Dingli, David

Abstract Multiple myeloma (MM) is a heterogeneous disease that may be evaluated by a broad array of imaging and laboratory techniques to measure disease activity and predict prognosis. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scanning has been shown to be predictive of patient outcomes throughout the disease course. We sought to corroborate these findings by examining the prognostic impact of PET/CT scanning in the posttransplant setting. We retrospectively analyzed PET/CT scans in 229 MM patients receiving an autologous stem cell transplant (ASCT) near day 100, and correlated these findings with time to progression(TTP) and overall survival (OS) to assess the impact of day 100 PET/CT scan findings as an independent prognostic factor. The median OS for the entire cohort was 61.5 months (95% confidence interval [CI], 49-75) and the median TTP was 18.5 months (95% CI, 15.4-21.8). Among patients with abnormal day 100 PET findings (PET+), median TTP was 12.4 months vs 24 months among those with normal PET findings (PET−) (P < .0001). The median OS in the PET+ group was 46 months compared with 99 months in the PET− group (P < .0001). We conclude that an abnormal PET/CT scan near day 100 post-ASCT is predictive of shorter TTP and OS, with prognostic significance retained after adjusting for disease response and other prognostic variables in MM.

Cancer therapy remains challenging due to the myriad presentations of the disease and the vast genetic diversity of tumors that continuously evolve and often become resistant to therapy. Viruses can be engineered to specifically infect, replicate, and kill tumor cells (tumor virotherapy). Moreover, the viruses can be “armed” with therapeutic genes to enhance their oncolytic effect. Using viruses to treat cancer is exciting and novel and in principle can be used for a broad variety of tumors. However, the approach is distinctly different from other cancer therapies since success depends on establishment of an infection within the tumor and ongoing propagation of the oncolytic virus within the tumor itself. Therefore, the target itself amplifies the therapy. This introduces complex dynamics especially when the immune system is taken into consideration as well as the physical and other biological barriers to virus growth. Understanding these dynamics not only requires mathematical and computational models but also approaches for the noninvasive monitoring of the virus and tumor populations. In this perspective, we discuss strategies and current results to achieve this important goal of understanding these dynamics in pursuit of optimization of oncolytic virotherapy.

AbstractMultiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B‐cell lymphoma 2 (BCL‐2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM, particularly those harboring t(11;14). We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December, 2016 and March, 2019. The data cut‐off date was August 06, 2020. We identified 56 patients of whom 42 (75%) harbored t(11;14). The median number of prior therapies was six (range 1–15) and 14% of patients had received ≥10 prior lines of therapy. Fifty‐three (95%) patients were refractory to an immunomodulatory drug and proteasome inhibitor. Venetoclax was used as monotherapy or doublet, in combination with dexamethasone in 55% (n = 31) and a triplet or quadruplet in 45% of patients. No patient experienced tumor lysis syndrome. Overall response rate in 52 evaluable patients was 44%. The median time to best response was 2 months and median duration of response was 13.6 months. The median PFS for the entire cohort was 5.8 (95% CI 4.9–10.3) months and median OS was 28.4 (95% CI 14.6‐not reached) months. The presence of t(11;14) was associated with improved PFS (median 9.7 months vs. 4.2 months, p = 0.019) and OS (median not reached vs. 10.8 9 months, p = 0.015). Venetoclax demonstrates encouraging activity in heavily‐treated patients with relapsed/refractory MM, particularly the t(11;14) patient‐population.

e20016 Background: An elevated serum LDH level is an adverse prognostic factor in NDMM. However, this category includes quantitative serum LDH levels that range from just over the upper limit of normal (ULN) to levels that may be 2 or more-fold higher than the ULN. This binary classification of serum LDH level of “normal versus elevated” fails to discriminate between the different disease biology that exists among NDMM patients with elevated serum LDH levels. Thus, we attempted to further stratify NDMM patients by the level of their serum LDH and determine its impact on OS. Methods: The cohort included patients diagnosed with NDMM from the Mayo Clinic, Rochester from 2003 - 2017 who were treated with novel agent induction therapy and had serum LDH levels measured at the time of diagnosis. The serum LDH levels were stratified into three levels: Normal (LDH < 222 U/L), Elevated (LDH 223-444 U/L), and Very Elevated (LDH >444 U/L or >2x upper limit of normal). Survival analysis was performed using the Kaplan-Meier survival analysis and compared via the log-rank method. Results: The cohort consists of 1,196 NDMM patients with a median age of 65 (22 – 95). R-ISS classification and cytogenetic risk were available for 968 and 970 patients respectively. The median serum LDH level was (162 U/L (3- 1260)) and an elevated LDH was present in 199 patients (17%). The median OS for patients with normal (N = 997; 83%), elevated (N = 170; 13%) and very elevated (N = 29; 3%) LDH levels were 76 months, 57 months and 23 months respectively (P < 0.001). The impact of these different levels of LDH on OS by R-ISS stage and cytogenetic risk is shown in the Table. Conclusions: A very small subset of NDMM patients has very elevated LDH levels that confer an exceptionally poor OS irrespective of R-ISS stage and cytogenetic risk. Future studies elucidating their disease biology responsible for such poor OS outcomes are warranted.[Table: see text]

