Mortality In Myeloma Patients Research Articles

Sample average treatment effect on the treated (SATT) analysis using counterfactual explanation identifies BMT and SARS-CoV-2 vaccination as protective risk factors associated with COVID-19 severity and survival in patients with multiple myeloma

Patients with multiple myeloma (MM), an age-dependent neoplasm of antibody-producing plasma cells, have compromised immune systems and might be at increased risk for severe COVID-19 outcomes. This study characterizes risk factors associated with clinical indicators of COVID-19 severity and all-cause mortality in myeloma patients utilizing NCATS’ National COVID Cohort Collaborative (N3C) database. The N3C consortium is a large, centralized data resource representing the largest multi-center cohort of COVID-19 cases and controls nationwide (>16 million total patients, and >6 million confirmed COVID-19+ cases to date). Our cohort included myeloma patients (both inpatients and outpatients) within the N3C consortium who have been diagnosed with COVID-19 based on positive PCR or antigen tests or ICD-10-CM diagnosis code. The outcomes of interest include all-cause mortality (including discharge to hospice) during the index encounter and clinical indicators of severity (i.e., hospitalization/emergency department/ED visit, use of mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)). Finally, causal inference analysis was performed using the Coarsened Exact Matching (CEM) and Propensity Score Matching (PSM) methods. As of 05/16/2022, the N3C consortium included 1,061,748 cancer patients, out of which 26,064 were MM patients (8,588 were COVID-19 positive). The mean age at COVID-19 diagnosis was 65.89 years, 46.8% were females, and 20.2% were of black race. 4.47% of patients died within 30 days of COVID-19 hospitalization. Overall, the survival probability was 90.7% across the course of the study. Multivariate logistic regression analysis showed histories of pulmonary and renal disease, dexamethasone, proteasome inhibitor/PI, immunomodulatory/IMiD therapies, and severe Charlson Comorbidity Index/CCI were significantly associated with higher risks of severe COVID-19 outcomes. Protective associations were observed with blood-or-marrow transplant/BMT and COVID-19 vaccination. Further, multivariate Cox proportional hazard analysis showed that high and moderate CCI levels, International Staging System (ISS) moderate or severe stage, and PI therapy were associated with worse survival, while BMT and COVID-19 vaccination were associated with lower risk of death. Finally, matched sample average treatment effect on the treated (SATT) confirmed the causal effect of BMT and vaccination status as top protective factors associated with COVID-19 risk among US patients suffering from multiple myeloma. To the best of our knowledge, this is the largest nationwide study on myeloma patients with COVID-19.

Statins Reduce Mortality in Multiple Myeloma: A Population-Based US Study

BackgroundWe studied the effect of statins on mortality in a nationally representative sample of patients with multiple myeloma, and explored the benefit of statins in a subgroup of patients treated with novel agents. MethodsPatients diagnosed with multiple myeloma between 2007 and 2013 were identified in the SEER-Medicare database using International Classification of Diseases (ICD)-03 codes. ICD-9 and Healthcare Common Procedure Coding System codes were used to identify comorbidities and treatments. We assessed the association of statins with mortality in patients with multiple myeloma using multivariate Cox proportional hazards regression analysis. For subanalysis, we used the same statistical technique to investigate the effect of statins on mortality in myeloma patients treated with novel agents. ResultsA total of 5922 patients were diagnosed with multiple myeloma within the study period. Use of statins was associated with 21% reduction in risk of death (adjusted hazard ratio [aHR] 0.79; 95% confidence interval [CI] 0.74-0.84) among all patients with multiple myeloma. Among the patents treated with novel agents (n = 3603), statins reduced mortality by 10% (aHR = 0.90, 95% CI 0.83-0.98). ConclusionsUse of statins is likely associated with lower mortality in patients with multiple myeloma.

