Abeykoon, Jithma P.

Abstract Background Waldenström macroglobulinemia (WM) is a rare, indolent immunoglobulin M- associated lymphoplasmacytic lymphoma characterized by the alternation in the MYD88 locus in 90-95% of the cases. MYD88L265P is the most common alteration in WM patients and is considered a key molecular signature with a pathophysiological role in WM. Because of extremely low prevalence of WM with MYD88 wild type (WT) genotype there is a paucity of clinical and outcome data in this unique patient population. A recent study (Treon et al, Blood May, 2014), in an analysis based on the patients' MYD88 status, reported on the clinical features including older age at presentation and an unexpectedly higher mortality (38%) in the MYD88WTcohort compared to MYD88L265P patients (mortality 6%, P < .0001). However, the sample size of the MYD88WT WM cohort was small (n=15), with a few events during the short follow-up (median 4.84 years). Herein, we report on larger cohort of WM patients with this rare genotype. Methods This study included patients evaluated at Mayo Clinic, Rochester in whom the diagnosis of WM was established based on their clinicopathologic features and the MYD88 mutation status was determined through AS-PCR (assay sensitivity 1% mutant allele) performed on archived bone marrow samples obtained between 2007-2014. Patients with MYD88WT status were the focus of this study. Clinical data were collected from the patients' medical records. The Kaplan-Meir method was utilized for the survival analysis calculated from the time of diagnosis of WM. Outcomes of MYD88WT patients were compared with those harboring the MYD88L265Pmutation. Results Our cohort of 171 patients with an established diagnosis of WM and known MYD88 mutation status was found to be enriched for MYD88WT (n=40) patients. All patients required therapy. At diagnosis, the median age of the patients with MYD88 WT was 63 years (range 37.5-83.5 years; comparable to that of the MYD88L265P cohort, median 65 years, range: 32-92 years, p=0.16). Familial WM was identified in 10% of patients. Sixty four percent of patients presented with constitutional symptoms at diagnosis. These symptoms included fatigue (45%), weight loss (17%), night sweats (8%) dizziness (10%), dyspnea (23%), bleeding (10%), headache (10%) and hyper viscosity syndrome (5%). Splenomegaly and lymphadenopathy was observed in 20% and 27% of patients, respectively. Thirteen percent of patients had concomitant AL amyloidosis. Additional baseline characteristics are reported in Table 1. Transformation to a higher grade lymphoma was noted in 9 (23%) of patients, four of whom had received a purine analog and /or chlorambucil previously. The estimated median follow of MYD88WT patients was 8.1years (95% CI: 6.4-8.9) and their median overall survival (OS) was 8.5 years (95% CI: 6.4-29.4). No OS difference was evident between this cohort and the remainder of the patients with the MYD88L265Pmutation (n=131, median OS 11.7 years, 95% CI: 10-18, p=0.7; median follow-up 7.7 years 95% CI: 6.4-9.1, Figure 1). Conclusion In this relatively large cohort of WM MYD88WT patients with a prolonged follow-up, the MYD88mutation status was not found to be a determinant of patients' outcomes. Our findings contradict the results of a seminal previous study and require external validation, preferably through prospective studies. Disclosures Kapoor: Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Kesios: Consultancy.