e20000 Background: In the novel agents’ era, refractoriness to induction in Multiple Myeloma (MM) is relatively rare. This population remain an unmet need and are often excluded from clinical trials. In the current era, chemotherapy-induced stem cell collections are used at Mayo Clinic in “poor responders” to induction, such as patients that progress prior to ASCT or patients with significant disease burden after induction. Methods: This is a retrospective study that includes all MM patients the underwent chemo-mobilization between January 2012 and September 2020 at Mayo Clinic. We compared our cohort to a cohort of 125 matched patients that were transplanted over the same time period and underwent mobilization with G-CSF and “on-demand” plerixafor. We matched the cohorts by level of response by IMWG at pre-transplant evaluation. Results: 125 newly diagnosed MM patients who received novel agents’ induction and had a poor response to induction were mobilized using IV intermediate-dose cyclophosphamide (83%) or VDT-PACE (17%) plus G-CSF and “on-demand” plerixafor. The median PFS and OS of the chemo-mobilized cohort were 16 months (95% CI 11-20) and 47 months (95% CI 37-71), respectively. Patients receiving chemo-mobilization had higher stem cell yields than the growth factor only cohort (median 9.88X106 cells/kg versus median 8.77X106 cells/kg, respectively (P<0.001)). The safety profile of chemo-mobilization was favorable, with no difference between the two groups in length of hospitalization during ASCT (P=0.95), days to neutrophil or platelet engraftment, and risk of bacteremia (P=0.38). 29% of the chemo-mobilized cohort and 66% of the matched cohort required plerixafor for adequate mobilization (P<0.001). Conclusions: Chemo-mobilization enhances stem cell collection in MM patients with a suboptimal response to induction and reduces the need for plerixafor without adversely impacting the post-transplant clinical course. [Table: see text]

7554 Background: Chimeric antigen receptor T-cell therapy (CAR-T) are commonly administered inpatient due to concern for early onset cytokine release syndrome (CRS), especially with axicabtagene ciloleucel (axi-cel). We report Mayo Clinic Rochester experience for hospital-based outpatient (HBO) management of patients (pts) receiving axi-cel and identify opportunities for improvement. HBO is closely integrated with inpatient practice and includes the same specialty trained clinical team. It is the first point of contact 24/7 for pts and triage evaluations. Lymphodepletion chemotherapy and CAR-T infusion is given on HBO followed by daily monitoring till day 8 and thereafter, as clinically needed until admission criteria is met. Methods: We retrospectively analyzed database of pts who received axi-cel between 1/2018 and 1/2021. After 06/2020, remote patient monitoring (RPM) tools were implemented to collect patient-reported neurologic symptoms and vital signs via bluetooth-enabled devices 4 times daily through month 1. Adverse data trends are addressed by the HBO team. Results: Among 72 recipients, 89% received their cells outpatient; 8% remained outpatient for the entire month. CRS and neurotoxicity incidence were comparable to those reported from CIBMTR. Median time to first admission was 2 days (Table). Use of bridging therapy, increased CRP and LDH were associated with early admission (≤3 days). Median time to tocilizumab, steroid, oxygen support, vasopressor was 4 days after admission. Half of HBO visits required intervention such as blood transfusions, IV medications through the first month. Nine pts had enrolled in RPM to date; with 8 having evaluable data. With 4 scheduled entries/day, a median of 1 entry/day was skipped and 2 entries/day were answered incompletely. An average of 57 additional unscheduled entries were generated per pt. Among a median of 373 (range 91-522) readings per pt over the first month, 4% (2%-20%) of the readings generated alerts. An average of 4 alerts were seen within 48 hours prior to admission. Data including additional subjects will be presented at ASCO meeting. Conclusions: We report a feasible outpatient care model for management of axi-cel recipients with safe outcomes. Clinical characteristics associated with more aggressive disease are associated with likelihood of early admission. Early RPM experience suggest use of digital tools could improve monitoring compliance and may predict evolution to symptoms requiring escalation of care.[Table: see text]