Three Decades of Autologous Stem Cell Transplantation for Myeloma; Trends in Early Mortality and Survival

Introduction: Outcomes in multiple myeloma have significantly improved in recent times owing to the availability of newer more effective therapies. Autologous stem cell transplantation (ASCT) has been used for over three decades to treat multiple myeloma. We aimed to evaluate the outcome of patients receiving ASCT at our institution between 1990 and 2015.Patients and Methods: A total of 2025 patients received ASCT at Mayo Clinic Rochester between 1st January 1990 and 31st December 2015. The patients were divided in to three cohorts of approximately equal time period, Cohort 1 (1990-1999, n=144), Cohort 2 (2000-2009, n=909) and Cohort 3 (2010-2015, n=972). Outcomes of interest were early mortality, progression free survival (PFS) and overall survival (OS). Disease characteristics were documented from time of diagnosis and PFS and OS were calculated from date of ASCT unless otherwise stated.Results: Median age for the whole cohort was 60 years (range 24-77) and increased over time (55 Cohort 1 vs 59 Cohort 2 vs 61 Cohort 3, p<0.0001). The proportion of males (60% for whole cohort) was not significantly different between the 3 time periods. Almost all patients (99%, n=2018) received chemotherapy prior to transplantation (median lines of therapy 1, range 0-6). The number of patients receiving >1 line of therapy prior to transplantation decreased over time (67% Cohort 1 vs 27% Cohort 2 vs 34% Cohort 3, p<0.0001). The use of novel agents was congruous with their availability and increased over time (0% Cohort 1 vs 59% Cohort 2 vs 100% Cohort 3, p<0.000).After a median follow up of 84 months (95% CI, 78-91 months), median PFS and OS for the whole cohort were 24 and 66 months respectively. Both PFS and OS improved significantly over time (median PFS: 12 months Cohort 1vs 18 months Cohort 2 vs 33 months Cohort 3, p<0.0001; median OS: 26 months Cohort 1vs 63 months Cohort 2 vs 83 months Cohort 3, p<0.0001), Figure 1. The improvement in PFS and OS over the 3 time periods was seen in patients receiving early (≤ 12 months from diagnosis) and delayed (>12 months) ASCT, Table 2. OS from diagnosis was no different for early versus delayed transplant in Cohort 1 and Cohort 2 (Cohort 1: median OS 57 months for early vs 56 months for delayed, p=0.24 and Cohort 2: median OS 81 months for early vs 82 months for delayed, p=0.70) and showed a trend towards a marginal benefit for delayed transplant in Cohort 3 (median OS 105 months for early vs 109 months for delayed, p=0.046).Treatment related mortality (100 days post transplant) improved over time (7.6% Cohort 1 vs 1.8% Cohort 2 vs 0.7% Cohort 3, p<0.0001), Figure 2A. Mortality within 12 months of ASCT also improved over time (24% Cohort 1vs 8% Cohort 2 vs 6% Cohort 3, p<0.0001). A landmark analysis of OS from 12 months post ASCT continued to reveal improved survival over time(median OS 26 months Cohort 1vs 63 months Cohort 2 vs 83 month Cohort 3, p<0.0001), Figure 2B.Conclusion: ASCT remains an important therapeutic option for eligible patients with multiple myeloma. There has been a marked improvement over time in PFS and OS and reduction in treatment related mortality and early mortality in myeloma patients receiving ASCT. This is likely to reflect the addition of novel agents to induction regimens and improved post transplant therapies. Despite these improvements myeloma remains incurable with patients continuing to relapse and die many years after ASCT. [Display omitted] DisclosuresDispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Amgen: Consultancy; spectrum: Consultancy, Honoraria; celgene: Consultancy; annexon: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; Ionis: Honoraria; Teva: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Prothena: Honoraria.

Younger Age at Diagnosis Is Associated with an Increased Risk of Venous Thromboembolism in Multiple Myeloma

