Citations

11041 Background: Twitter (TW) is an essential tool in the medical community. Few studies have examined the use of TW by medical trainees. We aimed to assess its utilization among trainees in hematology-oncology related areas (HORAs). Methods: 576 training programs in HORAs were obtained. We contacted a potential pool of 3,142 trainees. A 50 item survey was distributed between 2/2019-5/2019, focusing on: demographics, professional use, attitudes toward TW, and patient interactions. Responses were analyzed using parametric descriptive statistics. Results: 442 responses (14% response rate) were received; 203 (46%) used a TW account for professional activities. See table for demographics. The most common reasons for using TW were: continuous education (73%), dissemination of information (62%), and networking (62%). > 80% of users have positive views on using TW for: promoting academic discussions (92%), trainees education (89%), and conference networking (83%). 50 (25%) have used TW for collaborations, with abstracts and papers being the most common (20%). Most agreed or strongly agreed that TW: is a useful education tool (89%), and might be useful for career advancement (85%). The most common challenges were: the value of TW content can be decreased by irrelevant content and biased sources (64%), not peer-reviewed (51%), and difficulty searching information (50%). 68% considered that programs should promote the engagement of trainees, but only 21% reported instruction in the use of TW. 83% agree or strongly agree that TW is useful for physicians and patient interactions, but 82% have concerns about legal repercussions. Conclusions: Almost half of trainees in HORAs use TW for professional activities. The most common uses are for education, dissemination of information and networking. Most trainees that use TW have positive views regarding education and academic collaborations. Use of Twitter may strengthen trainees’ education, provide mentorship opportunities, and promote career advancement. Challenges on TW use should continue to be addressed. [Table: see text]

TPS8551 Background: Multiple myeloma (MM) remains an incurable disease, with estimated median survival of 8–9 months in patients with relapsed or refractory (R/R) disease (Kumar et al. 2014; Usmani et al. 2016). There is no uniform standard of care for R/R MM, and combinations used in later lines have diminishing responses, especially after re-exposure to previously received classes of therapy (Gandhi et al. 2019). New targets and treatment modalities are needed. Fragment crystallizable receptor-like 5 (FcRH5) is expressed on myeloma cells across lines of therapy, and is overexpressed by myeloma cells with 1q21 gain; expression in healthy tissue is restricted to the B-cell lineage, and is retained in plasma cells (Li et al. 2017). BFCR4350A is an IgG-based T-cell-dependent bispecific antibody that was specifically engineered to target the most membrane-proximal domain of FcRH5 on myeloma cells and cluster of differentiation 3 (CD3) on T cells, with dual binding resulting in efficient immune synapse formation and T-cell killing of myeloma cells. BFCR4350A demonstrates potent killing of plasma cells and patient-derived myeloma cells (including those with low levels of FcRH5 expression) in vitro, and complete depletion of bone marrow plasma cells in primates, without severe or prolonged cytokine release (Li et al. 2017). GO39775 (NCT03275103) is an open-label, multicenter Phase I dose-escalation and dose-expansion trial evaluating the safety, pharmacokinetics (PK), and activity of BFCR4350A monotherapy in patients with R/R MM. Methods: Patients must be aged ≥18 years and must have R/R MM for which no established therapies are available or appropriate, or be intolerant to those therapies. Patients with prior CAR-T therapy and/or prior BCMA-directed therapy are not excluded. BFCR4350A is administered by intravenous infusion, and q3w dosing with Cycle 1 single-step or multi-step dosing is being investigated in dose-escalation (Arms A and B, respectively). Enrolment into both arms is ongoing, with patients receiving up to 17 cycles of treatment until disease progression or unacceptable toxicity. Primary objectives are to evaluate safety (including the maximum tolerated dose and dose-limiting toxicities) and to identify a recommended Phase II dose. Secondary objectives include assessment of PK, activity, immunogenicity, and pharmacodynamic biomarkers. Clinical trial information: NCT03275103 .

The novel coronavirus, SARS-CoV-2, was first detected as a respiratory illness in December 2019 in Wuhan City, China. Since then, coronavirus disease 2019 (COVID-19) has impacted every aspect of our lives worldwide. In a time when terms such as social distancing and flattening the curve have become a part of our vernacular, it is essential that we understand what measures can be implemented to protect our patients and healthcare workers. Undoubtedly, healthcare providers have had to rapidly alter care delivery models while simultaneously acknowledging the crucial unknowns of how these changes may affect clinical outcomes. This special feature reviews strategies on how to mitigate transmission of COVID-19 in an effort to reduce morbidity and mortality associated with the disease for patients with cancer without infection, for patients with cancer with COVID-19 infection, and for the healthcare workers caring for them, while continuing to provide the best possible cancer care. [Editor’s Note: This article includes the most current information available at time of publication; however, recommendations regarding public safety and practice may change rapidly in this situation. Individuals should get the most up to date information from the CDC website.]

