Impact of cytogenetic abnormalities on the risk of disease progression in solitary bone plasmacytomas.

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 < .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.

Sarcopenia identified by computed tomography imaging using a deep learning-based segmentation approach impacts survival in patients with newly diagnosed multiple myeloma.

BACKGROUND: Sarcopenia increases with age and is associated with poor survival outcomes in patients with cancer. By using a deep learning-based segmentation approach, clinical computed tomography (CT) images of the abdomen of patients with newly diagnosed multiple myeloma (NDMM) were reviewed to determine whether the presence of sarcopenia had any prognostic value. METHODS: Sarcopenia was detected by accurate segmentation and measurement of the skeletal muscle components present at the level of the L3 vertebrae. These skeletal muscle measurements were further normalized by the height of the patient to obtain the skeletal muscle index for each patient to classify them as sarcopenic or not. RESULTS: The study cohort consisted of 322 patients of which 67 (28%) were categorized as having high risk (HR) fluorescence in situ hybridization (FISH) cytogenetics. A total of 171 (53%) patients were sarcopenic based on their peri-diagnosis standard-dose CT scan. The median overall survival (OS) and 2-year mortality rate for sarcopenic patients was 44 months and 40% compared to 90 months and 18% for those not sarcopenic, respectively (p < .0001 for both comparisons). In a multivariable model, the adverse prognostic impact of sarcopenia was independent of International Staging System stage, age, and HR FISH cytogenetics. CONCLUSIONS: Sarcopenia identified by a machine learning-based convolutional neural network algorithm significantly affects OS in patients with NDMM. Future studies using this machine learning-based methodology of assessing sarcopenia in larger prospective clinical trials are required to validate these findings.

Survival trends in young patients with Waldenström macroglobulinemia: Over five decades of experience.

Waldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10-year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960-1977, n = 12), Group 2 (1978-1995, n = 48), and Group 3 (1996-2013, n = 74). Among young patients, there was no disease-specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5-23), 16 years (95% CI 14-22), and 15 years (95% CI 10-NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years-of-life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age- and sex-matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

Thrombosis in multiple myeloma: Risk estimation by induction regimen and association with overall survival.

Lenalidomide-containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide-based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib-Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib-Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide-containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR = 2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR = 2.2, 95% CI = 1.6-3.3) was maintained in the multivariable analysis adjusted for high-risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR = 2.61, CI = 1.74-3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.

A phase 1/2 of carfilzomib and melphalan conditioning for autologous stem cell transplantation for multiple myeloma (CARAMEL).

In this phase 1/2 study, carfilzomib was added to high-dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days -6, -5, -2, and -1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m2 on days -4 and -3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m2 (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4-88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3-4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.

Natural history, predictors of development of extramedullary disease, and treatment outcomes for patients with extramedullary multiple myeloma.

Extramedullary multiple myeloma (EMM) can present either at initial diagnosis (de novo) or at disease relapse (secondary) and confers an aggressive clinical course. Limited data exist for choosing the optimal therapy for EMM and this remains an area of unmet clinical need. After excluding paraskeletal multiple myeloma and primary plasma cell leukemia, we identified 204 (68%) patients with secondary EMM and 95 (32%) with de novo EMM between January 01, 2000 and 31 December, 2021. The median overall survival (OS) was 0.7 (95% CI: 0.6-0.9) years for secondary EMM and 3.6 (95%CI: 2.4-5.6) years for de novo EMM. The median progression-free survival (PFS) with initial therapy was 2.9 months (95% CI: 2.4-3.2 months) for secondary EMM and 12.9 months (95% CI: 6.7-18 months) for de novo EMM. Patients with secondary EMM treated with CAR-T therapy (n = 20) achieved a partial response (PR) or better in 75% with a median PFS of 4.9 months (3.1 months-not reached; NR). Patients with EMM treated with bispecific antibodies (n = 12) achieved a ≥ PR in 33%, with a median PFS of 2.9 months (95%CI: 2.2 months-NR). In a matched cohort, multivariate logistic regression analysis demonstrated younger age at diagnosis, 1q duplication, and t(4;14) at diagnosis of MM to be independent predictors of development of secondary EMM. Presence of EMM was independently associated with inferior OS in the matched cohorts for both de novo (HR 2.9 [95% CI: 1.6-5.4], p = .0007) and secondary EMM (HR 1.5 [95% CI: 1.1-2], p = .001).

