Time Of Multiple Myeloma Diagnosis Research Articles

Association of Serum Free Light Chain Level with Long-Term Kidney Function in Patients with Newly Diagnosed Multiple Myeloma

Introduction: Multiple myeloma (MM) frequently involves the kidneys, resulting in acute, subacute, or chronic kidney disease (CKD). Patient- and treatment-related factors are associated with the long-term development of CKD. The aim of our study was to examine the association of serum free light chain (FLC) levels, measured at the time of diagnosis of MM, and CKD at subsequent follow-up. Methods: Patients with newly diagnosed MM were identified using cancer registries at five hospitals. The primary outcome was low eGFR (<60 mL/min/1.73 m2) or dialysis dependence and a secondary composite outcome of low eGFR, dialysis dependence, or death at the last follow-up, up to 12 months from diagnosis. Logistic regression analyses were performed. Results: A total of 149 patients met the inclusion criteria. Patients with an FLC level above the median had a higher frequency of hypertension (54% vs. 81%; p < 0.001), hyperlipidemia (37% vs. 56%; p = 0.018), low eGFR at the time of diagnosis (43% vs. 66%; p = 0.006), and a higher MM stage (p = 0.018). On multivariable analyses, after adjustment for several covariates, serum FLC level (per each 100 mg/L) was independently associated with low eGFR or dialysis dependence at follow-up (adjusted odds ratio [aOR] 1.021; 95% CI: 1.002, 1.041; p = 0.033). This association persisted for the composite outcome of low eGFR, dialysis dependence, or death (aOR 1.034; 95% CI: 1.006, 1.063; p = 0.018). Discussion/Conclusion: Higher serum FLC level measured at the time of MM diagnosis is independently associated with CKD at up to 12 months of follow-up.

Impact of Health Insurance and Access to Autologous Stem Cell Transplantation (ASCT) on Racial Inequity in Overall Survival (OS) Among Patients with Multiple Myeloma (MM)

Background: Survival for patients with MM has improved in the past two decades, largely attributed to the advent of novel therapies and increased use of autologous stem cell transplantation (ASCT). However, questions remain whether African Americans/Blacks (AAs) have benefitted equally from survival improvement compared to whites. Few studies have examined the simultaneous impact of health system inequities ( i.e. insurance, access to ASCT) on differential outcomes by race. We addressed these knowledge gaps using the real-world data of the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Methods: We included 5722 patients newly diagnosed with MM between January 1, 2011 and December 1, 2021. The study was limited to those with known state of residence, diagnosed in the community oncology setting, had available first-line therapy and insurance data. Longitudinal insurance data included the start and end dates of documented insurance coverage which were used to determine the insurance type at time of initial MM diagnosis. Insurance was grouped as Private, Medicare (± private or non-Medicaid government programs), any Medicaid, or Other (non-Medicaid government program ± unknown payer type). Follow-up was from diagnosis until death or last known activity in the EHR, to December 31, 2022. Patients with del(17p), t(14;16), t(4;14), or amp(1q21) were considered to have high cytogenetic risk (CR); standard risk otherwise. Dates of Medicaid expansion adoption by states were obtained from public data. Missing data on International Staging System (ISS), CR, and insurance type at diagnosis (missingness: 40%, 59%, 19%, respectively) were multiply imputed 10 times. Multivariable step-wise Cox regression was used to examine the effects of race, ASCT, and insurance on OS, treating ASCT as time-varying covariate. For access to ASCT as outcome, we used Fine-Gray subdistribution hazard regression taking death as competing risk. Covariates considered in the multivariable model included: ISS, CR, age at diagnosis, sex, and prior history of cancer. Results: Median age (range) at diagnosis was 70.5y (24 - 85); 32% were &amp;lt;65y at diagnosis; 54% were male; 24% were AA. Median follow-up was 2.9y (0.01 - 12). Compared to whites, AAs were more likely to be diagnosed at a younger age (median, 67y vs 71y), have less aggressive disease (ISS Stage I: 41% vs 31%) and standard CR (41% vs 36%), and more likely to reside in states without Medicaid expansion at time of MM diagnosis (74% vs 58%). Medicare was more common in whites (65.4% vs 50.5%) while Medicaid was more common in AAs (15.3% vs 4.4%). Impact of Insurance: Adjusted analyses showed a higher overall mortality risk in AAs compared to whites (adjusted Hazard Ratio [aHR]=1.10, p=0.042). Racial difference was abrogated (aHR=1.06, p=0.28) when the model was adjusted for insurance type. Compared to patients with Private insurance, patients with Medicare had lower mortality risk (aHR=0.78, p&amp;lt;0.0001) while the risk was higher (aHR=1.29, p=0.004) in patients with Medicaid or Other insurance (Medicaid/Other ). Impact of ASCT: Adjusted for disease, demographics, and insurance, mortality risk was higher without receipt of ASCT (aHR=1.73, p&amp;lt;0.0001). Of note, while ASCT utilization was lower in AAs compared to whites (aHR=0.70, p&amp;lt;0.0001, adjusted for insurance), this difference did not manifest as racial difference in OS within each insurance type (p&amp;gt;0.5). Impact of Insurance + ASCT: Considering the joint effects of ASCT and insurance type, mortality risk was highest for Medicaid/Other insurance without receipt of ASCT (aHR=3.05, 95% CI: 1.94 - 4.80); reference Private/Medicare with receipt of ASCT ( Figure). With the receipt of ASCT, mortality risks were not different between Private/Medicare and Medicaid/Other insurance (p=0.46). Similar trends were observed for AAs and whites. Conclusions: Adjusted for relevant risk factors, survival was worse in AAs with MM compared to whites. However, racial differences were abrogated after adjusting for insurance type. Overall, OS was worse in patients with Medicaid compared to those who had private insurance or Medicare. OS was also worse without receipt of ASCT, independent of insurance type. The highest mortality risk was seen in patients with Medicaid without receipt of ASCT. These findings provide real-world evidence of how inequity in health insurance and access to ASCT can impact MM survival.