Abstract Background: Multiple mechanisms exist for the positive selection of genes involved in oncogenesis such as gene amplification and transcriptional deregulation associated with chromosome translocations. Here we describe the case of a myeloma cell line that over time acquired extra copies of a derivative chromosome 4 involved in the t(4;14). These changes occurred over time both in vitro (in the generated JMW myeloma cell lines) as well as in vivo from extramedullary myeloma samples collected from the patient at various time points. In the case of the t(4;14)(p16;q32) 30% can be unbalanced translocations, always with loss of the der(14) and consequent loss of the FGFR3 gene expression, suggesting an indispensable role for MMSET located in the der(4). Results: We performed serial analysis on patient samples obtained at 9, 10 and 12 mos from diagnosis, along with a time course analysis of the cell line. At diagnosis the patient tumor cells displayed a complex clinical karyotype subsequently characterized by hypodiploidy, a t(4;14)(p16;q32), 13 monosomy and 17p13.1-. The remaining chromosome 13 and 17 were involved in an unbalanced reciprocal translocation. Notably, over time the cell line duplicated the total chromosome number becoming near-tetraploid. At the time of diagnosis, FISH analysis was performed on the patient sample revealing the translocation t(4;14)(p16.3:q32) in nearly all cells. The t(4;14) was also present in the stable cell line. It was noted that the patient cells exhibited more than one fusion signal per cell for the t(4;14) by FISH. As the disease progresses both in vitro and in vivo, the number of t(4;14)(p16.3:q32) fusion signals detected per cell increased with time suggesting a positive selection of the derivative chromosomes of the translocation. We further analyzed the t(4;14) in the JMW cells by FISH using MMSET/VH, and FGFR3/CH probe combinations. The full-length (MMSET/FGFR3+VH/CH) probe was used to detect the total number of fusions in the JMW cells. At the time of analysis (cell line passage #23), the majority of the cells (69%) had 6 fusion signals per cell while 23% had 5 fusions and 8% of the cells had 4 fusions. We found that most of the cells (88%) displayed 4 fusion signals detected using the MMSET/VH probes. In parallel studies using the FGFR3/CH probes, 61% of the cells had 2 fusion signals and 39% with 1 fusion signal. It is evident that the tumor cells display positive selection of the derivative chromosome der(4) of the t(4;14)(p16.3;q32), accompanied by an increased dosage of the target gene (MMSET) upregulated by the translocation. Conclusion: We present evidence for the amplification of the translocated chromosome in multiple myeloma, which we have termed “trans-amplicons”. Trans-amplicons may provide a selective growth and survival advantage to the myeloma tumor cells in an analogous manner to amplicons of DNA segments, but with much more powerful transcriptional consequences. Importantly, the evolution of genomic instability exemplified by the “trans-amplicons” in the patient cells was paralleled in vitro in the JMW cells.

