Citations

In the era of novel biological agents, multiple myeloma (MM) is often approached as a chronic condition. While survival continues to improve, population‐level data indicate that early mortality remains a substantial barrier to advances in MM outcomes. Here we provide “do's and don'ts” management recommendations that may minimize the risk of early mortality and ensure that patients have the opportunity to benefit from the long term impact of new effective MM agents. Such recommendations encompass the early introduction of novel agents even in the presence of comorbidities and advanced age and aggressive management of MM‐related complications. Am. J. Hematol. 91:101–108, 2016. © 2015 Wiley Periodicals, Inc.

Over the past decade, use of novel agents, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has resulted in high response rates and improvement in overall survival (OS) for patients with multiple myeloma (MM); however, the prognostic significance of refractoriness to these agents when used as initial therapy has not been extensively studied. We reviewed the outcomes of 816 consecutive patients treated for MM at our institution since 2006 to evaluate the survival difference between those achieving at least a partial response (PR) to induction therapy and those who were primary refractory. The median OS from start of therapy was significantly shorter for the primary refractory group at 3.6 vs. 7.6 years for the responding patients ( P < 0.001). The difference in median OS persisted when only patients receiving a novel agent as part of induction therapy were considered (3.6 vs. 7.9 years, P < 0.001) and in a 4‐month landmark analysis (4.2 vs. 7.6 years, P < 0.001). The median OS for patients achieving a complete response (CR), very good partial response (VGPR), PR, or less than PR was not reached (NR), 6.1, 6.4, and 4.2 years from the 4‐month landmark, respectively ( P < 0.001). The comparatively poor outcomes of patients refractory to induction therapy in the current era of novel agents suggests that this high‐risk subpopulation must be further studied for predictors of resistance and, when identified, should be targeted for clinical trials. Am. J. Hematol. 90:981–985, 2015. © 2015 Wiley Periodicals, Inc.

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. © 2015 Wiley Periodicals, Inc.

Abstract Background: Genome wide association studies (GWAS) have recently identified 8 loci identified with multiple myeloma (MM) susceptibility. We hypothesized that germ line genetic variants may also affect MM progression. We performed the first GWAS of MM survival, by conducting a meta-analysis of two existing studies at University of California San Francisco (UCSF) and the Mayo Clinic, and replicating findings in the International Multiple Myeloma rESEarch (IMMEnSE) consortium. Methods: The UCSF study included 353 MM patients genotyped on an Illumina Omni5 and Illumina 660 array. The Mayo clinic study included 239 MM patients genotyped on an Affymetrix 6.0 array. We imputed missing genotypes using the 1000 Genomes dataset and performed a GWAS for survival using proportional hazards models adjusting for age and gender and genetic ancestry using principal components analysis. We conducted a meta-analysis of the results from the two GWAS. We replicated the top SNPs in the IMMEnSE cohort which included 772 patients with survival data from 7 European countries and one North American site. We used the dataset from Grundberg et al (Nat Genetics 2012) to test for an association between SNPs associated with survival and gene expression in immortalized lymphocytes. We used gene expression data from Zhan et al (Blood 2006) to analyze the association between expression and survival. Results: In meta-analysis, we found a genome wide significant association between SNPs on a region at 16p13 and survival (rs72773978; p=2.9x10e-10). Patients with the minor allele were at increased risk for mortality (HR 2.73; 95% CI: 1.99 - 3.73). The top associated SNPs were all in strong linkage disequilibrium and were centered over the gene FOPNL. We replicated the association in the IMMEnSE cohort and found a significant association between the top SNP from the discovery dataset (rs72773978 p=0.037). We used previously published data to determine the association between gene expression and the top associated SNPs from the GWAS. The top SNP (rs72773978) was not in previously published eQTL databases, so we used rs7201759 which was also associated with survival in our data (p=3.8x10e-10) as a proxy. The minor allele for this SNP was associated with increased levels of expression of FOPNL (p=9x10e-5), but not with expression of any other genes within a 1 megabase region. Finally, we also observed an association between increased expression of FOPNL and shorter survival (HR: 2.62 per standard deviation.; 95% CI: 1.08 - 6.32). Conclusion: Germ line variants at 16p13 near the FOPNL gene are associated with survival among MM patients. FOPNL is thought to be involved in centrosomal function, and centrosomal activity has previously been associated with survival in MM patients. Our results support this previous observation. Furthermore, they suggest that germ line variants could also be useful in assessing prognosis for patients with MM. Citation Format: Elad Ziv, Eric Dean, Donglei Hu, Alessandro Martino, Daniel Serie, Daniele Campa, Blake Aftab, Paige Bracci, Gabriele Buda, Jennifer Caswell, Charles Dumontet, Marek Dudziński, Laura Fejerman, Alexandra Greenberg, Scott Hunstman, Artur Jurczyszyn, Krzysztof Jamroziak, Shaji Kumar, Herlander Marques, Thomas Martin, Joaquin Martinez-Lopez, Vincent Rajkumar, Juan Sainz, Annette Juul Vangsted, Marzena Watek, Jeffrey Wolf, Susan Slager, Federico Canzian, Celine Vachon. Genome wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5078. doi:10.1158/1538-7445.AM2014-5078