Risk factors for severe infection and mortality In patients with COVID-19 in patients with multiple myeloma and AL amyloidosis.

Patients with multiple myeloma (MM) have a lower efficacy from COVID-19 vaccination and a high rate of mortality from COVID-19 in hospitalized patients. However, the overall rate and severity of COVID-19 infection in all settings (including non-hospitalized patients) and the independent impact of plasma cell-directed therapies on outcomes needs further study. We reviewed the medical records of 9225 patients with MM or AL amyloidosis (AL) seen at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 and identified 187 patients with a COVID-19 infection (n = 174 MM, n = 13 AL). The infection rate in our cohort was relatively low at 2% but one-fourth of the COVID-19 infections were severe. Nineteen (10%) patients required intensive care unit (ICU) admission and 5 (3%) patients required mechanical ventilation. The mortality rate among hospitalized patients with COVID-19 was 22% (16/72 patients). Among patients that were fully vaccinated at the time of infection (n = 12), two (17%) developed severe COVID-19 infection, without any COVID-related death. On multivariable analysis, treatment with CD38 antibody within 6 months of COVID-19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p = .02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p = .014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p = .029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p = .038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2-0.8); p = .008].

Impact of belantamab mafodotin-induced ocular toxicity on outcomes of patients with advanced multiple myeloma.

Belantamab mafodotin (BLMF) is a B-cell maturation antigen-directed antibody-drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF-induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity-related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2-not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent.

Kidney Transplantation in Patients With Monoclonal Gammopathy of Renal Significance (MGRS)-Associated Lesions: A Case Series.

RATIONALE & OBJECTIVE: Data on kidney transplantation outcomes among patients with monoclonal gammopathy of renal significance (MGRS) are lacking. STUDY DESIGN: Case series of patients with MGRS, some of whom received clone-directed therapies before kidney transplantation. SETTING & PARTICIPANTS: 28 patients who underwent kidney transplantation from 1987 through 2016 after diagnosis with MGRS-associated lesions including light-chain deposition disease (LCDD), C3 glomerulopathy with monoclonal gammopathy (C3G-MG), and light-chain proximal tubulopathy (LCPT). FINDINGS: Of the 19 patients with LCDD, 10 were treated before kidney transplantation and 9 were treatment-naive. Among the treated patients with LCDD, 3 (30%) experienced histologic recurrence, 2 (20%) grafts failed, and 2 (20%) died during a median follow-up of 70 (range, 3-162) months after transplant. In the treatment-naive LCDD group, 8 (89%) had histologic recurrence, 6 (67%) grafts failed, and 4 (44%) patients died during a median follow-up of 60 (range, 35-117) months. Of the 5 patients who had a complete response before transplant, none died, and only 1 experienced graft failure, 162 months after transplant. Of 5 patients with C3G-MG, 3 were treatment-naive before transplant. Both patients who were treated before transplant had histologic recurrence, and 1 experienced graft failure and died. Among the 3 patients with treatment-naive C3G-MG, histologic recurrence occurred in all, and graft loss and death were observed in 2 and 1, respectively. In the LCPT group (n=4), histologic recurrence was observed in all 3 patients who did not receive clone-directed therapies before transplant, and 2 of these patients died, 1 with a functioning kidney. The 1 patient with LCPT who received therapy before transplant did not have histologic recurrence or graft loss and survived. LIMITATIONS: Small sample size, nonstandardized clinical management, retrospective design. CONCLUSIONS: Recurrence is very common in all MGRS-associated lesions after kidney transplant. Achieving a complete hematologic response may reduce the risks of recurrence, graft loss, and death. More studies are needed to determine the effects of hematologic response on outcomes for each MGRS-associated lesion.

Impact of achieving a complete response to initial therapy of multiple myeloma and predictors of subsequent outcome.

