Moritz Binder

Occurrence and prognostic significance of cytogenetic evolution in patients with multiple myeloma

Cytogenetic evaluation at the time of diagnosis is essential for risk stratification in multiple myeloma, however little is known about the occurrence and prognostic significance of cytogenetic evolution during follow-up. We studied 989 patients with multiple myeloma, including 304 patients with at least two cytogenetic evaluations. Multivariable-adjusted regression models were used to assess the associations between the parameters of interest and cytogenetic evolution as well as overall survival. The prognostic significance of baseline cytogenetic abnormalities was most pronounced at the time of diagnosis and attenuated over time. In the patients with serial cytogenetic evaluations, the presence of t(11;14) at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow-up (odds ratio (OR)=0.22, 95% confidence interval (CI)=0.09–0.56, P=0.001), while the presence of at least one trisomy or tetrasomy was associated with increased odds (OR=2.96, 95% CI=1.37–6.42, P=0.006). The development of additional abnormalities during the 3 years following diagnosis was associated with increased subsequent mortality (hazard ratio=3.31, 95% CI=1.73–6.30, P<0.001). These findings emphasize the importance of the underlying clonal disease process for risk assessment and suggest that selected patients may benefit from repeated risk stratification.

Predictors of early response to initial therapy in patients with newly diagnosed symptomatic multiple myeloma

Response to therapy in newly diagnosed symptomatic multiple myeloma (NDMM) can impact long‐term outcomes. It is not clear if baseline laboratory parameters can predict an early, deep response. Totally 1,304 patients with NDMM seen between 2001 and 2013 at Mayo Clinic Rochester were studied. The association between baseline laboratory parameters and early, deep response defined as a very good partial response or better (VGPR+) within four cycles of treatment was investigated. Multivariable logistic regression was used to assess the associations between the parameters of interest and response. Multivariable proportional hazards regression was used to assess the association between response and overall survival. In the entire cohort, greater absolute free light chain (FLC) differences (OR 2.38, 95% CI 1.48–3.82), younger age (OR 2.18, 95% CI 1.28–3.71), lower hemoglobin (OR 1.68, 95% CI 1.12–2.54), and IgA myeloma (OR 1.66, 95% CI 1.10–2.51) were associated with increased odds of achieving VGPR+ after four cycles. Among patients receiving novel agents in general and immunomodulators in particular, these effects were more pronounced. In patients receiving proteasome‐inhibitors, higher creatinine (OR 3.83, 95% CI 1.37–10.1), lower calcium (OR 3.37, 95% CI 1.36–8.35), and greater absolute FLC differences (OR 2.50, 95% CI 1.10–5.71) were associated with better response. In a landmark analysis at 4 months from diagnosis, achieving VGPR+ was associated with decreased risk of subsequent mortality (HR 0.69, 95% CI 0.53–0.86). In summary, several parameters were associated with an early, deep response to treatment, revealing distinct sets of predictors for immunomodulator‐ and proteasome‐inhibitor‐containing regimens. Achieving VGPR+ after four cycles translated into increased overall survival. Am. J. Hematol. 90:888–891, 2015.

Development of a Microscopic Colitis Disease Activity Index: a prospective cohort study

Objective Microscopic colitis (MC) is a common cause of chronic diarrhoea, often with additional symptoms. No validated instruments exist to assess disease activity in MC, making it difficult to compare efficacy of treatments between clinical trials. We aimed to identify clinical features that independently predicted disease severity and create a Microscopic Colitis Disease Activity Index (MCDAI). Design Patients with MC were prospectively administered a survey assessing their GI symptoms and the IBD Questionnaire (IBDQ). A single investigator also scored a physician global assessment (PGA) of disease severity on a 10-point scale. Multiple linear regression identified which symptoms best predicted the PGA. These symptoms were then combined in a weighted formula to create the MCDAI. The relationship between MCDAI and the IBDQ was investigated. Results Of the 175 patients enrolled, 13 (7.4%) did not complete the survey. The remaining 162 had a median age of 66 years (range, 57–73) and 74% were female. Several clinical features were independently associated with PGA (number of unformed stools daily, presence of nocturnal stools, abdominal pain, weight loss, faecal urgency and faecal incontinence). These parameters were combined to create the MCDAI, which strongly predicted the PGA (R2=0.80). A 1-unit decrease in disease activity (ΔMCDAI) was associated with a 9-unit increase in quality of life (ΔIBDQ). Conclusions The MCDAI strongly predicted the PGA and correlated with a validated measure of quality of life. Several symptoms in addition to diarrhoea are associated with disease severity in MC.

