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Background Chromosome 1 abnormalities (C1A) are frequently identified in multiple myeloma (MM). We assessed impact of C1A in a post hoc analysis of E1A11 trial. Methods E1A11 randomized newly diagnosed (ND) MM patients (pts) with traditional ‘standard risk’ features or t(4;14), not intended for upfront transplant, to bortezomib (V) or carfilzomib (K), in combination with lenalidomide (R) and dexamethasone (d), followed by indefinite or 2-year (y) R maintenance. Impact of C1A and ultra-high risk (UHR) MM [≥2 of the following: +1q [gain1q (3 copies) or amplification (amp)1q21 (≥4 copies)], deletion (del)1p and t(4;14)], was assessed. Results Of 1087 pts, 912 were evaluated for + 1q (gain1q or amp1q) and 774 for del1p. Gain1q, amp1q and del1p were noted in 23%, 7.5% and 9% pts, respectively. Best responses to VRd or KRd within each response category were similar, irrespective of +1q/del1p status. Within each arm, progression-free survival (PFS) was inferior for pts with +1q versus (v) pts without +1q; median 29 v 42 months (m) for both arms [VRd, HR 1.51 p 0.011; KRd, HR 1.63, p 0.002]. Corresponding 3y overall survival (OS) rates on VRd were 74 v 86% (HR 1.47, p 0.069) and 82 v 88% (HR 1.34, p 0.185) on KRd. Regarding copy number, pts with gain1q v those without +1q had inferior PFS with both VRd (median 29m, HR 1.59, p 0.012) and KRd (median 33m, HR 1.41, p 0.051). OS rates with gain1q were inferior within VRd arm only (3y 71%, HR 1.78, p 0.014; KRd 3y OS 89%, HR 1.02, p 0.93). By contrast, pts with amp1q, v pts without +1q, had inferior outcomes with KRd (median PFS 24m, HR 2.37, p Conclusion Gain1q or amp1q portends poor outcome among NDMM pts treated with either VRd or KRd. Specifically, pts with amp1q as a sole high-risk abnormality have distinctly poor outcomes with KRd. By contrast, KRd, but not VRd, appears to abrogate the adverse impact of del1p. Given the limitations of the trial design and post hoc subset analyses, longer follow up and confirmatory studies are warranted for definitive conclusions.

Context This is the first in human Phase 1 dose escalation trial of oncolytic Vesicular Stomatitis Virus (VSV) incorporating interferon beta and sodium iodine symporter transgenes (VSV-IFNβ-NIS) to be administered intravenously in patients with relapsed and refractory hematologic malignancies. Objective The primary objective was to determine the maximum tolerated dose of VSV-IFNβ-NIS as a single agent. The secondary objectives were to determine safety and efficacy of VSV-IFNβ-NIS. Correlative objectives included monitoring viremia and virus shedding. Design This was a 3+3 phase 1 clinical trial from April 2017 to August 2020 including adult patients (pts) with relapsed refractory multiple myeloma (MM), T-cell lymphoma (TCL), or acute myeloid leukemia (AML). Results Fifteen patients received VSV-IFNβ-NIS: MM (7), TCL (7), and AML (1); median age was 64 years, 60% male, and median prior lines of systemic cancer therapies was 5 (range, 2 to 11). Three patients were treated at each dose level (DL) 1 through 3 (respectively 0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL 4 (1.7x1011 TCID50). There were no dose-limiting toxicities. Hematologic AEs, particularly lymphopenia (73%) were the predominant grade 3 and 4 AEs. Non-hematologic AE of interest were grade 1 (6.7%) and 2 (46.6%) cytokine release syndrome, of which only 1 patient required transient norepinephrine support. Objective responses were seen in patients with TCL. There was a 3-month partial response (PR) in a patient treated at DL 2 after 11 prior systemic therapies. However, compelling responses were seen at DL 4 with a deepening 6-month PR in a patient with PTCL and ongoing CR, even 14 months after VSV in another patient with cutaneous relapse of PTCL; both patients received 5 prior lines of therapy. Viremia rapidly declined after infusion, and there was no significant viral shedding. Neutralizing anti-VSV antibodies developed by day 29. IFNβ appeared to indicate intratumoral amplification with TCL patients mounting the highest levels. Conclusions A single intravenous dose of VSV-IFNβ-NIS up to 1.7x1011 is safe in heavily pre-treated patients with hematologic malignancies and appears to be most effective as a single agent at DL 4, especially in patients with TCL. Future trials of combination strategies with immune-modulatory drugs are currently being planned. Grant Acknowledgements Mayo Clinic Multiple Myeloma Specialized Program of Research Excellence (SPORE), Grohne gifts, Phillips gift, and Liu gift.