Freedo mm: A Multicenter Observational Study of Multiple Myeloma in Second Relapse in Colombia

Introduction: The incidence of multiple myeloma (MM) has been increasing globally (Institute for Health Metrics and Evaluation ; Cancer Research UK 2021), particularly in high-income countries (Ferlay J et al. (2020); Cowan et al. 2018). However, low-income countries, including Colombia, have also experienced a progressive increase in new cases (Fondo Colombiano de Enfermedades de Alto Costo. Cuenta de Alto Costo (CAC) ; Martínez Cordero et al. 2020). In the context of MM, the duration of progression free survival decreases after each relapse rendering as highly important the election of and adequate treatment (Yong et al. 2016), yet there is a lack of local data on patients experiencing a second relapse in Colombia to guide these decisions. This study aims to characterize Colombian patients with MM in second relapse, the current treatment patterns, and assess clinical response to address this knowledge gap. Methods: An observational retrospective study was conducted, utilizing chart review data from five specialized cancer treatment institutions in Colombia. Adult MM patients with diagnosed second relapse between January 1, 2013 and June 30, 2021 who had received at least two prior lines of treatment including lenalidomide and a proteasome inhibitor were included. Patients receiving only palliative care were excluded. Data on the effectiveness and safety of treatment patterns were collected from the start of the second relapse treatment pattern until the occurrence of treatment withdrawal, death, initiation of treatment pattern for third relapse diagnosed, loss of follow-up or study cutoff date (June 30, 2022), whichever happened earlier. The main outcomes were progression free survival (PFS), time to treatment failure (TTF), overall survival (OS), and overall response rate (ORR). All variables were analyzed descriptively utilizing appropriate statistics measures such as, means or medians, with corresponding standard deviation or interquartile range for continuous variables, and frequencies and percentages for categorical variables. OS was determined using the Kaplan-Meier method. Results: A total of 84 Patients were included from 5 centers in 3 of the Colombian regions (Andean, Pacific and Caribbean), 47 (56%) were male. The mean age at the time of MM diagnosis was 62.3 (SD 11.7) years. On average, the time from initial diagnosis to the occurrence of the second relapse was 3.6 (SD 2.1, min: 0.6 max: 11.2) years. The most frequent type of relapse observed was biochemical relapse, accounting for 42 cases (51%). Immunoglobulin levels were used as biomarkers, with IgA M-protein (g/dL) measuring 0.7 (SD 2.8, min:0 max: 16.2) and IgG M-protein (g/dL) measuring 31.8 (SD 185.4, min 0, max: 1,144.3). Furthermore, 41 patients (49%) exhibited bone lesion as a sign of second relapse. The most frequent treatments received for second relapse included lenalidomide 33 (14.7%), carfilzomib 29 (12.9%), bortezomib 23 (10.3%) and daratumumab 22 (9.8%). Among the patients who received lenalidomide, 87.9% had received bortezomib as first-line therapy, while 18.2% leniladomide. Conversely, 75.8% had received lenalidomide as second-line therapy, and 45.5% bortezomib. Table 1 displays the main outcomes according to the treatment received. Regardless of the treatment, the average PFS was 12.7 (IQR 3.7-23.4) months, the TTF was 5.3 (IQR 1.9-12.9) months, and the ORR was 47.1%. Figure 1 illustrates the OS, revealing that at 27.5 months 50% of the study population had either died (21, 25%) or been censored (21, 25%). Treatment-emergent adverse events (TEAE) were reported in 10 patients (11.9%). The most frequent TEAE were anemia and neutropenia, reported in 2 patients. At the end of study cut off 21 patients (25%) had died, 8 (9.5%) had discontinued treatment, 42 (50%) had a third relapse, 4(4.8%) were lost to follow-up, 9 (10.7%) were still undergoing treatment. Conclusions: The FreedoMM study is the first to our knowledge, to describe comprehensively the characteristics, treatment patterns, and clinical response of Colombian patients experiencing a second relapse of MM. The study highlights the poor outcomes observed in this specific population. Indeed, the study underscore the clear necessity for additional research and the development of treatment guidelines tailored specifically to patients in their second of MM in Colombia and other similar countries.