Optimization of a Scoring System to Predict Microscopic Colitis in a Cohort of Patients With Chronic Diarrhea.

Goals: Our aim was to develop a scoring system to predict risk of microscopic colitis (MC), to identify patients at low risk, potentially avoiding unnecessary biopsies. Background: Patients with chronic diarrhea often undergo colonoscopy with biopsy, but few have histologic abnormalities. Study: We conducted a retrospective study of patients with chronic diarrhea and a macroscopically normal colonoscopy at our institution over a 9-month period. Multivariable logistic regression assessed the association between predictors and the presence of biopsy-proven MC. Results: The derivation cohort included 617 patients. Median age was 55.1 (39.6 to 68.1) years; 397 (64.3%) were female and 81 (13.1%) had MC. Age ≥55 years, duration of diarrhea ⩽6 months, ≥5 bowel movements per day, body mass index <30 kg/m2, current smoking, and current use of selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitorss and non-steroidal anti-inflammatory drugs were independently associated with MC. A score of ≥10 points in our scoring system, yielded an area under the ROC curve (AUC) of 0.83 with a sensitivity of 93% and specificity of 49% in predicting which patients have MC. The negative predictive value (NPV) was 97.8% (95.0% to 99.1%). In the validation cohort, the scoring system performed similarly (AUC 0.79, sensitivity 91%, specificity 49%, NPV 97%). By avoiding biopsies in patients at low risk of having MC, costs associated with colon biopsies could be reduced by almost 43%. Conclusion: This scoring system including 7 clinical variables was able to identify patients unlikely to have MC, with excellent sensitivity, reasonable specificity, and a high NPV, translating into important potential cost savings.

Prognostic implications of abnormalities of chromosome 13 and the presence of multiple cytogenetic high-risk abnormalities in newly diagnosed multiple myeloma

Fluorescence in situ hybridization evaluation is essential for initial risk stratification in multiple myeloma. While the presence of specific cytogenetic high-risk abnormalities (HRA) is known to confer a poor prognosis, less is known about the cumulative effect of multiple HRA. We studied 1181 patients with newly diagnosed multiple myeloma who received novel agents as first-line therapy. High-risk abnormalities were defined as t(4;14), t(14;16), t(14;20) and del(17p). There were 884 patients (75%) without any HRA and 297 patients (25%) with HRA, including 262 (22%) with one HRA and 35 (3%) with two HRA. The presence of one HRA (versus zero, hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.32–2.05, p<0.001) and the presence of two HRA (versus zero, HR 3.15, 95% CI 2.00–4.96, p<0.001) were of prognostic significance after adjusting for other prognostic factors. Abnormalities of chromosome 13 were of prognostic significance independent of the established HRA: Monosomy 13 (HR 1.27, 95% CI 1.04–1.56, P=0.022) and del(13q) (HR 0.48, 95% CI 0.28–0.81, P=0.006) with opposite effects. Patients with HRA experienced worse overall survival suggesting a cumulative adverse effect of multiple HRA. Abnormalities of chromosome 13 were of prognostic significance after adjusting for other prognostic factors.