Abstract Background WM remains an incurable cancer despite recent advances. While a phase II trial has demonstrated efficacy of dexamethasone, rituximab and cyclophosphamide (DRC) in the treatment-naïve (TN) patients, this regimen has not been studied systematically in the relapsed/refractory (R/R) setting. Recent data has suggested the MYD88mutation status in WM patients can serve as a predictive marker with therapies such as ibrutinib. We examined the efficacy and tolerability of up to 6 cycles of DRC, with focus on R/R population and activity of this regimen with respect to the patients' MYD88L265Pstatus. Methods Records of WM patients seen consecutively at Mayo Clinic campuses in Rochester, Arizona and Florida from 01/2007 to 12/2014 were reviewed. MYD88L265P status, as assessed by AS-PCR, was recorded when available. Data obtained from symptomatic patients treated with DRC (dexamethasone 20 mg intravenously followed by rituximab 375 mg/m2 intravenously on day 1 and cyclophosphamide 100 mg/m2 orally bid on days 1 to 5) were analyzed. Time-to-event analyses were performed from DRC therapy using the Kaplan-Meier method. We used the Consensus response criteria (6th International Workshop). Results Of 100 symptomatic patients who received DRC, 50 had R/R WM (40% refractory) and 50 were TN. Table 1 shows the patients' baseline characteristics. In the R/R population, DRC was 2nd line (range 2-8) therapy in 58% of patients. The median IgM levels declined from 3,870 mg/dL to 1,846 mg/dL (p=0.0001) at best response. Median follow-up from DRC was 51 months (95% CI: 38-55). The median time-to-best response was 6.8 (0.5-28) months. Overall response rate (ORR) was 87% [VGPR 4%, PR 64%, MR 19%]. Four patients (9%) achieved SD and 2 patients (4%) had PD. Of the sixteen deaths (32%) noted at time of analysis, 11 were related to progressive disease. The median disease-specific survival (DSS) from DRC was not reached (NR) (95% CI: NR-NR). The median progression-free survival (PFS) and time-to-next-therapy (TTNT) were 32 months (95% CI: 15-51) and 50 months (95% CI: 35-60), respectively. In contrast, in the TN patients the median IgM levels declined from 4,130 mg/dL to 1,250 mg/dL (p=0.0001) at best response; median time to best response was 11 (0.6-47) months; median follow-up from DRC was 30 months (95% CI: 21-36). ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. Of the 7 deaths (14%) at time of analysis, 4 were related to WM progression. Median DSS from DRC was NR (95% CI: NR-NR); median PFS and TTNT were 34 months (95% CI: 23-NR) and NR (95% CI: 37-NR), respectively. Among 29 genotyped patients in whom MYD88 mutation status was available, MYD88L265P was present in 25 patients (8 of 10 TN and 17 of 19 R/R patients). The response rates and the time-to-event outcomes were similar in the MYD88L265P and wild-type patients. Grade ≥3 adverse effects included neutropenia (20%), thrombocytopenia (7%) and infections (3%). Conclusions Similar to the frontline setting, DRC is an active and well-tolerated salvage regimen. In contrast to ibrutinib, DRC offers a less expensive, limited-duration treatment option, with preliminary data suggesting activity independent of patients' MYD88 mutation status. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Kumar:Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Kesios: Consultancy; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Celgene: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

Abstract Background Bendamustine/rituximab (BR) and dexamethasone/rituximab/cyclophosphamide (DRC) combination therapy are acceptable options for the treatment of WM, both in the frontline or salvage setting. Prospective data, however, are only available in treatment-naïve (TN) WM patients, and no direct comparison between BR and DRC has been reported. We compared outcomes of BR and DRC in relapsed/refractory (R/R) and TN WM patients seen at a single institution. Methods Records of WM patients seen consecutively at Mayo Clinic from 01/2007 to 12/2014 were reviewed. The MYD88L265P status, as assessed by AS-PCR, was recorded when available. The data obtained from symptomatic patients treated with DRC or BR were analyzed. The time-to-event analyses were performed from DRC or BR therapy using the Kaplan-Meier method. We used the Consensus criteria (6th International Workshop) for response assessment. Results Of 160 WM patients, 60 patients received BR (73% in R/R setting) and 100 patients received DRC (50% in R/R setting). In the R/R population, BR was the 2nd line (range 2-11) therapy in 47% of patients, while DRC was 2nd line (range 2-8) in 58% of patients. Rituximab monotherapy was the only prior line of therapy in 8 (20%) patients in the BR group and 20 (40%) in the DRC group (p=0.66). Baseline characteristics were similar in patients treated with BR or DRC (Table 1). Six patients received both BR and DRC during their disease course and overlapped between the 2 cohorts. Among the previous untreated patients, the median IgM levels decreased from 3,785 mg/dL to 724 mg/dL (p=0.0001) at best response with BR, while it decreased from 4,130 mg/dL to 1,250 mg/dL (p=0.001) with DRC. The median