2537 Background: Orva-cel is a B-cell maturation antigen–targeted chimeric antigen receptor (CAR) T cell therapy being evaluated in the phase 1/2 EVOLVE study (NCT03430011) in pts with RRMM who had at least 3 prior lines of therapy (Tx). We previously reported safety and efficacy in the phase 1 study and established the recommended dose (RD) of orva-cel as 600 × 106 CAR+ T cells (Mailankody et al, ASCO 2020). Cytokine release syndrome (CRS), a dominant toxicity of CAR T cell therapy, is mediated in part by IL-1. We explore the role of ppx with AKR, an IL-1 signaling inhibitor, on reducing the incidence of grade (G) ≥2 CRS after orva-cel treatment at the RD. Methods: Fourteen pts were enrolled sequentially for AKR ppx and treated with orva-cel at the RD. The non-AKR ppx control group comprised the remainder of the phase 1 pts receiving orva-cel at the RD (n = 19). The median follow-up (range) was 3.0 mo (1.8–6.2) for the AKR ppx group and 8.8 mo (5.3–12.2) for the non-AKR ppx group. AKR was administered as 100 mg SC the night before orva-cel infusion, 3 h before the infusion (Day 1), and q24 h on Days 2–5. Dosing was increased to q12 h if CRS developed. CRS was graded by Lee (2014) criteria. Tocilizumab (T) and steroids (S) were used per protocol-specified treatment management guidelines. Results: Disease characteristics and outcomes are shown in the table. In AKR ppx and non-AKR ppx groups, median number of prior regimens was 6 and 5, and bridging Tx was used in 57% and 68% of pts, respectively. The total frequency of CRS was similar in the 2 groups, but with less G 2 in the AKR ppx pts; relative risk (95% CI) = 0.54 (0.21, 1.38). No G ≥3 CRS was seen in either group. The incidence of neurological events (NE), G ≥3 infection, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) was similar. T and S use was numerically lower with AKR ppx. Orva-cel expansion kinetics were similar in the 2 groups. All pts had a 2-month efficacy assessment, with ORR in 100% of AKR ppx and 95% of non–AKR ppx pts. Conclusions: In this nonrandomized evaluation of AKR ppx with orva-cel treatment, the incidence of G ≥2 CRS was lower in pts receiving AKR ppx. The use of AKR ppx produced no adverse effect on the incidence of NE, infection, or MAS/HLH, nor on orva-cel expansion or disease response. These results warrant further study of AKR ppx in CAR T cell therapy. Clinical trial information: NCT03430011. [Table: see text]

Abstract Comparative data guiding initial therapy for Waldenström macroglobulinemia (WM), an infrequently encountered non‐Hodgkin lymphoma, are sparse. We evaluated three commonly used rituximab‐based frontline regimens: rituximab‐bendamustine (R‐Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment‐naïve patients with WM, seen at Mayo Clinic between November 1, 2000 and October 31, 2019. The median follow‐up was 4.5 (95%CI: 4–5) years. The R‐Benda cohort (n = 83) demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n = 92, ORR: 78%) or BDR (n = 45, ORR: 84%) cohorts, p = 0.003. Similarly, longer progression‐free survival (PFS) was evident with R‐Benda use [median 5.2 vs. 4.3 (DRC) and 1.8 years (BDR), p < 0.001]. The time‐to‐next therapy (TTNT) favored R‐Benda [median, not‐reached, 4.4 (DRC) and 2.6 years (BDR), p < 0.001). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p = 0.77. In a subset analysis of 142 patients genotyped for MYD88 L265P mutation, the ORR, PFS and TTNT were unaffected by the patients' MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R‐Benda are superior compared to DRC or BDR in treatment‐naïve patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88 L265P mutation status.

Abstract The utility of systemic light chain (AL) amyloidosis staging systems has been validated for newly diagnosed patients, but their role in restaging after treatment has not been explored. We designed this study to evaluate whether the currently used systems are of prognostic value at 3 and 6 months of starting first-line treatment, and whether stage migration from diagnosis impacts survival. This is a retrospective study including Mayo Clinic patients with AL amyloidosis diagnosed between 1 January 2006 and 30 June 2019; 536 and 204 patients had restaging data for at least 1 system at 3 and 6 months, respectively. Using modified Mayo 2004 staging at 3 months, median overall survival (OSs) were 11.8, 10.8, 4.6, and 1.1 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, median OSs were 11.8, 9.0, 5.2, and 0.8 years for stage I, II, III, and IV, respectively. Using modified Mayo 2004 staging at 6 months, median OSs were not reached (NR), NR, 5.4, and 0.9 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, OSs were NR, NR, 4.6, and 0.9 years for stage I, II, III, and IV, respectively. Worsening stage at 3 or 6 months was associated with worse survival than retaining baseline stage. In conclusion, the current staging systems can be used for restaging at 3 and 6 months from treatment initiation. Migration to higher stage predicts poor prognosis.