Background Smoldering multiple myeloma (SMM) prognostication models routinely used in clinical practice were developed for use at diagnosis. However, retrospective studies in SMM patients have shown that the risk of progression to multiple myeloma (MM) decreases over time. Therefore, this study assessed whether the Mayo 2018 and IMWG 2020 scores could be used dynamically to risk stratify patients post-diagnosis, and whether they could identify SMM patients with evolving disease markers. Methods We retrospective studied 704 SMM patients diagnosed between January 2000 to January 2020. Patients with a baseline FLCr ≥100 and involved FLC ≥10 mg/dL or baseline bone marrow plasma cells ≥60% were excluded. We collected serial laboratory data and re-applied the Mayo 2018 and IMWG 2020 SMM risk stratification models at annual landmark timepoints up to 4 years post SMM diagnosis. Survival analyses were performed using the Kaplan-Meier method. Time to progression was defined as time from diagnosis or landmark timepoint to treatment initiation for MM or systemic AL amyloidosis. Results At SMM diagnosis, 271 (38%) patients were low risk, 228 (32%) were intermediate risk, and 205 (29%) were high risk per the Mayo 2018 score. Applying the IMWG 2020 score at diagnosis, 90 (34%) of patients were low risk, 111 (42%) were low-intermediate risk, 54 (21%) were intermediate risk, and 9 (3%) were high risk. The Mayo 2018 and IMWG 2020 risk scores was re-assessed annually post-diagnosis in patients without progression (respective sample sizes: n=430 and n=197 at year 1 landmark, n=326 and n=143 at year 2 landmark, n=260 and n=106 at year 3 landmark, n=203 and n=73 patients at year 4 landmark). The Mayo 2018 and IMWG 2020 models reliably stratified patients based on progression risk post diagnosis; the respective 2-year progression risk in Mayo 2018 high-risk versus IMWG 2020 intermediate-high risk patients was 51% versus 62% at the 1-year landmark, 60% versus 65% at the 2-year landmark, 47% versus 62% at the 3-year landmark, and 47% versus 45% at the 4-year landmark. Patients evolving to a higher Mayo 2018 or IMWG 2020 risk category during follow up consistently had an increased risk of progression compared to patients with a stable/decreased risk categorization. We showed that patients categorized as Mayo 2018 high-risk at follow-up had a similar risk of progression regardless of whether the baseline risk categorization was low-intermediate versus high-risk (HR 0.87, 95% CI 0.51-1.48, p=0.606 at 2-year landmark; HR 1.01, 95% CI 0.59-1.73, p=0.972 at 3-year landmark; HR 0.75, 95% CI 0.34-1.65, p=0.467 at 4-year landmark). Conclusion Our findings support the use of the Mayo 2018 and IMWG 2020 scores post-diagnosis. We showed that patients migrating to a higher risk category have an increased risk of progression, suggesting that patients evolving to a high-risk score during follow-up should be considered for early intervention treatment approaches.

