Dingli, David

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.

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.

AbstractThree sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5–5.3, p = .001] and 2.5 [CI: 1.4–4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17–0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post‐treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post‐treatment. These differences are important when choosing endpoints for clinical trials.

AbstractInduction therapy for multiple myeloma with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (d) (VRd) was traditionally administered as bortezomib given twice weekly on a 3 week cycle. A modified schedule of weekly bortezomib has been adopted over time to decrease treatment burden for patients and reduce treatment‐emergent neuropathy. This study evaluates the response rates and outcomes with different schedules of bortezomib in VRd administered for first‐line treatment for patients with newly diagnosed MM (NDMM). We retrospectively analyzed patients treated with upfront VRd from June 30th 2008 to December 31st 2018, for variations of bortezomib administration. Five hundred and fifty‐five (555) NDMM patients met inclusion criteria; median age 63 years and 61% men. Bortezomib was administered twice weekly every 21 days in 43%, once weekly every 21 days in 41% and once weekly every 28 days in 16%. Though peripheral sensory neuropathy was more frequent with twice weekly dosing (P = .002), this group achieved shorter time to best response (P = .01). Weekly every 21‐day treatment saw higher VGPR or better rates (P = .02). However, with median follow up time of 37 months (IQR 22–56), we found no difference in PFS or OS among the groups. While small differences in response rates were found among the varying administration schedules of bortezomib administration, there was no significant effect on PFS or OS. Given that VRd remains a first line standard of care option for newly diagnosed MM, in the absence of a large trial comparing bortezomib dosing schedule modifications, these results are helpful in supporting current practices of once weekly administration.

AbstractTriple‐class‐refractory multiple myeloma (MM) describes MM refractory to proteasome inhibitors, immunomodulatory agents, and anti‐CD38 monoclonal antibodies. In the Phase IIb STORM study (NCT02336815), oral selinexor plus low‐dose dexamethasone (Sel‐dex) demonstrated a 26.2% overall response rate in triple‐class‐refractory MM. Here, we compare overall survival (OS) of 122 patients with triple‐class‐refractory MM who received Sel‐dex in STORM Part 2 with that of 64 similar patients treated with other available therapies in a Flatiron Health Analytic Database (FHAD) cohort. OS from the date that the patients’ MM became triple‐class‐refractory was longer in STORM versus FHAD, with an unadjusted hazard ratio (HR) of 0.43 (P = .0002; adjusted HR 0.35 [P = .011]). In a subset analysis of highly resistant patients receiving further therapies after their MM first became at least triple‐class‐refractory (i.e., who received Sel‐dex in STORM,n = 64, and non‐Sel‐dex in FHAD,n = 36), the OS was significantly longer in STORM with an unadjusted HR of 0.52 (P = .0331; adjusted HR 0.33 [P = .041]). Within the limits of this analysis, the OS of patients with at least triple‐class‐refractory MM was significantly better with Sel‐dex versus available therapies, suggesting that Sel‐dex may be associated with a meaningful OS benefit in these patients.

AbstractIntroductionLittle is known on continued response following completion of therapy in light chain (AL) amyloidosis.MethodsWe studied 373 AL amyloidosis patients who achieved complete response (CR) or very good partial response (VGPR) to first‐line therapy.ResultsBy end of therapy (EOT), 46% of patients achieved a CR and 54% a VGPR. With no further therapy, 17.5% of patients were upstaged from VGPR to CR (delayed CR), with a median of 9 months. Compared with CR and VGPR at EOT, patients with a delayed CR were characterized by higher proportion of t(11;14) and lower rate of trisomies. Autologous stem cell transplant was more frequent in the delayed CR group. Patients with a delayed CR were characterized by minimal residual disease negativity and organ response rates similar to patients with CR at EOT and higher than patients achieving VGPR at EOT. Patients with a delayed CR had a longer PFS/OS compared to patients with CR or VGPR by EOT (median PFS 149 vs 92 vs 52 months, P < .001; 10‐year OS 87% vs 71% vs 56%, P < .001).ConclusionsThis study characterizes delayed CR in AL amyloidosis, highlights its prognostic impact which is at least similar to those who achieved CR at EOT, and underlines another aspect of response monitoring.

SummaryMeasurable residual disease (MRD) assessment by marrow‐based next‐generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false‐negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MASS‐FIX). Of all 61 complete responders who were NGF‐negative for MRD, around day‐100 post ASCT, 59% were MASS‐FIX‐positive. At median follow‐up of 26 months, 69% of MASS‐FIX(+)/NGF(−) patients were alive and progression‐free versus 96% of MASS‐FIX(‐)/NGF(−) patients, P = 0·02. MASS‐FIX, a simple peripheral blood‐based assay complements marrow‐based NGF to accurately prognosticate patients with myeloma.