IntroductionMultiple Myeloma (MM) patients are at an approximately 9-fold increased risk of developing venous thromboembolism (VTE), with risk being highest in the first year following diagnosis1. VTE is associated with significant morbidity and negatively influences survival in MM2. Although the Khorana score has been shown to predict rate of thrombosis in solid tumors, the validity of this score in haematological malignancies has yet to be assessed. Given the elevated rates of VTE in these conditions, in particular MM, clinically relevant risk prediction scores are essential. Additionally, data from the MRC-XI trial indicates that standard thromboprophylaxis may not prevent VTEs in MM3. Therefore identification of risk factors for MM-VTE are required to improve our understanding of the pathophysiology of thrombosis and to develop risk-adapted clinical practice guidelines. Through interrogation of an extensive clinical database we sought to identify factors predictive for VTE in our MM population.MethodsWe performed a retrospective cohort study of all newly diagnosed MM patients at our centre from 2001-2017. Patient medical records were reviewed for clinical and laboratory data including FBC parameters, beta-2-microglobulin, paraprotein and serum free light chain on the day of diagnosis, to minimize steroid effect. All VTE events were recorded, along with MM treatment regimen and thromboprophylaxis at time of event. History of thrombosis was defined as occurring within 6 month prior to, or following a diagnosis of MM. Patients with MGUS or smoldering MM were excluded. Statistical analysis including logistic regression and cox proportional hazard modelling was performed using SPSS (IBM Analytics, USA). A comparison of mortality was also performed between age matched cases with VTE and controls without VTE.ResultsOver a period of 17 years, 266 patients were diagnosed with myeloma, of which 34 (12.7%) developed VTE following MM diagnosis or within the preceding six months. The mean age of the VTE cohort at MM diagnosis was younger than the mean age of the non-VTE cohort (62.5 years vs. 68.6 years). Pulmonary embolisms and deep vein thromboses were equally represented (44% and 56% respectively) and additional risk factors for thrombosis were present in 46% of patients, not related to MM therapy. Of the patients on immunomodulatory drugs or corticosteroids at time of VTE, all were receiving thromboprophylaxis with either low molecular weight heparin (LMWH) or aspirin at time of VTE.The mortality odds ratio was 3.3 (95% CI 2.4-4.5) in patients who developed VTE in comparison to age matched controls with MM. Younger age at MM diagnosis (<64 years) predicted for VTE occurrence in logistic regression univariate (p-value=0.002) and multivariate analysis (p=0.004). Higher white cell count (WCC) at MM diagnosis showed a trend toward significance in univariate analysis (p-value=0.06) and, in combination with age, demonstrated an area under the curve of 0.72 on ROC analysis for prediction of VTE. Interestingly, the increased risk of VTE in younger patients was not related to longer duration of MM exposure or longer follow up as there was no statistically significant difference in time to VTE between all age groups (median 9 months). Other parameters incorporated in the Khorana score, such as haemoglobin and platelet count did not increase the risk of VTE (p-value=0.57, and 0.25 respectively).ConclusionsOur data confirms that VTE is associated with an increased mortality in MM patients and estimates the risk of death to be 3.3 fold higher in these patients. As recently reported in a large cohort of MM patients, younger age is associated with an increased risk of VTE development4, our data support this finding and excludes longer duration of MM, and follow-up time, as confounding variables. Importantly, our data confirms, in unselected “real world” patients the signal that is now apparent from analysis of VTE in the MRC-XI trial3, that thromboprophylaxis with LMWH or aspirin is suboptimal for VTE prevention. This may point to alternative thrombotic mechanisms in MM-VTE and further data in larger MM cohorts is needed to develop risk adapted strategies for prevention strategies for these patients.ReferencesKristinsson SY et el, Blood. 2008 Nov 1;112(9):3582-6.Schoen MW et al. J Clin Oncol 36, 2018 (suppl; abstr 8051).Bradbury CA et al, Blood 2017 130:553.Sanfilippo KM et al. Blood 2016;128:4726. DisclosuresQuinn:Janssen: Honoraria. Lavin:Shire: Honoraria, Research Funding, Speakers Bureau. O'Donnell:Baxter: Research Funding, Speakers Bureau; Octapharma: Speakers Bureau; CSL Behring: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Leo Pharma: Speakers Bureau.

Early mortality in myeloma patients treated with first-generation novel agents thalidomide, lenalidomide, bortezomib at diagnosis: A pooled analysis.

Early toxic death (≤60 days of diagnosis) in elderly multiple myeloma (MM) patients is attributable to active disease, age and co-morbidities. Rate of early toxic deaths is 10% with conventional chemotherapy mainly due to infection and renal failure. Novel agents have improved MM outcome at the expense of newer toxicity. We analyzed 1146 individual patient data to assess toxic deaths during induction treatment with first-generation novel agents thalidomide, lenalidomide, bortezomib. During first-line therapy, 119/1146 patients (10%) died for any cause, and 47/1146 (4%) due to toxicity, including 12/1146 (1%) early deaths. The 24-month cumulative incidence was 4.1% without any difference between bortezomib (18/503 patients, 4%) and lenalidomide (29/643patients, 5%; p = 0.31). Toxic deaths occurred in 34/1039 (3%) patients <80 years and 13/107 (12%) patients ≥80 years. Causes were cardiac events (28%), infections (26%) and vascular complications (15%). In a multivariate analysis, older age and unfavorable ISS stage increased the risk of death. First-generation novel agents significantly reduced toxic deaths compared to conventional chemotherapy. One third of deaths during first-line therapy were due to cumulative drug-related toxicities, thus supportive approaches and prevention strategies should be optimized. The higher mortality rate for toxicity in octogenarians confirms the need for a careful frailty assessment.