Context Elevated serum LDH level is an adverse prognostic factor in NDMM. Quantitative serum LDH levels range from over the upper limit of normal (ULN) to levels 2- or more-fold higher than ULN. Objective The “normal versus elevated” classification of serum LDH level can fail to discriminate between different NDMM disease biology. Thus, we attempted to further stratify NDMM patients by their serum LDH level and determine the impact on OS outcomes. Design and Setting The cohort included patients diagnosed with NDMM from the Mayo Clinic, Rochester, from 2003 to 2017, treated with novel agent induction therapy with measured serum LDH levels at the time of diagnosis. Patients The cohort consists of 1,196 NDMM patients with median age of 65 (22–95) years. R-ISS classification was available for 968 patients and is distributed as follows: 210 (22%) stage 1, 639 (66%) stage 2, and 119 (12%) stage 3. Cytogenetic risk data was available for 970 patients: 215 (22%) high-risk and 755 (78%) standard-risk. Main Outcome Measures The serum LDH levels were stratified into three levels: normal (LDH 444 U/L). Survival analysis was performed using the Kaplan–Meier method and compared via Wilcoxon method. Results Median serum LDH level was 162 U/L (3–1260), and an elevated LDH was present in 199 patients (17%). 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 Conclusion A small subset (3%) of NDMM have very elevated LDH levels that confer exceptionally poor OS, irrespective of R-ISS stage and cytogenetic risk. Future studies determining disease biology responsible for such poor OS outcomes are warranted. Acknowledgments Research was supported by the National Cancer Institute [Grant Number CA254961], the Helen Diller Family Foundation, and the Marion Schwartz Foundation for Multiple Myeloma.

Context Waldenstrom macroglobulinemia (WM) is a rare lymphoma for which scant comparative data exist to guide frontline therapy. Objective To compare the efficacy of the most frequently used rituximab-based fixed-duration anti-WM regimens in routine practice [rituximab, bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR)] to inform clinicians about the benefits/limitations of choosing one regimen over the other. Design A retrospective cohort study. Participants Patients with active WM seen at Mayo Clinic Rochester, Arizona, and Florida campuses between 10/01/2000 and 10/31/2019 who received R-Benda, DRC, or BDR as primary therapy were included. Outcomes Measures Overall response rate (ORR), event-free survival (EFS), progression-free survival (PFS), overall survival (OS), time-to-next therapy (TTNT) and treatment related adverse-effects (AEs) based on the three treatment regimens. The MYD88L265P mutation status was assessed using allele-specific polymerase-chain-reaction (sensitivity 1%). Response rates were assessed by Consensus Criteria. Time-to-event analyses were performed from the frontline therapy, using Kaplan-Meier method. CTCAE v4.03 was used to grade toxicities. Results The study included 220 patients with active WM who were treated with R-Benda (n=83), DRC (n=92) or BDR (n=45). The median follow-up was 4.5 (95% CI: 4-5) years. The R-Benda cohort demonstrated superior ORR (98%), in comparison to DRC (78%) or BDR (84%) cohorts, p=0.003. Similarly, longer PFS was evident with R-Benda use [median 5.2 versus 4.3 (DRC) and 1.8 years (BDR), p=0.0003]. The TTNT favored R-Benda [median, not-reached, versus 4.4 (DRC) and 2.6 years (BDR), p=0.0002]. 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 MYD88L265P mutation, the ORR, PFS and TTNT were unaffected by the MYD88 signature within each cohort. Toxicity profiles across the three groups were comparable, barring a higher incidence of neutropenia and neuropathy in patients who received R-Benda and BDR regimens, respectively. Conclusions The ORR, PFS and TTNT with R-Benda are superior compared to DRC or BDR in treatment-naive patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88L265P mutation status.

