Dispenzieri, Angela

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]

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]

2500 Background: Oncolytic virotherapy is a novel immunomodulatory therapeutic approach for relapsed refractory hematologic malignancies. The Indiana strain of Vesicular Stomatitis Virus was engineered to encode interferon beta (IFNβ) and sodium iodine symporter (NIS) to produce VSV-IFNβ-NIS. Virally encoded IFNβ serves as an index of viral proliferation and enhances host anti-tumor immunity. NIS was inserted to noninvasively assess viral biodistribution using SPECT/PET imaging. We present the results of the phase 1 clinical trial NCT03017820 of systemic administration of VSV-IFNβ-NIS among patients (pts) with relapsed refractory Multiple Myeloma (MM), T cell Lymphoma (TCL) and Acute myeloid Leukemia (AML). Methods: VSV-IFNβ-NIS was administered at 5x109 TCID50 (50% tissue culture infectious dose) dose level 1 to dose level 4, 1.7x1011 TCID50. The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. Secondary objectives were determination of safety profile and preliminary efficacy of VSV-IFNβ-NIS. Correlative objectives included monitoring viremia and virus shedding. Adverse events (AEs) are reported based on CTCAE V4; cytokine release syndrome (CRS) grading was based on Lee (Blood 2014) criteria. Results: 15 pts received VSV-IFNβ-NIS: MM (7), TCL(7) and AML(1); 3 pts were treated at each dose level (DL) 1 through 3 (respectively 0.05, 0.17, and 0.5 x 1011 TCID50), & 6 pts were treated at dose level 4 (1.7x1011 TCID50). There were no dose limiting toxicities. The most frequent grades 3 & 4 AEs were hematologic: lymphopenia (46.6 & 26.6%), neutropenia (13.3% & 6.7%). CRS grades 1 (6.7%) and 2 (46.6%) were the non-hematologic AEs of note; mostly at DL 4. Only 1 pt required transient pressor support. Responses were seen in pts with T cell lymphoma. At DL2, there was a partial response (PR) lasting 3 months in a pt, post 12 prior lines of therapy. At DL4 there was a 6 month PR in a pt with PTCL and another pt with cutaneous relapse of PTCL who enjoys an ongoing CR, more than 1 year post VSV infusion; both pts received 5 prior lines of therapy. Viremia was detected in all pts at the end of infusion only up to 72 hrs post infusion; no infectious virus was recovered in buccal swabs or urine. Neutralizing anti-VSV antibodies were present by day 29. IFN levels were detectable within 30 mins of infusion, peaking between 4 & 48 hrs. TCL pts mounted higher hIFNβ levels within 48 hrs; the pt with CR mounted peak hIFNβ response of 18213.3pg/ml at 48 hrs post infusion, 15-fold higher than any other pt. Conclusions: VSV-IFNβ-NIS can be safely administered by IV infusion among heavily pretreated pts with hematologic malignancies. VSV-IFNβ-NIS as a single agent appears to be most effective at DL4 among patients with TCL, with an ongoing CR in a patient at DL4 more than 1 year post administration. Future trials of combination strategies with immune-modulatory drugs are currently being planned. Clinical trial information: NCT03017820.

AbstractDisease overviewPOEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis.DiagnosisThe diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria.Risk stratificationBecause the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary hypertension, and reduced eGFR.Risk‐adapted therapyFor those patients with a dominant plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3–6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

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 Patients with immunoglobulin M (IgM) light chain (AL) amyloidosis have a distinct clinical presentation compared with those with non-IgM amyloidosis. We hypothesized that differential immunoglobulin light-chain variable region (IGVL) gene usage may explain the differences in organ involvement, because IGVL usage correlates with organ tropism. IGVL usage was evaluated by mass spectrometry of amyloid deposits (IgM, n = 45; non-IgM, n = 391) and differed across the 2 groups. In the λ family, LV2-08 (13% vs 2%; P &lt; .001) and LV2-14 (36% vs 10%; P &lt; .001) usage was more common in IgM vs non-IgM amyloidosis, whereas LV1-44 (0% vs 10%; P = .02) and LV6-57 (2% vs 18%; P = .004) usage was less common. In the κ family, there was a trend toward higher KV4-01 (11% vs 4%; P = .06) usage in IgM amyloidosis. IGVL usage correlated with disease characteristics/organ tropism. LV2-14 (more common in IgM amyloidosis) has historically been associated with peripheral nerve involvement and lower light chain burden, which were more frequent in IgM amyloidosis. LV1-44 (less common in IgM), associated with cardiac involvement, was less frequent in IgM patients. LV6-57 (less common in IgM) is associated with t(11;14), which was less frequent in IgM patients. In conclusion, IGVL gene usage differs in patients with IgM vs non-IgM amyloidosis and may explain the distinct clinical presentation.

Abstract Background Light chain (AL) amyloidosis is a plasma cell neoplasm associated with high early mortality and severe morbidity that can cause severe disability. We explored the impact of AL amyloidosis on symptoms and well-being from the perspectives of patients and health care providers who regularly care for AL patients. We intended to develop a conceptual understanding of patient-reported outcomes in AL amyloidosis to identify the context of use and concept of interest for a clinical outcome assessments tool in this disease.Method Twenty patients and 10 professionals were interviewed. Patient interviews captured the spectrum of amyloidosis experience including time from diagnosis, type of organ involvement, and presence and type of treatment received. Interviews with professionals included physicians, advanced practice providers, registered nurse, and a patient advocate; these interviews covered similar topics. Results The impact of AL amyloidosis on patients’ life was multidimensional, with highly subjective perceptions of normality and meaning. Four major themes from patients and experts included diagnosis of AL amyloidosis, living with AL amyloidosis, symptom burden, and social roles. Barriers to patient-reported outcomes data collection in patients were additionally explored from experts. The themes provide a comprehensive understanding of the important experiences of symptom burden and its impact on daily life from AL amyloidosis patients’ and from the perspectives of professionals who care for patients with AL amyloidosis. Conclusion These findings further the conceptual understanding and identification of a preliminary model of concept of interest for development of a clinical outcome assessments tool for AL amyloidosis.