Unraveling the Dynamics of Protein Secretion in Multiple Myeloma: A Comparative Study of Non-Secretory Patterns and Disease Evolution

Background Non-secretory multiple myeloma (NSMM), 1-2% of all multiple myeloma (MM) cases, was traditionally defined by the absence of detectable M-Spike in serum or urine. Advancements in diagnostic methodologies have revealed that a proportion of NSMMs are, in fact, more accurately categorized as oligo-secretory, highlighting the dynamic nature of MM and its classification. Disease evolution, especially towards less secretory types, significantly impacts monitoring, progression, and prognosis. This study examines MM secretion patterns (SP) and evolution, particularly NSMM and oligo-secretory types, comparing current classification with medical notes. Methodology Using the HealthTree Cure Hub for Multiple Myeloma (PMID: 35271305), we analyzed real-world data from 140 patients. SP evolution was assessed as Secretory (SC), Light Chain Only Oligosecretory (LCO), Heavy Chain Oligosecretory (HCO), and True Non-secretory (TNSC) at diagnosis and last lab follow-up. TNSC patients showed no myeloma activity on the M-protein, and light chain assay. LCO patients exhibited activity only on their light chain assay. HCO patients met the IMWG criteria for Non-Measurable Myeloma. SC patients didn't meet the criteria for the other categories. Changes to less secretory patterns were recorded based on office notes, indicating a relapse diagnosis. The chi-square test of independence assessed the association between secretion types at diagnosis and current state and the concordance between IMWG criteria and medical notes. Kaplan-Meier ‘Time to Next Treatment’ (TTNT) analysis was implemented for the first line of therapy to assess the impact of secretion type at diagnosis and currently. Patients whose SP could not be determined were excluded. Results The mean age was 65±8.5 y.o., and 56.5% were female. Of the 122 patients that had an mSMART stage available, 13% were high-risk, and 6% were double-hit. At their last follow-up, the SPs of the 140 patients analyzed were as follows: 48% SC, 28.5% LCO, 10% HCO, and 13.5% TNSC patients. When comparing SPs at the time of MM diagnosis, 16 patients (11.5%) were found to have changed to a less secretory type. This change took a mean of 66.5 months from the time of diagnosis, with SC-to-HCO (43.25 mo) and HCO-to-TNSC (34.5 mo) being the fastest and SC-to-TNSC being the slowest (96.5 mo). Among the 73 patients with LCO, HCO, or TNSC patterns, 75.3% had their SP accurately reported, 12.3% had it incorrectly classified, and 12.3% were not classified. The median TTNTs of the observed events at the time of the last follow-up using the SP at diagnosis were: SC (39 mo), LCO (50 mo), HCO (23 mo), and TNSC (33 mo) ( p = 0.63). The median TTNTs, when using the current SP, were: SC (32 mo), LCO (50 mo), HCO (31.5 mo), and TNSC (33 mo) ( p = 0.44). After two years of follow-up, the TTNT survival rates using the SP at diagnosis were: SC (53.3%), LCO (65.9%), HCO (38.5%), and TNSC (50%). The TTNT survival rates, when using the current SP, were: SC (50.7%), LCO (67.5%), HCO (42.9%), and TNSC (57.9%). Conclusions Our study elucidates the dynamic evolution of MM SPs, with 11.5% of patients transitioning to less secretory types. Understanding these patterns is pivotal for effective disease monitoring and therapy planning. While the limited number of NSMM patients prevents definitive conclusions, our findings align with existing literature suggesting that the NSMM at onset does not confer additional risk (PMID:28894562). Interestingly, we found no retrospective impact of SP evolution at disease onset, which has been linked to a worse prognosis at relapse. However, one of four patients had inaccurate or missing SP information in their office notes, highlighting the need for improved documentation and awareness. Future research should explore the clinical implications of these findings and continue to refine MM classifications according to the testing technology available.

Association of venetoclax-based therapy with increased survival in multiple myeloma (MM) harboring t(11;14): A single-center experience.

e20055 Background: The BCL-2 inhibitor venetoclax (Ven) has shown activity in MM with t(11;14). However, a randomized trial comparing bortezomib and dexamethasone ± Ven in unselected MM patients was notable for decreased overall survival (OS) in the non-t(11;14) population treated with Ven despite improved progression free survival (PFS). In a subgroup analysis of 35 t(11;14) patients, those randomized to the Ven arm had superior OS (HR, 0.61 [95% CI, 0.16-2.32]) but this did not reach statistical significance (Kumar et al, Blood 2021). We sought to investigate the real-world impact of Ven-based therapy in t(11;14) MM and to explore patient and disease-related factors impacting response and durability. Methods: We retrospectively identified all t(11;14) MM patients treated at Moffitt Cancer Center between 2000-2022. The primary endpoint was OS measured from the time of MM diagnosis compared between Ven-treated patients and those who did not receive Ven. Secondary endpoints were ≥VGPR rate, PFS, and key toxicities. The era of MM diagnosis (5-year intervals) was included in analyses to account for novel therapies. Kaplan-Meier estimates and Cox regression were employed. Results: 262 MM patients were included. Median age was 64 years (interquartile range [IQR], 56-71 years); 61% were male; 87% were White. Ven was used in 78 patients (30%) on median in the 5th line (IQR, 4-7) and most commonly in combination with anti-CD38 antibodies (42%) or proteasome inhibitor (32%). Most patients (77%) initiated treatment at 400 mg daily and 25% required dose reduction. At a median follow-up of 52 months, 18 (23%) patients died in the Ven group as compared to 87 (47%) in the non-Ven group. Median unadjusted OS was longer in the Ven group (206 months [95% CI, 112-249 months] vs 75 months [95% CI, 65-97 months]; p &lt; 0.01). In multivariable analysis accounting for demographics, high-risk cytogenetics, time of diagnosis, penta-exposed status, autologous stem cell transplant and BCMA-directed therapy, Ven was associated with a reduced risk of death (HR, 0.26; 95% CI, 0.15-0.47). Of 73/78 with available response data, 38% achieved ≥VGPR with Ven-based therapy. Median PFS was 27 months (95% CI, 13-39 months). In univariable analyses, 1q amplification/gain was associated with inferior PFS (13 months [95% CI, 6.5-28 months]) vs 33 months [95% CI, 23 months-not reached/NR]; p = 0.04). Median PFS was longer anti-CD38 antibody (33 months [95% CI, 13 months-NR]) compared to proteasome inhibitor combinations (11 months [95% CI, 7 months-NR]), but this difference was not statistically significant (p = 0.1). No grade 3/4 infections or deaths were directly attributable to Ven. Conclusions: In this real world dataset, MM patients with t(11;14) treated with Ven-based combinations exhibited superior survival. The response to Ven may be impacted by the partner agent and concurrent cytogenetic abnormalities.