Common Genetic Variation in CYP17A1 and Response to Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer

Treatment with abiraterone acetate and prednisone (AA/P) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. We evaluated the genetic variation in CYP17A1 as predictive of response to AA/P. A prospective collection of germline DNA prior to AA/P initiation and follow-up of a mCRPC cohort was performed. Five common single-nucleotide polymorphisms (SNPs) in CYP17A1 identified using a haplotype-based tagging algorithm were genotyped. Clinical outcomes included biochemical response and time to biochemical progression on AA/P. Logistic regression was used to assess the association between tag SNPs and biochemical response. Proportional hazards regression was used to assess the association between tag SNPs and time to biochemical progression. Odds or hazard ratio per minor allele were estimated and p-values below 0.05 were considered statistically significant. Germline DNA was successfully genotyped for four tag SNPs in 87 patients. The median age was 73 years (54–90); the median prostate-specific antigen was 66 ng/dL (0.1–99.9). A single SNP, rs2486758, was associated with lower odds of experiencing a biochemical response (Odds ratio 0.22, 95% confidence interval 0.07–0.63, p = 0.005) and a shorter time to biochemical progression (Hazard ratio 2.23, 95% confidence interval 1.39–3.56, p < 0.001). This tag SNP located in the promoter region of CYP17A1 will need further validation as a predictive biomarker for AA/P therapy.

Associations between elevated pre-treatment serum cytokines and peripheral blood cellular markers of immunosuppression in patients with lymphoma

Higher ratios of the pre‐treatment peripheral blood absolute lymphocyte (ALC) to absolute monocyte counts (AMC) are associated with improved outcomes in lymphoma. Conversely, elevated pre‐treatment serum cytokines are associated with inferior outcomes. The relationship between pre‐treatment serum cytokines and ALC/AMC ratios remains unknown. We studied twelve serum cytokines and the ALC/AMC ratios in 390 patients with untreated diffuse large B‐cell, follicular, mantle cell, T‐cell, and Hodgkin lymphoma. Different pre‐treatment serum cytokine concentrations correlated with ALC, AMC, and ALC/AMC ratios depending on the lymphoma type. In the entire cohort (n = 390) lower ALC/AMC ratios modestly correlated with higher IL‐2R (r = −0.36), IL‐12 (r = −0.17), IP‐10 (r = −0.23), and MIG (r = −0.32) concentrations (p < 0.001). Elevated IL‐2R was independently associated with suppressed ALC (OR 2.69, 95% CI 1.77–4.07, p < 0.001), elevated AMC (OR 2.05, 95% CI 1.34–3.14, p < 0.001), and suppressed ALC/AMC ratios (OR 3.51, 95% CI 2.31–5.34, p < 0.001). Both elevated IL‐2R (HR 2.27, 95% CI 1.48–3.49, p < 0.001) and suppressed ALC/AMC ratios (HR 1.53, 95% CI 1.03–2.28, p = 0.037) were independently associated with inferior overall survival. These data support the notion that elevated serum cytokines are immunosuppressive and provide further rationale to target the tumor microenvironment for therapeutic benefit.

Relative Morphokinetics Assessed by Time-Lapse Imaging Are Altered in Embryos From Patients With Endometriosis

