Dispenzieri, Angela

Abstract Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM), despite common toxicities, including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 mg once weekly was associated with lower mortality than higher doses. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM has not been fully characterized. We conducted a secondary pooled analysis of the SWOG 0777 and SWOG 1211 studies of NDMM, which used lenalidomide and dexamethasone (Rd) alone, with or without bortezomib, and with or without elotuzumab. The planned dexamethasone intensity was 40 to 60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for grade 3+ toxicities per both study protocols). Of the 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There were no differences in PFS or OS between the FD-DEX and LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in the multivariate models were treatment arm, age ≥70 years, and thrombocytopenia. FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given the many toxicities and unclear benefits of dexamethasone in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective studies. These trials were registered at www.clinicaltrials.gov as #NCT00644228 and NCT01668719.

AbstractRenal AL amyloidosis can be complicated by end‐stage renal disease (ESRD) requiring renal replacement therapy (RRT). In this study, we describe the long‐term outcomes of renal AL amyloidosis patients undergoing autologous stem cell transplantation (ASCT) and assess the utility of the renal staging system. Retrospective study of renal AL patients (n = 697; Mayo Clinic, Boston University) who underwent ASCT between 2003 and 2020. Renal stage was assigned based on 24‐h proteinuria and estimated glomerular filtration rate measurements. Renal survival was defined as the time from ASCT until initiation of RRT, while patients who were not placed on RRT were censored at their last follow‐up. With a median follow‐up of 10.4 years, RRT was required in 149 patients (21%). The median time from ASCT to ESRD was 3.4 years, with late events of progression to ESRD seen >10 years from ASCT. Pre‐ASCT renal stage was significantly associated with the cumulative incidence of RRT: 3‐year RRT rate was 3%, 10%, and 37% for renal stages I, II, and III, respectively. However, in the 2012–2020 period subset, a significant decrease in ESRD risk was noted across all renal stages (3‐year RRT 0%, 5%, and 24%, respectively). In multivariate analysis, renal survival was independently associated with the pre‐ASCT renal stage, lambda isotype, bone marrow plasmacytosis ≥20%, post‐ASCT hematologic response, and year of ASCT. Long‐term outcomes of renal AL amyloidosis treated with ASCT are presented. Renal stage reliably predicts renal outcomes in patients with AL undergoing ASCT, despite a reduction in the proportion of patients progressing to RRT in recent years.

Abstract We performed an international retrospective study on 283 patients with light chain (AL) amyloidosis to investigate the prognostic impact of cytogenetic abnormalities by fluorescence in situ hybridization, when treated with frontline daratumumab–based therapy. The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) (hereafter, +1q), hyperdiploidy, deletion(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The end points of interest were rate of hematologic complete response (heme-CR), very good partial response (VGPR) or better, and hematologic event-free survival (heme-EFS). The incidence of abnormalities was as follows: t(11;14), 53.4%; deletion (13q), 28.9%; +1q, 22.3%; hyperdiploidy, 19.4%; HR translocations, 6.6%; and deletion(17p), 4.5%. The heme-CR rate by cytogenetic subgroups were as follows: t(11;14) vs no t(11;14), 45.2% vs 41.8% (P=0.597); del(13q) vs no del(13q), 46.8% vs 42.8% (P=0.594); +1q vs no +1q, 30.2% vs 47.9% (P=0.022); hyperdiploidy vs no hyperdiploidy, 39.5% vs 44.9% (P=0.541); HR translocations vs none, 45.5% vs 43.1% (P=0.877); and del(17p) vs no del(17p), 50.0% vs 42.9% (P=0.658), respectively. Similarly, +1q was the only subgroup with a significantly lower VGPR or better rate (64.2% vs 79.0%; P=0.033). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months (95% CI, 24.7-not reached [NR]), and the 2-year overall survival (OS) was 80.98% (95% CI, 75.6-85.4). The presence of +1q was significantly associated with worse heme-EFS on multivariate analysis (HR 2.06, 95% CI, 1.14-3.71; P=0.017). Notably, there was no adverse prognostic impact of t(11;14) on heme-EFS or OS. In conclusion, +1q is associated with worse outcome in the daratumumab-era. Clinical trials testing novel frontline immunotherapies should be enriched in +1q to further improve outcomes in this subgroup.

PURPOSE Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88 L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively ( P < .0001). CONCLUSION Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.

Abstract The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n=71), 51 progressed by last follow-up; the MDEs included: bone lesions(37%), anemia(35%), hypercalcemia(8%), and renal failure(6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression(14%), bone pain(20%), and hospitalization/ED presentations due to MM complications/symptoms(4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Abstract Most patients with solitary bone plasmacytomas (SBP) progress to multiple myeloma (MM) after definitive radiation therapy as their primary treatment. Whether the presence of high-risk (HR) cytogenetic abnormalities by fluorescence in situ hybridization (FISH) in the clonal plasma cells, obtained either directly from the diagnostic SBP tissue or the corresponding bone marrow examination at the time of diagnosis, is associated with a shorter time to progression (TTP) to MM is unknown. This study evaluated all patients diagnosed with SBP at the Mayo Clinic from January 2012 to July 2022. The presence of del(17p), t(14;16), t(4;14), or +1q (gain or amplification) by FISH in clonal plasma cells was defined as HR. A total of 114 patients were included in this cohort, and baseline FISH was available for 55 patients (48%), of which 22 were classified as HR (40%). The median TTP to MM for patients with SBP and HR FISH was 8 months (95% confidence interval [CI], 6.3-26) compared with 42 months (95% CI, 25-not reached [NR]) in patients with SBP without HR FISH (P &lt; .001). In a multivariate analysis, only HR FISH was a significant predictor for shorter TTP to MM, independent of minimal marrow involvement and an abnormal serum free light chain ratio at diagnosis. Deletion (17p) and gain 1q abnormalities were the most common FISH abnormalities responsible for the short TTP to MM. Thus, assessing for HR FISH abnormalities in clonal plasma cells derived from either the diagnostic SBP tissue or the staging bone marrow examination of patients with newly diagnosed SBP is feasible and prognostic for a shorter TTP to MM.