Cytogenetic and survival analysis in 315 multiple myeloma patients; five with orbital and eight with extramedullary disease

ABSTRACT Purpose To describe cytogenetic abnormalities in five patients with orbital involvement of multiple myeloma (MM) and to determine if high-risk cytogenetic abnormalities were more prevalent in patients with extramedullary disease (EMD). The final goal was to determine predictors of poor survival in the entire cohort. Methods Retrospective cohort study of 315 patients diagnosed with multiple myeloma over a 9-year period at a single institution. Results Males comprised 61% of the 315 patients and the majority (54.3%) were stage II at diagnosis of MM. Follow-up ranged 6 months to 18 years, mean 5.3 ± 3.7 years. Eight patients (2.5%), two of which had orbital involvement, developed EMD and an additional three patients had orbital involvement from adjacent bone disease. No genetic abnormality reached statistical significance between non-EMD and EMD groups. At the time of analysis 127 (41%) non-EMD patients and 6 (75%) EMD patients have died. The median survival time for the EMD group was 2 years, whereas for the non-EMD group it was 9 years (P-value of log rank test = .00015). Stage at time of MM diagnosis and age were associated with worse prognosis. Median survival for patients over 65 years of age was 7 years, compared to 12 years for patients 65 or younger (P-value for the log-ranked test <.001). Conclusions Cytogenetic abnormalities are described in five patients with orbital involvement of MM. No genetic abnormality reached statistical significance between non-EMD and EMD groups. EMD status, stage of MM at diagnosis and age are associated with poorer overall survival. Abbreviation: MM: Multiple Myeloma; EMD: Extramedullary disease; FISH: fluorescence in situ hybridization; B2M: beta-2 microglobulin; LDH: lactate dehydrogenase; OS: overall survival.

Analysis of High-Risk Extramedullary Relapse Factors in Newly Diagnosed MM Patients.

Extramedullary relapse of multiple myeloma (MM) is often resistant to existing treatments, and has an extremely poor prognosis, but our understanding of extramedullary relapse is still limited. The incidence, clinical characteristics, impact on the prognosis of extramedullary relapse, and the risk factors for extramedullary relapse in NDMM patients were analyzed. Among the 471 NDMM patients, a total of 267 patients had disease relapse during follow-up, including 64 (24.0%) patients with extramedullary relapse. Extramedullary relapse was more common in patients with younger age, IgD subtype, elevated LDH, extensive osteolytic lesions, extramedullary involvement, and spleen enlargement at the time of MM diagnosis. Survival analysis showed that extramedullary relapse patients had significantly worse median OS than patients with relapse but without extramedullary involvement (30.8 months vs. 53.6 months, p = 0.012). Multivariate analysis confirmed that elevated LDH (OR = 2.09, p = 0.023), &gt;2 osteolytic lesions (OR = 3.70, p &lt; 0.001), extramedullary involvement (OR = 3.48, p &lt; 0.001) and spleen enlargement (OR = 2.27, p = 0.011) at the time of MM diagnosis were independent risk factors for extramedullary relapse in NDMM patients. Each of the above four factors was assigned a value of 1 to form the extramedullary relapse prediction score, and the 3-year extramedullary relapse rates of patients in the 0-2 and 3-4 score groups were 9.0 % and 76.7 %, respectively. This study suggested that extramedullary relapse was associated with poor clinical characteristics and poor prognosis in NDMM patients. The extramedullary relapse prediction score model composed of LDH, osteolytic lesions, extramedullary involvement and spleen enlargement has a better ability to predict extramedullary relapse than the existing ISS and R-ISS stages.

Clinician and Patient Perspectives on Treatment Decision-Making in Multiple Myeloma: A Qualitative Survey