Cardiac Assessment of Global Longitudinal Strain May Predict Early Mortality in Myeloma Patients Undergoing Melphalan ASCT

Cardiac Assessment of Global Longitudinal Strain May Predict Early Mortality in Myeloma Patients Undergoing Melphalan ASCT

Risk of Early Mortality in Patients with Newly Diagnosed Multiple Myeloma

▪BackgroundThe overall survival of patients with multiple myeloma has been improved greatly over the last two decades with the advances of treatment. Several studies reported that this improvement in survival has been ascribed to the broader use of novel drugs and autologous tandem transplantation. However, there were still a certain portion of myeloma patients died early after diagnosis. We therefore aim to investigate the risk factors of early mortality (death within 60 days after diagnosis) in patients with multiple myeloma.Patients and MethodsWe included in this study 451 consecutive patients with multiple myeloma, newly diagnosed at an Asian tertiary medical center between January 1, 2002 and April 30, 2015. A total 57 subjects who developed early mortality were identified. Risk factors for early mortality in myeloma patients were collected and analyzed.ResultsCompared with non-early mortality myeloma patients, early mortality patients had higher probability of being male, primary plasma cell leukemia, low platelet count, low serum albumin, high corrected serum calcium, high serum creatinine, high LDH, high serum β2-microglobulin, poor performance status, and high ISS stage. With multivariate analysis, we found that male (adjusted OR 2.93, 95% CI 1.17-7.31), serum albumin < 3.5g/dl (adjusted OR 2.76, 95% CI 1.17-6.52), corrected serum calcium ≥ 12mg/dl (adjusted OR 3.56, 95% CI 1.47-8.63) and LDH ≥ 250U/L (adjusted OR 3.30, 95% CI 1.62-6.74) were significant risk factors of early mortality. Pneumonia represented as the leading cause of early mortality in myeloma patients (n = 18, 31.5%), followed by renal failure (n = 7, 12.2%).ConclusionEarly mortality rate is high (12.6%) in patients with multiple myeloma. Patients of male gender, low serum albumin, high corrected serum calcium and LDH are at risk of early mortality. More than one third myeloma patients (21 out of 57) who developed early mortality are died of infection. Identifying the risk group and providing prompt intervention, such as prophylaxis antibiotics, may reduce the incidence rate of early mortality and improve the life expectancy of myeloma patients. DisclosuresNo relevant conflicts of interest to declare.

Risk of Early Mortality in Patients With Newly Diagnosed Multiple Myeloma.

The overall survival of patients with multiple myeloma (MM) has been improved greatly over the last 2 decades with the broader use of novel drugs and autologous tandem transplantation. However, more than one tenth of myeloma patients still die shortly after diagnosis. We therefore aim to investigate the risk factors of early mortality (death within 60 days after diagnosis) in patients with MM. We included in this study 451 consecutive patients with MM, newly diagnosed at an Asian tertiary medical center between January 1, 2002 and April 30, 2015. A total of 57 subjects who experienced early mortality were identified. Risk factors for early mortality in myeloma patients were collected and analyzed. Early mortality occurred in 57 (12.6%) of the myeloma patients. In the multivariate analysis, being male (adjusted OR 2.93, 95% CI 1.17-7.31), serum albumin < 3.5 g/dL (adjusted OR 2.71, 95% CI 1.09-6.74), primary plasma cell leukemia (adjusted OR 17.61, 95% CI 1.01-306.05), serum albumin (adjusted OR 2.70, 95% CI 1.15-6.38), corrected serum calcium ≥ 12 mg/dL (adjusted OR 2.94, 95% CI 1.21-7.14), and LDH ≥ 250 U/L (adjusted OR 3.07, 95% CI 1.50-6.27) were identified as independent risk factors of early mortality. Pneumonia with other infections contributed most to early mortality (n = 36, 65%), followed by renal failure and cardiac failure. The early mortality rate is high (12.6%) in patients with MM. Patients who are male and those with primary plasma cell leukemia, low serum albumin, high-corrected serum calcium, or LDH are at risk of early mortality. Nearly two thirds of the myeloma patients who experienced early mortality in our study (37 of 57, 65%) died of infection. Once a high-risk group is identified, much effort is required to target new approaches for prevention, early detection, and treatment of infections.