time to best response was 6.1 (1-25) months in the BR group and 11 (0.5-47) months in the DRC group (p=0.13). For patients treated with BR, the overall response rate (ORR) was 93% [VGPR 29% (n=4), PR 57% (n=8), MR 7% (n=1)]. One patient (7%) had progressive disease. For patients treated with DRC, ORR was 96% [VGPR 17% (n=8), PR 70% (n=32), MR 9% (n=4)]. One patient (4%) achieved SD. Median follow up in the BR and DRC groups were similar (30 months). The 2-year progression-free survival (PFS) was 88% and 61% in the BR and DRC groups, respectively (p=0.08). The 2-year time-to-next therapy (TTNT) was 88% and 76% in the BR and DRC groups, respectively (p=0.35). Median PFS, TTNT and disease specific survival (DSS) were not reached with either regimen. In the R/R setting, the median IgM levels decreased from 3,880 mg/dL to 659 mg/dL (p=0.0001) at best response with BR, and from 3,870 mg/dL to 1,846 mg/dL (p=0.001) with DRC. The median time to best response was similar [7 (1-39) months with BR and 7 (0.5-28) months with DRC (p=0.77)]. For patients treated with BR, ORR was 95% [CR 3% (n=1), VGPR 38% (n=14), PR 41% (n=15), MR 13% (n=5)]. Two patients (5%) had progressive disease. With DRC, the ORR was 87% [VGPR 4% (n=2), PR 64% (n=30), MR 19% (n=9)]. Four patients (9%) achieved SD and 2 patients (4%) had progressive disease. Median follow up from BR was 32 months and 51 months from DRC (p=0.24). The 2-year PFS was 66% and 53% in the BR and DRC groups, respectively (p=0.08). The 2-year TTNT was 75% and 68% in the BR and DRC groups, respectively (p=0.24). The median DSS in the BR group was 69 months (95% CI: 65-69) and NR (95% CI: NR-NR) in the DRC group (p=0.57). The proportion of patients with R/R disease was significantly higher in the BR cohort (Table 1). In a bivariate analysis of the entire cohort for PFS, incorporating the setting (TN vs. RR) and the regimen involved (BR vs. DRC), the latter emerged as a significant factor (hazard ratio 0.52, p=0.019) in favor of BR. Time-to-event outcomes and response rates were similar in the MYD88L265P and MYD88WT patients. Grade ≥ 3 adverse events were neutropenia (12%), infections (7%) and nausea/vomiting (2%) with BR, and neutropenia (20%), thrombocytopenia (7%) and infections (3%) with DRC. Conclusions Although both DRC and BR regimens show activity and comparable toxicities, BR regimen shows a trend for superior PFS in WM patients, both in the TN and R/R setting. No difference was seen in TTNT. MYD88 L265P mutation status does not appear to impact activity of BR or DRC. Randomized controlled trial(s) are needed to confirm our findings. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Dispenzieri:Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees. Kumar:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Glycomimetics: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

Abstract 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<0.0001). The ECOG performance score at diagnosis was ≥2 in 51% of cases compared to 78% of the controls (OR= 0.29, 95% CI: 0.14-0.63). The involvement by 3 or more organs at diagnosis was comparable [24 (48%) cases compared to 34 (34%) controls (p=0.11)]. Concomitant myelomatous (AL-CRAB) features were evident in 12% of each group and 27 (54%) cases and 37 (41%) controls had >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<0.001), (Figure 1b). Cardiac involvement was associated with a worse OS in both cohorts, (cases: median OS was 3.2 years with cardiac involvement (95% CI: 0.6-8.7) vs NR (95% CI: 8.0-NR) in those without; p=0.003; controls: median OS was 1.1 years with cardiac involvement (95% CI: 0.53-1.6) vs 4.8 years (95% CI: 3.7-8.1) in those without; p=0.02. Thirty one of 47 (66%) cases were eligible and 20 of 79 (25%) controls were eligible for upfront ASCT. In cases, upfront ASCT was associated with a longer OS. Median OS was NR (95% CI: NR-NR) in pts who underwent upfront ASCT (n=25) vs 4.0 years (95% CI: 0.5-8) in pts who did not, p≤0.0001. For controls, the median OS was 9 years (95% CI: 0.5-11) for pts who underwent upfront ASCT (n=7) vs 1.6 years (95% CI: 1.0-2.8) for pts who did not (n=93), p=0.26. In cases, six (12%) pts underwent solid organ transplantation (kidney 5, heart 1) and none in the control arm. CONCLUSIONS AL amyloidosis is infrequently encountered at the age of ≤40 years, but the loss of productive years of life and the disease burden are substantial in this cohort. A substantial delay in diagnosis from the onset of symptoms was noted in our study in the control population. Cardiac involvement remains a primary determinant of prognosis irrespective to age. Although over one-half of young pts are alive 10 years after the diagnosis (contrast ≈15% ≥ 65 years), early mortality remains substantial irrespective of age. An ASCT-based approach is associated with superior outcome in the young. A greater proportion of the young pts is fitter and ASCT-eligible at diagnosis, and should therefore be offered this approach. Disclosures Dispenzieri: Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding. Kumar:Array BioPharma: Consultancy, Research Funding; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding.