Background: Multiple myeloma (MM) is an incurable malignancy associated with significant morbidity. The recent expansion of available treatment choices has increasingly complicated later-line treatment decision-making, where standard of care (SOC) is not necessarily established. However, the patient (pt) and hematologist/oncologist (HEM/ONC) priorities that underlie treatment decision-making in real-world settings for MM have not been well studied. We aimed to better understand these factors using qualitative methods. Methods: In March 2021, we conducted in-depth interviews with 12 adults with MM (11 from the US and one from Canada) and 12 HEM/ONCs in the US (seven from community settings, five from academic settings; all of whom spend ≥50% of their time in direct pt care and currently manage ≥10 pts with active MM). A commercial healthcare database was used to recruit HEM/ONCs, and a pt advocacy group, the HealthTree Foundation for Multiple Myeloma, was used to recruit pts. A trained moderator used a semi-structured interview guide to facilitate discussion of MM treatment decision-making. NVivo, a qualitative analysis software program, identified key themes emerging from the interviews. Results: HEM/ONCs had a median of 17 years (range 5-30) in practice. Pts had a median age of 64 years (range 49-70) and a median time since MM diagnosis of 6 years (range 1-8). At the time of MM diagnosis, HEM/ONCs described MM as treatable with many therapeutic options. They noted that discussions of risk status, cytogenetics, and biomarkers can be difficult for pts to understand; as these factors may not always influence early-line treatment decisions, HEM/ONCs reported simplifying or delaying such discussions, instead focusing on immediate next steps such as the treatment plan. HEM/ONCs also recommended first-line SOC comprising lenalidomide/bortezomib/dexamethasone (n=9/12), regardless of pt risk status. Similarly, pts reported that initial MM diagnosis discussions focused on the treatment they would receive (n=8/12). Discussions with their treating physician were focused predominantly on treatability (n=4/12), reassurance (n=3/12), and symptom control (n=2/12), rather than individualized factors or therapy. No pts recalled detailed discussions of risks or cytogenetics at initial diagnosis (n=0/12) (Table 1). In treatment discussions for later lines of therapy, HEM/ONCs appear to offer more options and pts appear to participate more in treatment decisions: pts reported their preferences were considered for later-line therapy (n=5/12), for switching treatments due to side effects (n=3/12), and when offered a 'brand new' medication (n=2/12); HEM/ONCs also reported shared decision-making for later-line therapy (n=7/12; Table 2). Regarding treatment goals, all MM pts (regardless of line of therapy; n=12/12) and HEM/ONCs (n=12/12) prioritized efficacy. Among efficacy measures, pts prioritized response (n=10/12) and overall survival (OS; n=7/12), followed by progression-free survival (PFS; n=4/12). These efficacy goals aligned with the top treatment goals for HEM/ONCs (response: n=12/12; OS: n=11/12; PFS: n=8/12). Aside from efficacy, priorities for pts and HEM/ONCs overlapped on ability to do physical activities (n=4/12 pts, n=6/12 HEM/ONCs), participating in social activities (n=3/12 pts, n=6/12 HEM/ONCs), getting back to normal life (n=3/12 pts, n=4/12 HEM/ONCs), continuing to work (n=3/12 pts, n=4/12 HEM/ONCs), and maintaining a family role (n=2/12 pts, n=3/12 HEM/ONCs). Areas prioritized by pts but not by HEM/ONCs included avoiding being a burden on their family (n=5/12 pts, n=0/12 HEM/ONCs), and avoiding serious heart damage (n=5/12 pts, n=1/12 HEM/ONCs) and kidney damage (n=4/12 pts, n=1/12 HEM/ONCs). HEM/ONCs prioritized avoiding neuropathy and convenience of administration, which pts did not mention. Conclusions: The pt's role in treatment selection increases in later lines as they are offered more options, receive more information, and feel their preferences are considered. In the current study, both pts and HEM/ONCs prioritized disease control over most other aspects, particularly in later lines. Pts and HEM/ONCs prioritized maintaining quality of life over avoiding specific adverse events that are not life-threatening or requiring medical intervention. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Validation of the CIBMTR Scoring System in Predicting Early Relapse of Multiple Myeloma Post Autologous Hematopoietic Cell Transplant

Introduction: Despite good initial responses, many multiple myeloma (MM) patients eventually relapse post autologous hematopoietic cell transplant (AHCT). Risk stratification to Identify patients that are at an increased risk of early relapse may influence post-AHCT monitoring and selection of maintenance therapy. Recently, the Center for International Blood and Marrow Transplant Research (CIBMTR) scoring system was introduced as a tool to identify patients at risk of early relapse post-AHCT. The scoring system relies on each patient's albumin level at time of MM diagnosis, bone marrow plasma cell (BMPC) percentage at time of AHCT, and cytogenetic risk profile to classify them into three risk categories. Here, we aimed to test the validity of the CIBMTR scoring system by applying it to our cohort. Methods: We reviewed all patients who underwent AHCT for MM at Cleveland Clinic between 2011-2021, and then identified the patients with available data to be incorporated into the CIBMTR system. As per the scoring system's requirements, points were assigned for the following patient characteristics: 4 points for high risk (HR) cytogenetics, 4 points for BMPC ≥10% at AHCT, 2 points for albumin <3.5 g/dL at diagnosis, 1 point for standard risk (SR) cytogenetics, 0 points for normal cytogenetics, BMPC <10% at AHCT, and albumin ≥3.5 g/dL at diagnosis. Baseline demographic, clinical, and cytogenetic data of the included patients were retrospectively collected by reviewing electronic medical records to compare the three risk groups. Analysis was conducted through multivariate analysis using the Statistical Package for Social Sciences (SPSS), while median overall survival (mOS) and median progression free survival (mPFS) of the three groups were analyzed using GraphPad Prism. Results: A total of 313 patients met inclusion criteria and were included in our study. Our cohort had a median age of 61.7 years at AHCT, a 57.2% male preponderance and a median follow up of 31.9 months. With regards to the CIBMTR scoring system constituents, 106 (33.9%) had HR cytogenetics as compared to 146 (46.6%) with SR and 61 (19.5%) with normal cytogenetics. Albumin ≥3.5 g/dL occurred in 85 (27.2%) while BMPC ≥10% were present in 31 (9.9%). CIMBTR risk score application yielded 191 (61%) patients classified as low risk (score 0-3), 110 (35.2%) patients as intermediate risk (score 4-8), and 12 (3.8%) patients as high risk (score 9-10) of early relapse after AHCT. There were no significant differences between the low-, intermediate and high-risk groups with respect to median age at transplant (61 vs 63.1 vs 62.3%, P=0.1), Gender representation (Males 56.5 vs 60 vs 50%, P=0.7), Ethnicity (White 82.2 vs 86.4 vs 91.7%, P=0.5), median lines of therapy pre-AHCT (P=0.3), or remission status (partial/very good partial/complete) pre-AHCT (P=0.17). Compared to low- and intermediate-risk patients, respectively, patients belonging to the high-risk group had higher 1-year relapse (41.7 vs 10.5 vs 18.2%, P=0.0043), 2-year relapse (58.3 vs 17.8 vs 38.2%, P=0.0001) and 3-year relapse (66.7 vs 25.7 vs 50.9%, P<0.0001) rates. Kaplan-Meier based survival analysis confirmed a lower mPFS in the high-risk group compared to the low- and intermediate-risk groups, respectively (14.7 vs 67.7 vs 29 months, P<0.0001) (Fig 1A). Interestingly, the CIBMTR score also distinguished the three risk groups with respect to overall survival. High-risk patients had higher mortality at the 5-year (50 vs 15.7 vs 22.7%, P=0.0082) and 7-year (58.3 vs 17.3 vs 29%, P=0.0008) follow up intervals as compared to low- and intermediate-risk patients, respectively. Kaplan-Meier analysis further corroborated the mortality rates since high-risk patients had lower mOS relative to intermediate- and low-risk patients, respectively (56.6 vs 68 vs unreached, P=0.0046) (Fig 1B). Conclusion: We validated the CIBTMR scoring system criteria within an internal cohort, demonstrating that this system is a reliable tool for identification of patients with a higher risk of early relapse post-AHCT. We further identified differences between risk groups in mortality at 5- and 7-years following AHCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Second Primary Malignancy Risk in Multiple Myeloma from 1975 to 2018.