Introduction: Time-lapse technology allows almost continuous noninvasive assessment of embryonic development. It was shown previously that relative kinetics defining cleavage synchronicity are better predictors of blastocyst quality than absolute time points. This study aims to compare relative kinetics in embryos from patients with and without endometriosis. Methods: Time-lapse data were collected retrospectively from 596 patients undergoing infertility treatment for in vitro fertilization from January 2011 to July 2016. Four hundred twenty-eight patients with confounding comorbidities (ie, polycystic ovary syndrome, pathological spermiogram in the included cycle, numerical/structural genetic abnormalities, preimplantation genetic screening performed) or incomplete data sets were excluded. Of the 168 included patients, 72 (42.9%) had endometriosis. Indications for in vitro fertilization of controls were tubal factor, unexplained infertility, or prolonged infertility. Relative kinetics were calculated as defined previously: cleavage synchronicity (CS)2-8=((t3-t2) + (t5-t4))/(t8-t2), CS4-8=(t8-t5)/(t8-t4), CS2-4=(t4-t3)/(t4-t2), DNA replication time ratio (DR)=(t3-t2)/(t5-t3). In women with more than one embryo, the median time was analyzed. Results: Median age, body mass index, smoking status, and AMH levels were similar in both groups. Embryos from patients with endometriosis showed poorer relative kinetics. The relative time CS2-8 was decreased in embryos from patients with endometriosis (0.7 [0.0-0.93] vs 0.8 [0.0-0.94], P < .05) and CS4-8 was increased (0.4 [0.0-1.0] vs 0.3 [0.0-1.0], P < .05). The less powerful diagnostic relative kinetic parameters (CS2-4 and DR) were not significantly different. Conclusions: Embryos from patients with endometriosis presented with altered relative kinetics suggesting poorer embryo quality. These findings support recently published data demonstrating reduced oocyte quality in patients with endometriosis which is one possible explanation for their poor response to fertility treatment.

Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria

In 2014, the International Myeloma Working Group reclassified patients with smoldering multiple myeloma (SMM) and bone marrow-plasma cell percentage (BMPC%) ≥ 60%, or serum free light chain ratio (FLCr) ≥ 100 or >1 focal lesion on magnetic resonance imaging as multiple myeloma (MM). Predictors of progression in patients currently classified as SMM are not known. We identified 421 patients with SMM, diagnosed between 2003 and 2015. The median time to progression (TTP) was 57 months (CI, 45–72). BMPC% > 20% [hazard ratio (HR): 2.28 (CI, 1.63–3.20); p < 0.0001]; M-protein > 2g/dL [HR: 1.56 (CI, 1.11–2.20); p = 0.01], and FLCr > 20 [HR: 2.13 (CI, 1.55–2.93); p < 0.0001] independently predicted shorter TTP in multivariate analysis. Age and immunoparesis were not significant. We stratified patients into three groups: low risk (none of the three risk factors; n = 143); intermediate risk (one of the three risk factors; n = 121); and high risk (≥2 of the three risk factors; n = 153). The median TTP for low-, intermediate-, and high-risk groups were 110, 68, and 29 months, respectively (p < 0.0001). BMPC% > 20%, M-protein > 2 g/dL, and FLCr > 20 at diagnosis can be used to risk stratify patients with SMM. Patients with high-risk SMM need close follow-up and are candidates for clinical trials aiming to prevent progression.

Time to plateau as a predictor of survival in newly diagnosed multiple myeloma

Response rates in newly diagnosed multiple myeloma have improved dramatically with the introduction of highly effective novel therapies. However, survival in patients achieving optimal responses to initial treatment can vary significantly, and new prognostic indicators are required to improve risk stratification. We investigated the relationship between time to plateau (TPlat) and survival in 1099 newly diagnosed patients treated with novel agents at our institution from 2005 to 2015. TPlat was defined as time from initiation of first‐line therapy to best response to first‐line therapy. The median TPlat was 4.9 months (0.7‐58.6) and plateau duration was 1.8 years (0.2‐11.0). Patients who required > 120 days to achieve a plateau had longer modified overall survival (mOS) and progression free survival (mPFS) calculated from a landmark of best response (P < .001 for both comparisons). Statistically significant improvement in mOS was retained in subgroup analysis based on age and whether patients received upfront autologous hematopoietic stem cell transplantation (ASCT) (P < .001 for all comparisons). Our results suggest that patients who respond more gradually to initial therapy (TPlat > 120 days) experience longer survival compared to more rapid responders. Patients with a prolonged TPlat could represent an “ongoing responder” phenotype that portends a survival advantage independent of treatment with upfront ASCT, depth of response, and biologic markers such as ISS stage and cytogenetic risk.