Abstract Background Despite significant progress, MM remains an incurable disease. Synergistic activity of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has been established in preclinical and clinical studies. Data with respect to combination of newer IMiDs and PIs are scant. Recently, a small study (n=32) found the novel therapeutic regimen consisting of carfilzomib, pomalidomide and dexamethasone (KPd) to be well-tolerated and active in RRMM patients, but only 7% of patients in that study had ECOG > 1. KPd has not been extensively studied outside of clinical trials. Therefore, we evaluated real-world outcomes of KPd in RRMM patients seen in our routine dysproteinemia practice. Methods Records of MM patients consecutively seen at Mayo Clinic, Rochester from 01/ 2013 to 05/ 2016 were reviewed. Forty-five MM patients who received KPD in the R/R setting were identified and included in the analysis. The international uniform response criteria (IMWG 2006) were used to assess response rates. Additionally, minor response (MR) was assessed to determine the clinical benefit rate (CBR or ≥MR). Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 4. Duration of response was calculated for patients who have achieved a PR or greater response from time of first response to progression of disease. The time-to-event analyses were performed from the time of initiation of KPd therapy using the Kaplan-Meier method. All but one patient received K at 20/27 mg/m2 (days 1, 2, 8, 9 15, 16) dosing, P at 2 mg or 4 mg (day 1-21), and dexamethasone at 20 or 40 mg (day 1, 8, 15, 22), with 28-day cycles. Results The median age at KPd initiation was 65 years (range 29-75), 25 (56%) patients were males. 71% had an ECOG performance score of 0 to 1, and 29% had an ECOG >1. Forty percent were mSMART standard risk, while 60% were intermediate to high risk. Median time from MM diagnosis to KPd was 44 months (range 6-188), and the median number of prior treatment lines was 4 (range 1-14). Three (7%) patients were quadruple refractory to bortezomib (V), lenalidomide (R), P, and K. Ten (23%) were triple refractory to V, R, and P or K. Twenty seven (60%) were dual refractory to V and R. Table 1 shows prior treatment agents and refractoriness. The median duration of treatment with KPd was 2 months (range 0.3-16.4). KPd was used as a bridge to autologous stem cell transplant (ASCT) in 5 patients. One patient discontinued therapy due to toxicity (infection, weakness). Response was evaluable in 44 patients. The median time to first response was 1.4 months (range 0.5-6). Overall response rate (ORR) was 36%, [stringent complete response (sCR) in 1 (2%) patient, complete response (CR) in 3 (7%) patients, very good partial response (VGPR) in 2 (5%) patients, partial response (PR) in 10 (22%) patients]. Minimal response (MR) was seen in 3 (7%), leading to a CBR of 43%, while an additional 10 (23%) patients had stable disease (SD). Progressive disease (PD) was noted in 15 (34%) patients. At the time of analysis 20 (43%) patients were deceased, all from PD. The median follow up from initiation of KPd was 16.3 months (95% CI: 8.6-19.4). The median overall survival (OS) from KPd was 16.1 months (95% CI: 10.6-20.4). Median OS for dual refractory was 15.6 (95% CI: 10.6-20.5). Median OS for triple/quadruple refractory was similar to those with lesser degree of refractoriness [19.1 (95% CI: 0.92 - 27.1) months vs 13.6 (95% CI: 8.9-20.5), p= 0.82]. The median progression-free survival (PFS) was 3.3 months (95% CI: 1.9-6.4) and the median time-to-next therapy (TTNT) was 3.5 months (95% CI: 2.2-6.7). The media duration of response was 12.9 months (95% CI: 