Simple SummaryMultiple myeloma (MM) is the second most common hematological malignancy with median age of diagnosis between 65–70 years. Since the introduction of multiple novel agents in MM management, survival times of MM patients continue to improve. Longer survival in patients with MM may be associated with increased risks of developing second primary malignancies (SPM). In this study, we investigated the risk factors associated with SPM and survival among MM survivors from 1975 to 2018. Age, race, and sex were important factors for the risk of SPM. Moreover, after SPM development, MM patients had a statistically significant 1.4-fold increased risk of death than MM patients without SPM. Site- and time-specific surveillance strategies surveillance strategies should be recommended to monitor SPM in high-risk MM patients.As the survival times for multiple myeloma (MM) patients continue to extend, the risk of a second primary malignancy (SPM) among MM survivors has become a topic of increasing concern within the medical community. The Surveillance, Epidemiology, and End Results (SEER) 9 Registry Database was used to evaluate the risk and survival of SPM among MM survivors from 1975 to 2018. The standardized incidence ratio (SIR), absolute excess risk (AER), and cumulative incidence (CMI) of SPM for MM risk were calculated. Survival and the CMI were estimated by using hazard ratios (HRs). Subgroup analyses were performed according to race, sex, age, time of myeloma diagnosis, and the SPM site. A total of 43,825 cases were recorded with the initial diagnosis of MM from 1975 to 2018. A total of 3101 (7.1%) patients developed 3407 SPMs. Solid tumors were decreased in patients with MM (SIR = 0.93; 95% CI = 0.90–0.97) compared to the general population, whereas the risk of hematological malignancy was increased (SIR = 1.90; 95% CI = 1.72–2.10). Taking death as a competing event, the CMI of SPM in the whole population was 7.38% at 10 years (6.11% solid and 1.27% hematologic). Factors associated with SPM occurrence were age, sex, race, and time of MM diagnosis. The survival of SPM patients from MM diagnosis was longer than that of patients without SPM (HR = 0.67, 95% CI = 0.58–0.63). The median survival time was 17 months from SPM diagnosis and 34 months from MM diagnosis (HR = 1.4, 95% CI = 1.35–1.46). Age, race, and sex were important factors for the risk of SPM. Site- and time-specific surveillance strategies should be recommended to monitor SPM in high-risk MM patients.

ALL-346 Acute Lymphoblastic Leukemia Following Multiple Myeloma Therapy: A Single-Center Experience With 9 Patients

Patients with multiple myeloma (MM) have an increased risk of developing second malignancies, especially myeloid neoplasms (t-MDS/AML). However, little is known about the occurrence of lymphoid malignancies, in particular acute lymphoblastic leukemias (ALLs). We retrospectively analyzed the disease characteristics and outcomes of patients diagnosed with ALL following MM who presented to the MD Anderson Cancer Center between 2005 and 2018. A total of 9 patients were identified. The majority of patients were female (88%). The median age at the time of MM diagnosis was 67 years (range, 48-74) and 75 years (range, 54-85) at the time of diagnosis of ALL. All patients were receiving lenalidomide as part of MM therapy when they developed ALL. The median time from the diagnosis of MM to ALL diagnosis was 6.8 years (range, 0.33-9.86). All patients were diagnosed with Philadelphia chromosome-negative B-ALL, with a median blast percentage in the bone marrow of 83% (range, 45-100). Of the 9 patients, 3 had complex karyotype with monosomy 13/trisomy 4,5,9,15, 4 patients had a detected mutation of TP53, and 1 patient showed MLL rearrangement. Treatment of B-ALL consisted of a mini-hyper-CVD regimen (n=3) or mini-hyper-CVD + inotuzumab (n=6); 6 patients received blinatumomab as part of the consolidation therapy. Eight patients achieved CR after induction therapy. All patients during ALL diagnosis were MM free; however, 1 patient relapsed with MM after completion of ALL therapy. The median OS from the time of ALL diagnosis was 2.7 years (range, 0.46-5.21). B-ALL can occur in patients with MM with a median latency of 6.8 years. All patients were receiving lenalidomide at the time of diagnosis of ALL. All patients in our series had Ph-neg B-ALL, and 4/9 had a concomitant TP53 mutation.