Abstract Purpose: Lenalidomide (CC-5013) is an analogue of thalidomide and a lead clinical compound in a new group of drugs called IMiDS® which have immunomodulatory properties. Lenalidomide has shown promising results in relapsed refractory myeloma. It has a markedly different side-effect profile compared to thalidomide, with significantly fewer non- hematologic adverse events; myelosuppression, especially neutropenia, is the most common toxicity. We report the results of a phase II trial using the combination of lenalidomide plus dexamethasone (Rev/Dex) as initial therapy for newly diagnosed multiple myeloma. Patients and Methods: 34 patients (23 male and 11 female) were enrolled. Lenalidomide was given orally 25 mg daily on days 1–21 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1–4, 9–12, 17–20 of each cycle. Patients were allowed to go off treatment after 4 cycles of therapy to pursue stem cell transplantation, but treatment beyond four cycles was permitted at the physician’s discretion. For patients continuing therapy beyond 4 months, the dose of dexamethasone was reduced to 40 mg on days 1–4 of each cycle. Objective response was defined as a decrease in serum monoclonal (M) protein by 50% or greater and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours, confirmed by two consecutive determinations at least 4 weeks apart. Sub-classification as very good partial response (VGPR) required in addition to criteria for partial response, >=90% reduction in serum M protein, 24 hour urine M protein less than or equal to 100 mg, and 5% or fewer plasma cells on bone marrow examination. All patients received aspirin (81 mg or 325 mg daily) as prophylaxis against DVT. Results: The median age was 64 years (range, 32–78). All patients were evaluable for response and toxicity. Thirty-one of 34 patients (91%) achieved an objective response to therapy, including 2 patients (6%) achieving a complete response (CR) and 11 patients (32%) achieving very good partial response. Of the 3 patients not achieving an objective response, two met criteria for minor response and one had stable disease. Responses were rapid; the median time to response was 1 month. Adequate stem cells (>3.0 million CD34 cells/kg body weight) were obtained in all patients who proceeded to autologous stem cell transplantation. Forty-seven percent of patients experienced grade 3 or higher non-hematologic toxicity, most commonly fatigue (15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%) and rash (6%). One patient died on study, and this was attributed to infection unrelated to therapy; the patient had stopped all therapy for over a month before the fatal infection occurred. One patient developed a pulmonary embolism, but recovered with therapy; no other patient developed deep vein thrombosis or pulmonary embolism. Conclusion: Rev/Dex is highly active and well tolerated in the treatment of newly diagnosed multiple myeloma with overall responses in over 90% of patients including complete and very good partial responses in 38%. Two large cooperative group trials are currently testing Rev/Dex as initial therapy for multiple myeloma in the United States.

Abstract Background: Thalidomide is an active anti-myeloma agent with single agent activity in all stages of the disease. When combined with dexamethasone disease response is seen in nearly two-thirds of patients with newly diagnosed MM. Though initially evaluated for treatment because of its anti-angiogenic properties and the finding of increased bone marrow angiogenesis in MM, it has become clear that thalidomide exerts its anti-myeloma activity through several different mechanisms. While the mechanism of action of dexamethasone has been studied to a great extent in the setting of myeloma, the molecular basis for the activity of this combination is largely unknown. Methods: Myeloma cells from patients with newly diagnosed MM who were enrolled in a phase III trial (ECOG E1A00) comparing thalidomide and dexamethasone combination (T+D) with dexamethasone alone (D) were studied by gene expression profiling. Samples from diagnosis were compared to those at four months following therapy to study the effect of treatment. Four patients who achieved a partial response with T+D were studied and in addition compared to four patients achieving a partial response with D alone. Plasma cells from bone marrow aspirates were separated by magnetic bead selection of CD138 positive cells and studied using Affymetrix HG-U133A chips using standard methodology. The arrays were analyzed using Genespring 7.2 software following GCRMA normalization and genes with differential expression between the two datasets were examined. Differentially expressed genes were further analyzed using Ingenuity Pathways Analysis program Results: 549 genes were two fold or more differentially expressed between the pretreatment and post treatment samples in the T+D group, of which 275 genes were mapped to different networks using the Ingenuity program. Examination of the canonical pathways demonstrated several pathways that were altered as a result of the therapy. The most significant pathways included those related to immune function including antigen presentation (multiple HLA class II antigens), and PRG2 (NK cell activator). Several mediators of B cell signaling including CD45, PKC (α ,β), SHP2, and Erk1/2 were up regulated following treatment. Increase in the expression of several adhesion molecules including β integrins, fibronectin, VCAM1, L selectin, and LFA3 were noted. Up regulation of IL-6 signaling pathway including gp130, JAK2 and IL8 were noted following therapy. Striking increase in the gene expression for CXCR4 and its ligand SDF-1α was noted as well. 129 genes were differentially regulated by dexamethasone alone, of which 67 were mapped to different networks. The pathways influenced by the dexamethasone alone differed significantly from that of the combination. Conclusion: This exploratory analysis offers an interesting insight into the potential mechanisms of action of the T+D combination in MM. The up regulation of immune response related genes are in accordance with some of the mechanisms described for thalidomide. Also, the differences observed between the patients receiving T+D vs. D allows for assessment of the effects of thalidomide. These findings need confirmation in a larger study.