Abstract The incidence of multiple myeloma (MM) is twice as high in blacks compared with whites. MM consists of several different cytogenetic subtypes, with differing presentations, response to therapy, and prognosis. The studies that have characterized the distribution of the primary cytogenetic abnormalities by fluorescence in-situ hybridization (FISH) testing have been primarily conducted in white populations, and more data are needed on whether the distribution of these cytogenetic abnormalities differs in black compared with white MM patients, and to determine if the increased prevalence of MM in blacks is related to specific subtypes of the disease. In this multi-center study, we examined four common clinically assessed cytogenetic subtypes (t(11;14), t(4;14), del13q, and del17p) at time of MM diagnosis in 245 black patients from 3 clinics who had prior FISH testing available in medical records. We compared the prevalence of these subtypes with our previously characterized Mayo Clinic cohort which was all Caucasian (n=484). The t(11;14) translocation was seen in 9 of 245 (4%) black patients with MM; this was significantly lower than the rate of t(11;14) translocations seen in white patients from Mayo Clinic (18%), p &lt; 0.0001). In contrast to t(11;14), the prevalence of the t(4;14) translocation across the two groups was similar (p= 0.92). We conclude that the prevalence of t(11;14) translocation is significantly lower in blacks with myeloma compared with whites. Our findings suggest that the distribution of cytogenetic subtypes found in MM may differ significantly by race, and further studies assessing differences in the prevalence of other primary cytogenetic abnormalities such as trisomies, t(6;14), t(14;16), and t(14;20) are needed. Furthermore, these results support the hypothesis previously put forth that there are several different subtypes of multiple myeloma that may be defined by the major cytogenetic translocations. Since these results differ from those previously reported (Baker et al 2013, Blood), we are conducting further analyses of these data to examine possible factors that could account for the differential association of translocation by race, including probes used. Citation Format: Alexandra Joelle Greenberg, Sunita Philip, Agne Paner, Sylvia Velinova, Ashraf Badros, Rosalind Catchatorian, Dirk Larson, Rhett Ketterling, Robert A. Kyle, Shaji Kumar, Celine M. Vachon, S. Vincent Rajkumar. Evidence of decreased prevalence of the t(11;14) translocation in black patients with multiple myeloma: A multi-center study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 272. doi:10.1158/1538-7445.AM2014-272

The use of soluble cardiac biomarkers such as N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and troponin has revolutionized prognostication for patients with AL amyloidosis. Soluble ST2 (sST2) and galectin‐3 have also been reported to have prognostic value in other cardiac patient populations. We identified 502 patients with AL amyloidosis, who provided a research sample and consent to review their medical records between 1/1/2006‐12/31/2010 within 90 days of their diagnosis. Samples were assayed for sST2 and galectin‐3. Within this AL amyloidosis population, overall survival (OS) was 25.5 months (95% CI 18, 35.7 months). Receiver operating curve analyses were done to detect the best cut‐points for sST2 and galectin‐3 to predict both 1‐ and 5‐year OS. The respective cut points for sST2 were 30 and 29.7 ng/mL, while the median sST2 for the entire population was 31 ng/mL (IQR 19.8, 53.6). The respective cut points for galectin‐3 were 11 and 10.4 ng/mL while the median for the entire population was 16.6 ng/mL (IQR 11.5, 24.0). Although on univariate analysis, both sST2 and galectin‐3 were prognostic, upon multivariate analysis, only sST2 was independent of troponin, NT‐proBNP, serum immunoglobulin free light chain, and blood pressure. Not only did sST2 add to previously reported prognostication systems, but a novel prognostication 5‐point system including sST2 was possible. The addition of sST2 – but not galectin‐3 – to existing prognostication systems for patients with AL amyloidosis strengthens the ability to predict for death. Am. J. Hematol. 90:524–528, 2015. © 2015 Wiley Periodicals, Inc.

AL amyloidosis (AL) is rare and frequently remains undiagnosed until organ function is compromised, even among patients with known pre‐existing untreated plasma cell dyscrasias (PCD). We identified 168 patients with AL amyloidosis who had a prior untreated PCD. The earliest symptom or sign (s/s) was defined as the first symptom reported by the patient that could be attributed to organ dysfunction caused by AL. The interval from the time of development of s/s to the establishment of diagnosis of AL (Interval‐SA) was calculated. PCD diagnosis preceded recorded onset of s/s in 75% (114/152) of patients, with a median interval‐SA for this group of 10 months. PCD was diagnosed after s/s in 25% (38/152) of patients, with a median interval‐SA of 20 months. Overall survival (OS) from diagnosis of AL was not different between the two groups. AL amyloidosis patients with an identified pre‐existing PCD had less advanced cardiac disease at AL diagnosis when compared to a control group of AL patients without preidentified PCD. Long‐term OS was not significantly superior among patients with a pre‐identified PCD. In patients with “asymptomatic” PCD, symptoms and signs of AL amyloidosis should be solicited, since timely diagnosis is important in AL amyloidosis. Am. J. Hematol. 89:1051–1054, 2014. © 2014 Wiley Periodicals, Inc.

Key Points Elderly patients with myeloma are heterogeneous and assessment strategies are needed to define the frailty profile. The proposed frailty score aims to better assess patients and provide them with more suitable therapies.