2.5-19.6). The median OS from KPd for patients who achieved at least a PR was 20.4 months (95% CI: 13.6-NR), compared to 11 months (95% CI: 8.3-NR) for others (p=0.05). Grade ≥3 hematologic toxicity was seen in 19 (42%) of evaluable patients [grade ≥3 neutropenia (29%), thrombocytopenia (31%) and anemia (22%)]. The most common non-hematologic adverse events were fatigue (38%), infections (31%), diarrhea (12%) and dyspnea (12%). Of the 4 (9%) patients who developed venous thromboembolism (VTE), two were on aspirin prophylaxis while the other two were not receiving any VTE prophylaxis. Conclusions KPd shows activity in RRMM patients although the short PFS reflects the challenges encountered with managing heavily pretreated and often less fit patients in the real world setting outside of clinical trials. Disclosures Dispenzieri: Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; pfizer: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Kumar:BMS: Consultancy; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

SummaryIbrutinib‐related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment‐naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off‐study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major‐response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2–4] and 5·7 (95% CI: 4–12) months, respectively. The median follow‐up was 19 (95% CI: 14–21) months; 18‐month progression‐free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3–16·7) months, and the median duration‐of‐response was 32 (range: 23–32) months. Twenty‐five patients (31%) had discontinued therapy at last follow‐up (68% due to treatment‐related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial‐fibrillation (11%) were common non‐haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

BackgroundThere exist insufficient data characterizing patients with multiple myeloma (MM) who experienced prolonged survival. A population‐based analysis of long‐term survivors was conducted to investigate the roles of sociodemographic factors and upfront stem cell transplantation (SCT).MethodsThe National Cancer Data Base is a US cancer database of approximately 34 million patients from >1500 cancer centers. Patients with MM were identified using the International Classification of Diseases for Oncology (ICD‐O) code 9732 from January 2004 to December 2006 and were divided into 4 groups based on overall survival (OS). Sociodemographic characteristics, treatment facility, and use of SCT were recorded. The univariate and multivariate analyses were performed using multiple logistic regression and Pearson chi‐square tests.ResultsA total of 26,986 patients with MM were identified. The median OS was 2.74 years. The majority of patients were male (54%), white (77%), insured (93%) and otherwise healthy (78%), lived in a metropolitan area (82%), were of high income (66%) and educational (58%) levels, and received treatment at nonacademic facilities (63%). Upfront SCT was used in 10% of patients. One in 6 patients (16%) were long‐term survivors (group 4). When comparing group 4 (OS of ≥8.22 years) with the other groups (OS of <8.22 years), young age, female sex, high income and educational levels, residence in a rural area, insured status, no comorbidity, receipt of upfront SCT, and treatment at high‐volume facilities were associated with long‐term survival.ConclusionsKey differences in sociodemographic characteristics, patient volume at treatment facilities, and upfront SCT were associated with long‐term survival. Improvements in health care access and health literacy, upfront SCT, and treatment at high‐volume facilities might prolong patient survival.