Newly Diagnosed Multiple Myeloma Patients with Skeletal-Related Events and Abnormal MRI Pattern Have Poor Survival Outcomes: A Prospective Study on 370 Patients.

Contemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among newly diagnosed MMs (NDMM) and to explore the possible correlations with disease characteristics, imaging finding, and patient prognosis. A total of 370 patients with available baseline MRIs were included. Among them, 208 (56%) presented with at least one SRE at diagnosis. Fractures were the most common reported SREs (48%). The incidence of SREs at diagnosis was higher in patients with osteolytic lesions, abnormal MRI pattern, hypercalcemia, and at least 60% bone marrow infiltration by plasma cells. Importantly, the patients with normal MRI pattern, who did not present with SREs at diagnosis, had statistically significant improved median OS in comparison with the patients who had abnormal MRI patterns and/or the presence of SREs at diagnosis (9.3 vs. 6.6 years, p = 0.048). Our data, which represent one of a few systematic reports on the incidence and characteristics of SREs in the era of novel agents, was indicative of a high incidence of SREs at the time of MM diagnosis. Early detection of myeloma bone disease and tailored patient management are essential to optimize patient outcomes.

Assessment of Molecular Residual Disease Using Circulating Tumor DNA to Identify Multiple Myeloma Patients at High Risk of Relapse.

BackgroundDespite treatment with high-dose chemotherapy followed by autologous stem cell transplantation (AHCT), patients with multiple myeloma (MM) invariably relapse. Molecular residual disease (MRD)-negativity post-AHCT has emerged as an important prognostic marker predicting the duration of remission. Current techniques for MRD assessment involve bone marrow (BM) aspirate sampling, which is invasive, subject to sample variability and is limited by spatial heterogeneity. We compared the performance of a non-invasive, circulating tumor DNA (ctDNA)-based MRD assay with multiparameter flow cytometry (MFC) of marrow aspirate to predict relapse in AHCT recipients with MM.MethodsMRD assessment using ctDNA was retrospectively analyzed on 80 plasma samples collected at different time points from 28 patients, post-AHCT. MFC was used to assess MRD from BM biopsy. Individual archived BM aspirate slides or formalin-fixed paraffin-embedded slides from the time of MM diagnosis and matched blood were used to assess MRD at 3 months, post-AHCT, using a personalized, tumor-informed ctDNA assay.ResultsctDNA was detectable in 70.8% (17/24) of pre-AHCT patients and 53.6% (15/28) of post-AHCT patients (3-month time point). Of the 15 post-AHCT ctDNA-positive patients, 14 relapsed on follow-up. The median PFS for ctDNA-positive patients was 31 months, and that for ctDNA-negative patients was 84 months (HR: 5.6; 95%CI: 1.8-17;p=0.0003). No significant difference in PFS was observed in patients stratified by MFC-based MRD status (HR 1.2; 95%CI: 0.3-3.4;p=0.73). The positive predictive value for ctDNA was also significantly higher than MFC (93.3% vs. 68.4%).ConclusionsThis study demonstrates tumor-informed ctDNA analysis is strongly predictive of MM relapse.

Pathogenesis of Extramedullary Multiple Myeloma: From Resistance to Identification of Novel Therapeutic Targets