Context: Continuous Rd-based regimens are among the standards of care in the diverse, transplant-ineligible NDMM patient population. An all-oral triplet may be useful for patients who cannot/prefer not to travel to the clinic frequently. Ixazomib, the first oral proteasome inhibitor (PI), has predictable, manageable toxicities, enabling an all-oral PI-Rd regimen for use in this setting. Objective: Compare IRd vs. placebo-Rd in transplant-ineligible NDMM patients. Interventions: Patients were randomized to ixazomib 4 mg (n=351) or placebo (n=354) plus Rd (28-day cycles). After 18 cycles, dexamethasone was discontinued and lower ixazomib and lenalidomide doses were administered until progression or unacceptable toxicity. Main Outcome Measure: Progression-free survival (PFS) - final analysis. Results: In the IRd vs. placebo-Rd arms, the median age was 73 vs. 74 years (43% vs. 44% ≥75 years), 16% vs. 17% had International Staging System stage III MM, and 38% vs. 41% had high-risk cytogenetics [t(4;14), t(14;16), del(17p), or amp(1q21)]. The median PFS was 35.3 vs. 21.8 months (hazard ratio [HR] 0.830, p=0.073; median follow-up 53.3 vs. 55.8 months). Overall response rates were 82% vs. 80%; depth of response was greater with IRd vs. placebo-Rd (26% vs. 14% complete response [CR], odds ratio [OR] 2.10, p Conclusions: IRd in NDMM demonstrated a strongly positive trend in PFS, improved TTP and CR rate, and improved the poor PFS associated with high-risk cytogenetics, as seen in the TOURMALINE-MM1 study of IRd in relapsed/refractory MM. Safety was consistent with the well-characterized toxicity profile of ixazomib/IRd. IRd is a feasible treatment option for certain transplant-ineligible patients who could benefit from an all-oral triplet combination.

Introduction: Chemotherapeutic options for patients with systemic light chain amyloidosis (AL) who are not transplant candidates include bortezomib based therapy, melphalan with dexamethasone, and less commonly, immunomodulatory drugs (IMiDs). However, prospective clinical trial data comparing these regimens are lacking. This study aims to compare efficacy of bortezomib-based treatment to other therapies. Methods: All patients with AL seen within 90 days of diagnosis at our institution over a 10-year period (2006 to 2015) who did not undergo a stem cell transplant were identified from our institutional database. Data pertaining to demographics, diagnosis, treatment and follow-up were extracted from electronic medical records. Analyses were carried out by chi-square and Fisher9s exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Progression free survival (PFS) is defined as time to death, progression requiring treatment change or relapse requiring re-institution of treatment. PFS and overall survival was analyzed via the Kaplan-Meier method. Results: Seven hundred and twenty five patients met the inclusion criteria, of which 38% (n=275) received bortezomib containing regimens and 62% (n=450) received non-bortezomib based therapies. Bortezomib was used with dexamethasone in 24% (n=67) patients; and with other drugs, most commonly cyclophosphamide, in 76% (n=208) patients. Non-bortezomib treatment regimens included melphalan-based treatment in the majority (92%, n=414) followed by IMiDs with steroids and other drugs (8%, n=36). Baseline variables similar in both groups and their distribution in the entire cohort was as follows: gender distribution (63.3% males, n=459), median age of diagnosis (66.3 years, range 32.2 to 93.6), type of involved free light chain (FLC) (lambda 73%, n=523) and median plasma cell burden (10%, range 0 to 91). Median difference between the involved and uninvolved free light chain (dFLC) was higher in the bortezomib group (29 mg/dL vs. 23 mg/dL; p=0.017). There was no difference in organ involvement. In the bortezomib group, organ involvement was as follows: cardiac (81%, n=219), renal (62%, n=168) and hepatic (18%, n=48). In the non-bortezomib group, the rates of organ involvement were similar: cardiac (78%, n=346), renal (57%, n=247) and hepatic (19%, n=85). Median duration of first line treatment was similar in the 2 groups, with 178 days in the bortezomib cohort and 187 days in the non-bortezomib cohort. Response rates are illustrated in Table 1. Rates of very good