Background:Previous literature has established “long‐term survivors” as patients who survive greater than 10 years from diagnosis of active multiple myeloma (MM). With the rapid discovery and evolving use of novel therapeutic agents, a greater proportion of patients are reaching this milestone. Although these patients share in their extended survival, they also constitute a heterogeneous group in terms of treatments and outcomes.Aims:The aim of this study is to examine a large cohort of long‐term survivors with protracted follow‐up as an attempt to identify a subset of patients within ten‐year survivors who have longstanding disease remission, and examine the predictors of their especially exceptional prognosis.Methods:All patients with active MM evaluated at Mayo Clinic, Rochester between January 1, 1999 and July 1, 2008 were included in the study. Patients with MGUS, smoldering MM, and solitary plasmacytoma were excluded. The overall survival (OS) was calculated from time of symptomatic disease requiring treatment. Patients with greater than 10 year survival from diagnosis were then divided into three cohorts based upon treatment and remission status: Cohort 1 included patients off therapy ≥ 5 years and in sustained remission, Cohort 2 included patients on maintenance therapy ≥ 5 years and in sustained remission, and Cohort 3 included patients who had relapsed within the past 5 years. Differences between the groups were compared using Wilcoxon, Chi‐square, and Fisher's exact test as applicable. “Early” stem cell transplant was defined as patients who received a stem cell transplant within one year of diagnosis.Results:During the time frame of the study, 2,125 patients were identified who fulfilled the diagnostic criteria for active MM. Three‐hundred ninety nine (19%) had survived at least 10 years from diagnosis. Among these patients, based on the available data regarding remission and ongoing treatment status, 332 patients were categorized into three cohorts, seen in Table 1. Sixty patients (18% of long‐term survivors) comprised Cohort 1, 48 patients (14% of long‐term survivors) comprised Cohort 2, and 224 patients (68% of long‐term survivors) comprised Cohort 3. Sex difference was statistically significant between the groups, with more females constituting Cohorts 1 and 2 (p = 0.03). Within Cohort 1, 77% of patients underwent an autologous stem cell transplant (ASCT). The median progression free survival following ASCT in this cohort was not reached (95% CI 15–NR, p < 0.001). In addition, patients in Cohort 1 and Cohort 2 were more likely to undergo an early ASCT as compared to patients in Cohort 3 (p = 0.002). There were no significant differences in high or intermediate risk FISH/cytogenetics at diagnosis, ISS at diagnosis, or induction therapies used at diagnosis among the three groups.Summary/Conclusion:Our study identified a small subset (3% of all patients diagnosed with active MM) of long‐term survivors who are off of therapy and remain in sustained longstanding remission. Female sex, progression free survival following ASCT, and receiving an early ASCT were factors that portended a positive prognosis amongst long term survivors.image

Abstract Targeting the B-cell receptor and phosphatidylinositol 3-kinase/mTOR signaling pathways has shown meaningful, but incomplete, antitumor activity in lymphoma. Glycogen synthase kinase 3 (GSK3) α and β are 2 homologous and functionally overlapping serine/threonine kinases that phosphorylate multiple protein substrates in several key signaling pathways. To date, no agent targeting GSK3 has been approved for lymphoma therapy. We show that lymphoma cells abundantly express GSK3α and GSK3β compared with normal B and T lymphocytes at the messenger RNA and protein levels. Utilizing a new GSK3 inhibitor 9-ING-41 and by genetic deletion of GSK3α and GSK3β genes using CRISPR/CAS9 knockout, GSK3 was demonstrated to be functionally important to lymphoma cell growth and proliferation. GSK3β binds to centrosomes and microtubules, and lymphoma cells treated with 9-ING-41 become arrested in mitotic prophase, supporting the notion that GSK3β is necessary for the progression of mitosis. By analyzing recently published RNA sequencing data on 234 diffuse large B-cell lymphoma patients, we found that higher expression of GSK3α or GSK3β correlates well with shorter overall survival. These data provide rationale for testing GSK3 inhibitors in lymphoma patient trials.

BACKGROUND Waldenström macroglobulinemia (WM) is preceded by asymptomatic WM (AWM), for which the risk of progression to overt disease is not well defined. METHODS We studied 439 patients with AWM, who were diagnosed and observed at Dana-Farber Cancer Institute between 1992 and 2014. RESULTS During the 23-year study period, with a median follow-up of 7.8 years, 317 patients progressed to symptomatic WM (72%). Immunoglobulin M 4,500 mg/dL or greater, bone marrow lymphoplasmacytic infiltration 70% or greater, β2-microglobulin 4.0 mg/dL or greater, and albumin 3.5 g/dL or less were all identified as independent predictors of disease progression. To assess progression risk in patients with AWM, we trained and cross-validated a proportional hazards model using bone marrow infiltration, immunoglobulin M, albumin, and beta-2 microglobulin values as continuous measures. The model divided the cohort into three distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.8 years, an intermediate-risk group with a median TTP of 4.8 years, and a low-risk group with a median TTP of 9.3 years. We validated this model in two external cohorts, demonstrating robustness and generalizability. For clinical applicability, we made the model available as a Web page application ( www.awmrisk.com ). By combining two cohorts, we were powered to identify wild type MYD88 as an independent predictor of progression (hazard ratio, 2.7). CONCLUSION This classification system is positioned to inform patient monitoring and care and, for the first time to our knowledge, to identify patients with high-risk AWM who may need closer follow-up or benefit from early intervention.