Abstract Background: Lenalidomide has shown efficacy in patients with relapsed myeloma in phase II and III clinical trials, and is currently being investigated as initial therapy for the disease. We report results of a phase III trial comparing lenalidomide plus high-dose dexamethasone (Dex) versus lenalidomide plus low-dose Dex as first line therapy in newly diagnosed multiple myeloma (MM). Methods: Pts with newly diagnosed, untreated, symptomatic MM were eligible. Pts in both arms received lenalidomide 25 mg/day PO on days 1–21 every 28 days. In addition, patients in the high-dose Dex arm (Arm A) received Dex 40 mg on days 1–4, 9–12, and 17–20 PO every 28 days, while pts in the low-dose Dex arm (Arm B) received Dex 40 mg on days 1, 8, 15, and 22 PO every 28 days. The primary endpoint was best response at 4 months on intent to treat basis. At 4 months pts could go off study for stem cell transplant or elect to continue therapy until progression. Response was defined as a decrease in serum and urine monoclonal (M) protein by 50% or higher. If the serum M protein was unmeasurable, a 90% or higher decrease in urine M protein was required. Responses need to be confirmed at least 4 weeks apart. Patients with disease progression or not responding to lenalidomide within 4 months switched to thalidomide with the same dose of dexamethasone they were receiving (Arms C and D, respectively). An independent Data Monitoring Committee approved release of these results. Results: 445 pts were enrolled: 223 randomized to Arm A and 222 to Arm B. Median age was 65 yrs. Serious adverse event data based on expedited reporting (AdEERS) is available on all pts (see table). Common adverse events of Grade 3 or higher were thromboembolism (18.4% in arm A vs 5.4% in Arm B), infection/pneumonia (18.8% vs 9.0%) and hyperglycemia (5.8% vs 1.8%). Incidence of any grade 4 or higher toxicity was 22.0% in Arm A vs 12.6% in Arm B. Response data is being analyzed. Conclusions: Lenalidomide plus two different schedules of Dex was investigated in this phase III trial. Preliminary results suggest that toxicity rates are higher in the high-dose Dex arm. The differences in the response rates between the two arms will dictate future trials and clinical practice. Major Toxicties (AdEERS) Toxicity Arm A (n=223) Arm B (n=222) Cardiac ischemia (Grade >=3) 2.7% 0.5% Hyperglycemia (Grade >=3) 5.8% 1.8% Infection/Pneumonitis (Grade >=3) 18.8% 9.0% Neuropathy (Grade >=3) 0.9% 0.9% Thromboembolism (Grade >=3) 18.4% 5.4% Any non-Hem toxicity (Grade >=3) 53.4% 36.0% Any toxicity (Grade >=4) 22.0% 12.6% Death (Grade 5) 4.5% 1.4%

Abstract Fluorescence in situ hybridization (FISH) is an effective alternative for the analysis of cytogenetic abnormalities of low proliferative entities such as Waldenström macroglobulinemia (WM) but, to date, no studies have been carried out to explore the potential impact of molecular cytogenetics on disease evolution. Deletion of the long arm of chromosome 6 (6q-) is the most frequent cytogenetic abnormality in WM. In this study we have analyzed the incidence of this aberration (using both conventional cytogenetics and FISH analysis) in 102 WM patients, and we have correlated it with disease characteristics. Deletion of 6q21 was detected in 6% of patients by conventional cytogenetics, while FISH studies increased this incidence up to 39%. Moreover, in those patients analyzed by cIgM-FISH, the incidence of 6q- was higher (54%). Interestingly, 6q- patients displayed features associated with adverse prognosis (higher levels of ESR, CRP and beta-2 microglobulin), and a greater tendency to display anemia and hypoalbuminemia. Other differentiating variables without reaching statistical significance were a tendency of displaying a higher bone marrow lymphoplasmacytoid infiltration and the amount of monoclonal component in 6q- patients (table). In addition, patients with 6q- displayed shorter survival from time of diagnose (log-rank; p=0.09). In summary, our results show that 6q deletion in WM patients is currently the most frequently found cytogenetic abnormality. Patients with this deletion also shows a trend towards an aggressive disease and poorer outcome in WM. Further studies should focus on possible tumor suppressor genes in the minimal area of deletion at 6q and to determine their role in disease progression. table del6q present del6q absent p-value n 40 (39%) 62 (61%) β2M ≥4mg/dL 48% 16% 0.005 CRP ≥3.5 mg/dL 47% 11% 0.006 Albumin <4mg/dL 86% 55% 0.006 ESR ≥100 mm/h 73% 44% 0.02 Hb <11 g/dL 63% 40% 0.02 serum IgM >20 g/L 86% 73% 0.10 BM infiltration >40% 44% 31% 0.20