partial response (VGPR) or better response were higher in the bortezomib group (64 % vs. 54%, p=0.0002). Patients treated with bortezomib achieved VGPR faster with higher rates of VGPR or better response seen at 3 months (48% vs. 27%, p Relapse or progression requiring change in therapy was more common in patients treated with non-bortezomib based therapy (38%, n=143/372) compared to bortezomib-based treatment (28%, n=67/236); p =0.01). However, no difference in overall survival was observed in patients treated with bortezomib (2.2 years; 95% confidence interval (CI): 1.7 to 3.3) vs. non-bortezomib therapies (1.7 years; 95% CI: 1.3 to 2.5). Conclusion: Treatment with bortezomib-based regimens results in a deeper response including higher rates of early VGPR at 3 and 6 months from starting therapy. Moreover, these patients achieve cardiac response faster and have lower rate of relapse. However, no difference in overall survival was seen, which may be explained by subsequent use of bortezomib-based therapies in this population. Disclosures Dispenzieri:Celgene: Research Funding; Alnylam: Research Funding; pfizer: Research Funding; Jannsen: Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity9s Board of Directors or advisory committees; Prothena: Membership on an entity9s Board of Directors or advisory committees. Kumar:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

Monoclonal gammopathy of undetermined significance of the immunoglobulin M class was diagnosed in 213 patients at the Mayo Clinic, 29 (14%) of whom developed lymphoma, Waldenstrom macroglobulinemia, or a related disorder over 1567 person-years of follow-up. The cumulative probability of progression was 10% at 5 years, 18% at 10 years, and 24% at 15 years, or approximately 1.5% per year. The concentration of serum monoclonal protein at diagnosis and the initial serum albumin value were the only independent predictors of progression with multivariate analysis. By contrast, during 285 person-years of follow-up, 34 (71%) of 48 patients with smoldering Waldenstrom macroglobulinemia (SWM) progressed to Waldenstrom macroglobulinemia (WM), which required therapy, along with amyloid light chain (AL) amyloidosis (1) and lymphoma (1). The cumulative probability of progression was 6% at 1 year, 39% at 3 years, 59% at 5 years, and 65% at 10 years. The percentage of lymphoplasmacytic cells in the bone marrow, size of the serum monoclonal (M) spike, and hemoglobin value were significant independent risk factors for progression.

BACKGROUND Light-chain amyloidosis (AL) is the most common form of systemic amyloidosis, with an incidence of approximately 1 case/100,000 person-years. Clinically relevant data with regard to the very young (≤ 40 years) patients (pts) are scant. We present a case-control study of very young pts with AL seen at a single institution. METHODS We reviewed the medical records of all pts with AL who were consecutively evaluated at Mayo Clinic, Rochester, MN between 01/01/1995 and 12/31/2015. The clinical characteristics and survival outcomes of very young pts at the time of AL diagnosis (cases) were compared to a 2:1 matched cohort of pts (controls) with AL who were 65 years or older and matched by the time of diagnosis. Upfront autologous stem cell transplantation (ASCT) was defined as transplantation within 6 months of the diagnosis of AL. The Kaplan-Meier method was used to all time-to-event analyses. The average years of life lost was computed by subtracting the mean survival from diagnosis observed in the cohort from the mean survival expected in the population based on life-tables. RESULTS Of 3433 pts with AL, 50 (1.5%) pts were ≤ 40 years of age at diagnosis (cases). Fatigue, peripheral edema, dyspnea and bleeding were less common at presentation in cases compared to controls (table A). The cases were also more likely to have liver or GI involvement (OR= 3.45, 95% CI: 1.6-7.2). Unusual initial clinical features in the cases included unprovoked splenic rupture (2%) and erectile dysfunction (4%) observed 6-15 months prior to the diagnosis of AL in cases; no such features were observed in the control group. The median time between the onset of symptoms and definitive diagnosis was 0.4 years (95% CI: 0.3-0.7) for the cases and 1 year (95% CI: 0.8-1.2) for controls (p 10% BMPCs without active myeloma (AL-PCMM) (p=0.16). Monoclonal light chain involvement without involvement of heavy chain was seen in 23 cases (50%) and 31 controls (32%), (OR= 2.1, 95% CI: 1.04-4.37). The median follow-up was similar for cases and controls, [10.9 years (95% CI: 7.6-12) vs 9.9 years (95% CI 8-14)], respectively. The estimated average years-of-life lost was 8.6 years over 20 years of follow-up in cases, (Figure 1a). In cases, 1 and 10-year overall survival (OS) from diagnosis was 73% and 51%, respectively (median OS 12.7 years; 95% CI: 4.0-NR) while, in controls, 1 year and 10 year OS was 62% and 15% respectively (median OS 2.1 years; 95% CI (1.0-3.6), p

Background : Proliferation rate of plasma cells (PC) is a powerful tool in evaluating all types of monoclonal gammopathies, predicting for progression as well as survival in all phases of the disease. A flow cytometry (FC)-based method to delineate the cell cycle of clonotypic PCs and determine the proportion in S-phase was developed. This method replaces a labor-intensive slide based methodology, but the prognostic power of this FC approach has not been clearly elucidated. Methods : A total of 1061 patients who had bone marrow (BM) FC PC proliferation analysis at Mayo Clinic, Rochester from May 2012 to December 2013 were studied. These included MGUS/ SMM (n=134), newly diagnosed (NMM; n=88), plateau in response (>=PR; n=544), and stable disease (n=38), and relapsed disease (RMM; n=257). PC proliferation was measured by 8-color FC using antibodies to CD19, CD38, CD138, CD45, and cytoplasmic kappa and lambda Ig light chains, and DAPI DNA staining. The DNA content of the abnormal, clonotypic PCs was specifically analyzed and the %S-phase was determined by measuring the proportion of cells between G0/G1 and G2/M. All studies collected 5x105 events on BD FACSCanto II instruments and analysis was performed with BD FACSDiva software. The CV of the DAPI staining of G0/G1 lymphocytes as an internal control population was always less than 3.5. Patients with fewer than 300 PCs for assessment of %SP were designated as 0%. Results : The median follow up from testing for the entire cohort was 13 months (95% CI; 12.7, 13.3); 156 (15%) had died. The proportion of patients with adequate numbers of plasma cells available for %SP estimation and the median (IQR) %SP for the different groups are as shown in table. As expected, patients with MGUS/SMM and those in a response state had slightly lower proportions of patients with sufficient PCs to estimate %SP. The clinical features and outcomes were further analyzed using two cutoffs, %SP ≥1 and ≥2, in the different patient groups. Among most of the disease groups, especially the newly diagnosed MM and relapsed disease, %SP was prognostic for OS using both cutoffs ( Table ). Among the NMM in univariate analysis, %SP ≥2, B2microglobulin >5.5, age >70 and creatinine > 2 mg/dl were all significant, but only B2microglobulin >5.5 retained significance in multivariable analysis. Among the RMM, in univariate analysis, %SP ≥2, B2microglobulin >5.5, HR FISH (t4; 14, t14;16, t14;20 & del17p) and LDH >221 were all significant, but only %SP ≥2 was significant in multivariable analysis. Conclusion: The %S-phase of clonal PCs determined by FC is of prognostic value in patients with MM, in all disease phases. This is particularly relevant among patients with relapsed disease, where it is independent of some of the other known poor prognostic factors such as high risk FISH. This is in sharp contrast with recent studies that have shown no prognostic value for slide based labeling index in patients treated with novel agents. | | MGUS/ SMM | NMM | >=PR | SD | Relapse | | --------------------------------------------------------------------- | -------------------------------- | -------------------------------------- | --------------------------------------- | ------------------------------------- | ---------------------------------- | | N | 134 | 88 | 544 | 38 | 257 | | N (%) with PCs measurable for proliferation | 103 (77%) | 84 (96%) | 245 (45%) | 31 (82%) | 210 (82%) | | %SP (IQR) | 0.3 (0.1-0.7) | 0.8 (0.4- 1.5) | (0- 0.9) | 0.8 (0.3-1.3) | 1.2 (0.4- 2.7) | | OS (%SP >1 vs. rest) | NS | NR for either (P2 vs. rest) | NS | NR for either (P=0.03) | 20 vs. NR (P