Achievement of a complete response (CR) in multiple myeloma (MM) correlates with improvement in survival outcomes; however, its impact on prognostic variables at baseline outside of clinical trial settings is not well described. We sought to determine the impact of achieving a CR within 2 years from diagnosis, its effect on the prognostic value of fluorescence in situ hybridization (FISH) and International Staging System (ISS) risk, and examined additional predictors of outcome among those achieving a CR in a routine clinical setting. We evaluated 1869 newly diagnosed MM patients who had ≥ 2 monoclonal protein immunofixation studies in the serum and urine available within 24 months from diagnosis, categorizing those with ≥ 2 negative serum and urine immunofixations as achieving CR. With a landmark at 24 months, median progression-free survival (PFS) for CR versus non-CR patients was 29.8 versus 20.9 months (p ≤ .0002); median overall survival (OS) was 104 versus 70 months (p < .0001). The impact of achieving a CR was retained after adjusting for FISH, ISS, sex, transplant status, and involved heavy chain. Baseline FISH and ISS stage were not associated with PFS or OS among patients achieving a CR. The following variables were found as predictors of inferior OS within the CR cohort: age > 75 years, male gender, hypoalbuminemia, and non-immunoglobulin G involved heavy chain. Our study confirms that achievement of CR within 2 years from diagnosis is associated with improvement in survival outcomes and neutralization of the impact of FISH and ISS risk, thereby confirming observations from the clinical trial setting among a clinical practice cohort.

Characteristics and risk factors for thrombosis in POEMS syndrome: A retrospective evaluation of 230 patients.

Thromboses are prevalent in POEMS syndrome, but few risk factors for POEMS-associated thrombosis have been identified. The objective of this study is to identify novel risk factors for POEMS-associated thrombosis. In this retrospective cohort of 230 POEMS patients, 27% developed thrombosis. Arterial events were slightly more common than venous. Stroke accounted for 26% of all thromboses and 53% of arterial events. There were differences in baseline features between the thrombosis group and the no thrombosis group, and these were driven by patients with arterial thrombosis. Risk factors for arterial thrombosis included thrombocytosis, elevated hemoglobin/hematocrit, extravascular volume overload, and splenomegaly. Hyperprolactinemia appeared to be a risk factor for venous thrombosis. The risk of thrombosis was most striking among men with elevated hemoglobin (32% vs. 5%, p < .001) and hematocrit (42% vs. 5%, p < .001) compared to men without. Most thromboses occurred prior to POEMS directed therapy, and most that occurred during therapy happened within 3 months of diagnosis. Twenty-one percent of patients with thrombosis had recurrence. In recognition of high overall rates of thrombosis in this population, all patients with POEMS syndrome should receive prophylactic antiplatelet therapy, and clinicians should consider anticoagulation in patients with risk factors for POEMS-associated thrombosis.

Multicentric Castleman disease: A single center experience of treatment with a focus on autologous stem cell transplantation.

Castleman disease (CD) is a rare lymphoproliferative disease characterized by diverse clinical and pathologic features. Due to its rarity, there are limited studies comparing currently available therapies. The role of autologous stem cell transplantation (ASCT) in CD has not yet been established. In this paper, we describe the clinical characteristics, treatment choices, and outcomes in 34 Mayo Clinic patients diagnosed with multicentric CD from July 1, 2003 to April 30, 2018. Eighteen patients (53%) also met the criteria for POEMS, including 14 with the osteosclerotic variant. The first-line treatments included: steroid monotherapy (4), cytotoxic chemotherapy (6), rituximab alone (8) or with chemotherapy (2), anti-IL6 treatment (3), and ASCT (10). The median follow-up was 4.8 (range: 0.1-15.2) years. The 5- and 10-year overall survival rates were 84% and 71%, respectively. Sixteen patients received high-dose chemotherapy followed by ASCT during their disease course. Among those, 14 had multicentric CD associated with POEMS. There were no transplant-related deaths. All patients had at least a partial response to ASCT, most of whom achieved a complete response. The favorable outcomes seen with ASCT in this cohort suggest that transplantation may have a role in multicentric CD, particularly for patients with multicentric CD associated with POEMS.

Prognostic significance of acquired 1q22 gain in multiple myeloma.

Gain of 1q22 at diagnosis portends poorer outcomes in multiple myeloma (MM), but the prognostic significance of acquired 1q22 gain is unknown. We identified 63 MM patients seen at Mayo Clinic from 1/2004 to 12/2019 without 1q22 gain at diagnosis who acquired it during follow up and compared them to 63 control patients who did not acquire 1q22 gain with similar follow up. We also compared outcomes in the acquired 1q22 gain group with outcomes in 126 patients with 1q22 gain present at diagnosis. The incidence of acquired 1q22 gain was 6.1% (median follow-up 6.8 years); median time to acquisition was 5.0 years (range: 0.7-11.5 years). Abnormalities on baseline fluorescence in situ hybridization (FISH) included trisomies (54%) and monosomy 13 (39%); 16 (25%) had high-risk (HR) translocations or del(17p). Median progression-free survival with front line therapy was 29.5 months in patients with acquired 1q22 gain, versus 31.4 months in control patients (p = .34) and 31.2 months in patients with de novo 1q22 gain (p = .04). Median overall survival (OS) from diagnosis was 10.9 years in patients with acquired 1q22 gain, versus 13.0 years in control patients (p = .03) and 6.3 years in patients with de novo 1q22 gain (p = .01). Presence of HR FISH at baseline increased risk of 1q22 gain acquisition. We demonstrate that acquisition of 1q22 gain is a significant molecular event in MM, associated with reduced OS. Among HR patients for whom this clonal evolution is determined, a risk-adapted approach and/or clinical trial should be considered.