Abstract Background: The p53 tumor suppressor gene has a common sequence polymorphism that results in either proline or arginine at amino-acid position 72. The Pro72 and Arg72 variants have been reported to differ in its functional activity. The Arg72 variant induces apoptosis more efficiently than Pro72 variant by its greater ability to localize to the mitochondria and increase the release of cytochrome c into the cytoplasm. In addition, recent studies have demonstrated that Arg72 variant was a better suppressor of cellular transformation, an activity believed to rely on the pro-apoptotic function of p53. Moreover, the Pro72 variant has been associated with a higher incidence of tumors. Aim: To evaluate the effect of the polymorphic variants of codon 72 and clinical outcome in patients with plasma cell malignancies. Patients and Methods: We analyzed 79 patients with plasma cell malignancies seen at Mayo Clinic between 2000 and 2003. Genomic DNA was extracted from CD138+ sorted plasma cell from bone marrow aspirates. PCR amplification of codon 72 and posterior sequencing was used for the analysis. Results: A total of 79 patients were analyzed. Thirty-four patients (34%) were heterozygous for p53, 57 (59%) homozygous for Arginine and 6 (6%) homozygous for Proline. The distribution among disorders was as follow, 52 patients had MM, 14 patients with SMM and 13 with MGUS. Among patient with MM 25% were Pro/Arg heterozygous, 71 % were Arg/Arg homozygous and 3.8% Pro/Pro homozygous. Survival data among MM patients and genotype were analyzed to Kaplan- Meier method. No significant differences were found among patients who carried homozygous (72R) or heterozygous genotype and overall survival. We exclude the analysis in MGUS and SMM for a low number of patients available. Conclusions: These findings indicate that codon 72 arginine p53 may not be associated with a prolonged survival in patients with Multiple Myeloma, but further study is needed to assess whether this polymorphism is associated with progression of MGUS to MM, age of onset, clinical manifestations, response to treatment etc.

Abstract Background: We reported a high response rate with the combination of lenalidomide plus dexamethasone (Rev/Dex) as initial therapy for newly diagnosed multiple myeloma (Blood2005;106:4050–3). We now present new data on time to progression (TTP), progression free survival (PFS), and overall survival (OS) from this phase II trial, and also include updated response data. Patients and Methods: 34 patients (23 male and 11 female) were enrolled. Lenalidomide was given orally 25 mg daily on days 1–21 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1–4, 9–12, 17–20 of each cycle. Patients were allowed to go off treatment after 4 cycles of therapy to pursue autologous stem cell transplantation (SCT), but treatment beyond four cycles was permitted at the physician’s discretion. For patients continuing therapy beyond 4 months, the dose of dexamethasone was reduced to 40 mg on days 1–4 of each cycle. Response was assessed by modified EBMT/International Myeloma Working Group Uniform Response criteria. All patients received aspirin (81 mg or 325 mg daily) as prophylaxis against DVT. Results: The median age was 64 years (range, 32–78). All patients were evaluable for response and toxicity. Median follow up is 21 months. Thirteen patients proceeded to SCT following initial therapy with Rev/Dex and were censored at that time point for purposes of calculation of response, TTP and PFS. Patients who discontinued therapy to proceed to SCT received a median of 4 cycles of therapy (range, 4–13), while those staying on Rev/Dex (n=21) received a median of 19 cycles of therapy (range, 2–30). Thirty-one of 34 patients (91%) achieved an objective response to therapy; including 6 patients (18%) achieving a complete response (CR) and 13 patients (38%) achieving very good partial response for a CR+VGPR rate of 56%. The CR+VGPR rate among the 21 patients staying on Rev/Dex as primary therapy without SCT was 67% (CR 24%, VGPR 43%). Median TTP, PFS, and OS have not been reached (Figure). By Kaplan-Meier method, the estimated 2 year progression rate was 18%. The 2-year PFS rate and OS rate were 74% and 91%, respectively. Fifty-five percent of patients experienced grade 3 or higher non-hematologic toxicity at any point during therapy, most commonly fatigue (21%), neutropenia (21%), anxiety (6%), pneumonitis (6%), muscle weakness (6%), and rash (6%). Two patients died on study: one attributed to infection unrelated to therapy, the patient had stopped all therapy for over a month before the fatal infection occurred; the other death was due to infection felt possibly related to therapy. One patient developed a pulmonary embolism (grade 4 toxicity), but recovered with therapy; no other patient developed deep vein thrombosis or pulmonary embolism. Conclusion: Rev/Dex is highly active and well tolerated in the treatment of newly diagnosed multiple myeloma with a high CR+VGPR rate of 56% for the trial, and 67% among the subset of patients receiving this regimen as primary therapy. Responses are durable with a low progression rate at 2 years.