Introduction: Cardiac involvement is one of the main predictors for survival in patients with light chain (AL) amyloidosis. Biomarkers such as Troponin T and N-terminal pro b-type natriuretic peptide (NT-proBNP) are used routinely for detecting cardiac involvement. In addition echocardiogram (ECHO) is used to determine septal and left ventricular wall thickness and strain. Most patients with AL present with preserved ejection fraction (EF) however, the outcomes of AL patients undergoing autologous stem cell transplantation (ASCT) with decreased EF are not very well described. Methods: We retrospectively reviewed patients who had a diagnosis of AL amyloidosis and received ASCT between March 1996 and September 2017. All patients had an ECHO done before ASCT and the EF was documented. In our practice, the threshold for performing ASCT is an EF &gt;40%. We evaluated the outcomes of patients who had an EF &lt;55% compared to patients with an EF ≥55%. The baseline characteristics were compared between patients with high and low EF. Progression-free survival (PFS) was defined as time from ASCT to disease progression, relapse, or death of any cause. Overall survival (OS) was calculated from time of ASCT to death of any cause. Univariate and multivariate analysis for PFS and OS were done using the following variables: age&gt;65 vs. ≤65 years, Mayo 2012 stage 3/4 vs. 1/2, bone marrow plasma cell percentage (BMPC) ≥ 10% vs. &lt;10%, organs involved &gt;2 vs. ≤2, melphalan conditioning 200mg/m2 vs. 140 mg/m2 ,ASCT year &gt;2010 vs. ≤2010, and EF &lt;55% vs. ≥55%. Results: We identified 716 patients and 69 (10%) had an EF&lt;55%, with most (n=63, 91%)having cardiac involvement . Compared to patients with EF ≥55%, patients with EF &lt;55% were more likely to have Mayo 2012 stage 3/4 (58% vs. 22%, P&lt;0.0001) and more likely to have thicker interventricular septum (median 14 vs. 12 mm, P&lt;0.0001). The day 100 transplant related mortality (TRM) was higher in patients with EF &lt;55% compared to EF ≥55% (19% vs. 6%, P=0.0006). In patients with Mayo 2012 stage 3/4, the day 100 TRM was higher in patients with an EF&lt;55% compared to EF ≥55% (27% vs. 7%, P=0.004). Overall, PFS and OS were significantly shorter in patients with EF &lt;55% compared to patients with EF ≥55% (Figure 1 A,B). Evaluating PFS and OS according to EF specifically in Mayo 2012 stage 3/4 patients is displayed in Figure 1 (C,D). Predictors for PFS included Mayo 2012 stage 3/4 vs. 1/2 (hazard ratio (HR): 1.4, P=0.006), BMPC ≥ 10% vs. &lt;10% (HR: 1.5,P=0.0005), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.7, P=0.01), ASCT year &gt;2010 vs. ≤2010 (HR: 0.7, P=0.01), and EF &lt;55% vs. ≥55% (HR: 1.5, P=0.02). For OS, age &gt;65 vs. ≤65 years (HR:1.4, P=0.04), Mayo 2012 stage 3/4 vs. 1/2 (HR: 1.96, P&lt;0.0001), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.5, P&lt;0.0001), BMPC ≥ 10% vs. &lt;10% (HR: 1.8, P=0.03), ASCT year &gt;2010 vs. ≤2010 (HR: 0.5, P&lt;0.0001), and EF &lt;55% vs. ≥55%(HR:1.9, P=0.003) were predictive. Conclusion: Having an EF &lt;55% is associated with a higher day 100 TRM and is an independent predictor for PFS and OS in patients with AL amyloidosis undergoing ASCT. Disclosures Sidiqi: Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Other: Travel grant. Dingli:Alexion: Consultancy; Apellis: Consultancy; Sanofi-Genzyme: Consultancy; Millenium: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Rigel: Consultancy. Kapoor:Janssen: Research Funding; GlaxoSmithKline: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Research Funding. Dispenzieri:Janssen: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Sanofi: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Cellectar: Other; Carsgen: Other, Research Funding. Gertz:Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Sanofi: Other; Research to Practice: Other; Celgene: Other; Medscape: Other: personal fee, Speakers Bureau; Proclara: Other; DAVA oncology: Speakers Bureau; Alnylam: Other: personal fee; Johnson and Johnson: Speakers Bureau; Physicians Education Resource: Other: personal fee; Teva: Speakers Bureau; Ionis/Akcea: Other: personal fee; Amgen: Other: personal fee; Springer Publishing: Patents & Royalties; Aurora Bio: Other; Appellis: Other: personal fee; Abbvie: Other; Annexon: Other: personal fee; Prothena: Other: personal fee.