Disease outcomes and biomarkers of progression in smouldering Waldenström macroglobulinaemia.

Patients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and ß2 -microglobulin (ß2 M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and ß2 M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.

Implications of detecting serum monoclonal protein by MASS-fix following stem cell transplantation in multiple myeloma.

Measurable 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.

Characterization and prognostic implication of delayed complete response in AL amyloidosis.

INTRODUCTION: Little is known on continued response following completion of therapy in light chain (AL) amyloidosis. METHODS: We studied 373 AL amyloidosis patients who achieved complete response (CR) or very good partial response (VGPR) to first-line therapy. RESULTS: By 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). CONCLUSIONS: This 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.

Venetoclax for the treatment of multiple myeloma: Outcomes outside of clinical trials.

Multiple 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.

Comparison of the current renal staging, progression and response criteria to predict renal survival in AL amyloidosis using a Mayo cohort.

Three 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.

Prognostic Role of Beta-2 Microglobulin in Patients with Light Chain Amyloidosis Treated with Autologous Stem Cell Transplantation.

The prognostic impact of increased beta-2 microglobulin (B2M) in patients with light chain (AL) amyloidosis undergoing autologous stem cell transplantation (ASCT) is unknown. The Mayo 2012 stage and increased bone marrow plasma cell (BMPC) percentage are known predictors for survival. Increased B2M is predictive of survival in patients with multiple myeloma. We evaluated the prognostic role of B2M in patients with newly diagnosed AL undergoing ASCT. We retrospectively reviewed patients with a diagnosis of AL amyloidosis who were treated with ASCT between July 1996 and September 2017. Patients with a creatinine level >1.2 mg/dL were excluded, because that affects B2M levels. The receiver operator characteristic curve was used to determine the best cutoff for B2M before ASCT in predicting survival, which was 2.5 µg/mL, which was also the upper limit of normal in our laboratory. Baseline characteristics were compared between patients with B2M >2.5 µg/mL and ≤2.5 µg/mL. Progression-free survival (PFS) was defined as the time from ASCT to relapse or death, whichever occurred first. Overall survival (OS) was calculated from the time of ASCT to death of any cause. Univariate and multivariate analyses were done for OS. Five hundred and ten patients were identified, 222 of whom (44%) had a B2M >2.5 µg/mL. These patients were more likely to be older (median age, 61 versus 57 years; P = .0002), to have Mayo 2012 stage III/IV disease (33% versus 8%; P < .0001), to have more than 2 organs involved (25% versus 14%; P = .001), and to have ≥10% BMPCs (56% versus 40%; P = .0002) compared with patients with B2M ≤2.5 µg/mL. The median PFS and OS were shorter in patients with B2M >2.5 µg/mL (median PFS, 64 months versus 80 months [P = .03]; median OS, 104.9 months versus 175.5 months [P < .0001]). On univariate analysis, predictors for OS included age >60 years (hazard ratio [HR], 1.61; P = .001), Mayo 2012 stage III/IV (HR, 3.36; P < .0001), more than 2 organs involved (HR, 1.36; P = .07), ≥10% BMPCs (HR, 1.5; P = .005), melphalan conditioning with 200 mg/m2 (HR, .29; P < .0001), B2M >2.5 µg/mL (HR, 1.82; P < .0001), and transplantation during or after 2010 (HR, .4; P = .0006). On multivariate analysis, only Mayo 2012 stage III/IV (HR, 1.89; P = .005), melphalan conditioning with 200 mg/m2 (HR, .39; P < .0001), B2M >2.5 µg/mL (HR, 1.84; P = .003), and transplantation performed during or after 2010 (HR, .58; P = .03) remained independent predictors of OS. Our findings identify B2M >2.5 µg/dL before ASCT as an independent predictor for OS in patients with AL amyloidosis and normal kidney function and should be routinely measured.

Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes.

Ibrutinib-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.