Treatment of myeloma patients with renal impairment

Renal impairment is a common phenomenon in myeloma patients. Pathogenesis is mainly based on the presence of monoclonal paraprotein but may include myeloma-independent mechanisms as well. There are various forms of paraprotein-related renal impairment. The majority of severe cases are due to cast nephropathy where precipitation on the basis of monoclonal free light chains causes complex tubular damage. Cast nephropathy requires quick diagnosis and specific treatment. Renal impairment increases mortality in myeloma patients. A quick and sustained response to treatment is crucial for preventing long-term dialysis dependence. Apart from preventing or treating other conditions endangering kidney function, an effective antimyeloma treatment is the mainstay of therapy. Available data are limited but novel substances added considerable efficacy to preexisting treatment concepts. Bortezomib gained importance due to its rapid action and missing nephrotoxicity, but also immunmodulatory substances such as lenalidomide were shown to restore kidney function. Cytostatic substances such as cyclophosphamide, bendamustine, and doxorubicin remain valuable combination partners for novel substances in order to achieve significant tumor responses. Extracorporeal removal of free light chains by plasmapheresis or extended daily high cut-off hemodialysis, if available, may further optimize management of acute myeloma-related renal failure.

Recent advances in stem cell transplantation. Abstracts from the 11th International Symposium. Del Mar, California, USA. May 8-10, 2003.

TANDEM AUTOLOGOUS FOLLOWED BY NON-MYELOABLATIVE ALLOGENEIC TRANSPLANTS FOR MYELOMA DG Maloney, Fred Hutchinson Cancer Research Center and the University of Washington High dose therapy and autologous BM or peripheral blood hematopoietic cell transplantation (HCT) has been associated with longer disease-free survival and improved overall survival compared with chemotherapy alone for patients with responding myeloma. While generally safe [transplant-related mortality (TRM) of generally B/5%], few if any patients are cured using these conventional approaches, and patients appear to face a continuing risk of relapse. Tandem autologous HCT may be superior to a single transplant. Recent analysis of the IFM94 trial [1] using tandem autologous transplants demonstrated a 7-year overall survival of 40% and a progression-free survival of 20%. Thus, even in patients with tandem autologous HCT the majority of patients eventually progress. The source of relapse following autologous HCT is likely due either to chemotherapy resistant disease left in the patient, or clonogeneic myeloma cells infused with the stem cell rescue. Current ‘purging’ methods have not improved outcome, suggesting that the former is the greater problem. In contrast, the use of allogeneic stem cells provides a tumor-free graft and, in addition, the opportunity to develop graft-versus-myeloma immune responses that can lead to prolonged myeloma-free survival in a minority of patients. Myeloablative allogeneic transplant regimens have been associated with a high mortality in myeloma patients, with Day 100 or 6 month TRM as high as 50%. The use of peripheral blood HCT rather than marrow may decrease TRM. Analysis of the European Bone Marrow Transplant (EBMT) Registry data demonstrates a 21% 6-month TRM and a 30% 1-year TRM for myeloma patients treated with conventional high-dose conditioning and allogeneic HCT. These patients were a median age of approximately 45, and were treated a median of 10 months from diagnosis. Thus, even in optimal situations, allogeneic transplantation can only be applied to a minority of patients with myeloma, due to age or co-morbid medical issues. In contrast to autologous HCT, following allogeneic HCT patients continue to be at risk for significant toxicity from GvHD, and infection and treatment is limited to younger, medically fit patients. The use of reduced-dose conditioning regimens (non-myeloablative conditioning) has allowed engraftment of donor cells with a lower TRM, using a wide variety of treatment regimens. This approach shifts the burden of anti-tumor activity from the conditioning regimen to that of the graft-versus-tumor effects of the donor immune system. As the development of graft-versus-myeloma activity takes time to develop, this limits the application of the lower intensity regimens to patients with significant disease cytoreduction prior to the allograft, and to diseases sensitive to graft-versus-tumor immune responses. In the Seattle consortium we have developed a non-myeloblative conditioning regimen for allografts using low-dose TBI (200 cGy) and immunosuppression with cyclosporine and mycophenolate mofetil (MMF). This has allowed the application 1 No abstract available. Cytotherapy (2003) Vol. 5, No. 6, 562 /580