT-treated RBCs, 23/23 (100%) of blood bank laboratories from around the world were able to identify a clinically significant Ab initially masked by the presence of DARA. The DTT method is robust, reproducible, and can be implemented by blood banks globally to help provide safe blood products to patients on DARA. As DTT denatures Kell antigens, K- RBC units should be provided when using the DTT method.1. Chapuy CI, Nicholson RT, Aguad MD, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion. 2015;55(6pt2):1545-1554. [Display omitted] DisclosuresUnger:Janssen: Employment. Doshi:Janssen: Employment. Kaufman:Janssen: Consultancy, Research Funding.

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib.

Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination with lenalidomide or bortezomib for the treatment of lenalidomide- and bortezomib-refractory patients. In ex vivo assays, mainly evaluating antibody-dependent cell-mediated cytotoxicity, and in an in vivo xenograft mouse model, we evaluated daratumumab alone or in combination with lenalidomide or bortezomib as a potential therapy for lenalidomide- and bortezomib-refractory multiple myeloma patients. Daratumumab induced significant lysis of lenalidomide/bortezomib-resistant multiple myeloma cell lines and of primary multiple myeloma cells in the bone marrow mononuclear cells derived from lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide effectively reduced the tumorigenic growth of primary multiple myeloma cells from a lenalidomide- and bortezomib-refractory patient. Our results provide the first preclinical evidence for the benefit of daratumumab plus lenalidomide combination for lenalidomide- and bortezomib-refractory patients.

Resolving the daratumumab interference with blood compatibility testing.

Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. Normal plasma samples spiked with DARA (0.1-10 µg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients.

Impact of Novel Treatments on Multiple Myeloma Survival

BACKGROUNDMultiple myeloma survival has significantly improved with the introduction of new therapeutic classes in the early 2000s. The magnitude of improvement in survival with better tolerated therapy is essentially transforming the disease from an acute condition, to a potentially manageable chronic disease . The impact of further advances in multiple myeloma therapy is not yet known but can be projected based on analysis of historical data and positive outcomes that are expected for future clinical trials. METHODOLOGYAnalysis of data from the Surveillance, Epidemiology and End Results (SEER) were performed using SEERStat software. The first part of this analysis compares the median relative survival, based on cohort analysis, and five year relative survival, based on period analysis, for different time periods that coincided with the introduction of newer, better tolerated, more effective therapies for treating multiple myeloma. The second part of this analysis attempts to estimate future changes in survival, that may potentially result from additional disease modifying therapies planned to become available over the next 5-10 years. This will be accomplished through analysis of evidence-based metrics including extrapolation from early phase clinical trial data and validation with key opinion leaders. RESULTSMedian, cumulative and 5 year relative survival of multiple myeloma have improved over the last decade primarily as a result of the introduction of newer therapies such as thalidomide, lenalidomide and bortezomib. Based on analysis of SEER data, median relative survival from the 1980s to 2000 showed modest changes, averaging approximately 30 months through the two decades. Thereafter, median survival increased to nearly 50 months by 2007 (FIGURE 1). Five year relative survival improved from about 30% in 1990 to over 46% in 2010 (FIGURE 2). SUMMARYThis analysis highlights the dramatic improvements in multiple myeloma survival over the last three decades in the U.S., and demonstrates the transformative impact and value of novel therapies for multiple myeloma. The most substantial improvements were observed during the period between 2001 and 2007, when multiple myeloma median survival rates increased by 45%. This improvement has predominantly been driven by the introduction of novel classes of drugs and agents, including immunomodulatory and proteasome inhibitors. Over the next 10 years we expect to see a similar trend, where further advances in the treatment of multiple myeloma will yield additional novel therapies that could result in improvements of comparable or better magnitude. [Display omitted] [Display omitted] DisclosuresKaura:Celgene: Employment, Equity Ownership. Kiely:Celgene: Employment, Equity Ownership. Hussein:Celgene: Employment, Equity Ownership. Durie:Celgene: Advisory Board Celgene, IRC Onyx, DMC Millennium, IRC J&J Other.

Novel Agents for the Treatment of Multiple Myeloma: Proteasome Inhibitors and Immunomodulatory Agents

The integration of novel agents into the treatment of multiple myeloma (MM) has shifted the focus from an incurable disease to one that is chronic, with a realistic hope of someday achieving a cure. Proteasome inhibitors and immunomodulatory agents are the backbone of novel therapies for MM. These agents are particularly important for patients with relapsed or refractory disease, a fate faced by the majority of myeloma patients over the course of their disease. Review of recent clinical trial data for the proteasome inhibitors and immunomodulatory agents, including clinical efficacy and safety information, will assist the advanced practitioner in oncology with integrating these data into the current treatment guidelines for MM.