IntroductionExtramedullary disease (EMD) is a less frequent manifestation of multiple myeloma (MM), where MM plasma cells become independent of the bone marrow (BM) microenvironment and infiltrate other tissues and organs. The incidence of EMD is increasing and is associated with worse prognosis and drug resistance. The specific and efficient treatment is lacking. Therefore, a better understanding of EMD pathogenesis is desperately needed.AimsTo identify biological pathways leading to EMD development and to evaluate therapeutic targets in EMD plasma cells with further focus on EMD tumor microenvironment to reveal presence of effector immune cells that are crucial for immunotherapy.MethodsTo identify EMD specific genes, FACS/MACS sorted aberrant plasma cells were collected from: i) fresh 11 EMD relapse tumors for which we had ii) 7 corresponding cryopreserved paired BM samples from the time of MM diagnosis (NDMM), iii) 9 unpaired fresh NDMM without EMD confirmed by PET-CT and iv) 6 unpaired fresh relapsed MM (RRMM). For library preparation, we used total RNA with rRNA depletion protocol and Illumina sequencing. Residual rRNA was filtered out by SortMeRNA. Differential expression analysis was performed using Salmon for read mapping and quantification and Deseq2 package. For single-cell RNAseq we used 10x Genomics technology for sequencing and CellRanger and Seurat for data processing and analysis.ResultsTo better understand the aggressive nature of EMD, we have analyzed bulk RNA samples (7 EMD samples plus 7 corresponding cryopreserved paired BM samples from the time of MM diagnosis). Our preliminary analysis revealed a unique EMD profile (Fig 1A) with 423 up-regulated and 421 down-regulated genes in EMD samples (adjusted p-value < 0.1; absolute fold change > 1.5), with G2M checkpoint proteins being the most enriched hallmark pathways pointing to higher proliferation of EMD cells. EMD down-regulated genes mainly belong to genes of the adaptive immune response which together with lower immunoglobulin production suggest loss of mature plasma cell function.Among the top genes uniquely overexpressed in EMD (versus RRMM or NDMM) were SCD and ELOVL6 that regulate crucial steps in unsaturated fatty acids synthesis. Also their transcription factor SREBF1 was significantly up-regulated. The importance of these genes in EMD pathogenesis can be supported by the involvement of SREBP1 in stem cell differentiation and mediation of bortezomib resistance by ELOVL6 (Yi et al. 2018, Lipchick et al. 2021). Our dataset also revealed several deregulated lncRNA in EMD compared to NDMM. MALAT1 was highly expressed, however, we did not confirm results by Handa et al. 2017 showing lncRNA MALAT1 as upregulated in EMD.Furthermore, we aimed to evaluate expression of known immunotherapy MM targets being currently in use or under investigation. We compared the information about expression level in EMD vs paired NDMM, with unpaired NDMM without EMD lesion confirmed by PET/CT, and with RRMM. The analysis revealed a decrease in the expression of several antigens commonly used in anti-MM immunotherapy (e.g. CD38, SLAMF7, BCMA or PDL1) on EMD PCs (Fig 1B). Intriguingly, our data show EMD specific elevated expression of EZH2 gene being promising target in preclinical MM investigation which can prove efficient especially for the aggressive MM stage - EMD.Effective immunotherapy depends on the presence of effector immune cells. Therefore, we have evaluated immune cell types and their proportion in EMD tumors. Using flow cytometry we identified T and NK cells as the only immune cell subsets present in EMD tumors (median 0.9% and 0.5%, respectively). Single-cell RNAseq analysis of two EMD samples supported these findings.ConclusionsHere, we present up to our knowledge the worldwide largest cohort of 11 EMD samples (including 7 longitudinal pre-EMD/EMD samples) analysed using RNAseq with focus on biological pathways and dysregulation of particular genes leading to EMD development. Drop of expression of several known drug targets may suggest limited efficacy of the modern treatment in EMD as already presented by Jelinek et al., 2021. Importantly, we are also providing the initial insight into the microenvironment (including single-cell RNA analysis) of EMD tumors, where we detected presence of T cell and NK cells in very limited numbers. [Display omitted] DisclosuresHajek: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Pharma MAR: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Clonal Hematopoiesis Prevalence Increases throughout Treatment of Newly Diagnosed Multiple Myeloma Patients

Clonal Hematopoiesis Prevalence Increases throughout Treatment of Newly Diagnosed Multiple Myeloma Patients

Survival Analysis of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients in Czech Republic

Introduction: Although highly effective agents and novel therapeutic strategies are being developed, high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) has not been overcome in the first-line treatment for fit patients (pts) with multiple myeloma. The objective of this work is to retrospectively analyze the use of this procedure in newly diagnosed Czech patients.Methods: Data were derived using the Czech Myeloma Group Registry of Monoclonal Gammopathies. By February 2 nd 2021, a total of 2154 newly diagnosed multiple myeloma patients who underwent HDT/ASCT were identified.Results: At the time of multiple myeloma diagnosis, the median age was 59 years; 24%/56%/14%/5%/1% pts were ECOG 0/1/2/3/4; 44%/32%/24% pts were ISS stage I/II/III; 14.5%/17.5%/68% and 84%/16% pts were Durie-Salmon stage I/II/III and subclassification A/B, respectively. The combinations of agents used in the induction regimen were proteasome inhibitor (PI), immunomodulatory drug (IMiD) and glucocorticoid (GC) in 28.5% (613/2154) pts; PI, GC and chemotherapy (CHT) in 24.8% (534/2154) pts; GC and CHT in 22,5% and IMiD, GC and CHT in 16.1% (346/2154). Other combination of drugs was used in 8.2% (177/2154) pts. It was registered that 3.7% (79/2154) induction regimens were switched to a different combination because of toxicity, patient's choice, poor peripheral venous access or other reasons. Single HDT/ASCT was performed in 77.3% (1665/2154) cases whereas tandem HDT/ASCT was given to 11.8% (254/2154) patients. In 10% (215/2154) cases, the transplantation technique was not specified. Nine percent (193/2154) patients were treated within a clinical study. The median progression free survival (mPFS) and the median overall survival (mOS) of the whole cohort was 28.9 and 92.1 months, respectively. Information about response to treatment before and after the high-dose therapy were available for 75.7% (1627/2154) and 92.2% (1987/2154) patients, respectively. Disease status at the time of HDT/ASCT was defined as stringent complete response (sCR) at 2.2% (36/1627), complete response (CR) at 11.9% (194/1627), very good partial response (VGPR) at 38.2% (621/1627), partial response (PR) at 40.9% (666/1627), minimal response (MR) at 3.6%, (58/1627), stable disease (SD) at 2.2% (36/1627), progressive disease (PD) at 1% (16/1627) patients. The overall response rate (ORR) on day 100 was 92.8% (sCR: 10.5% [209/1987], CR: 22.4% [446/1987], VGPR: 35% [696/1987], PR: 24.8% [493/1987], MR: 2.7% [54/1987], SD: 1.4% [27/1987], PD: 3.1% [62/1987]). We also performed a survival analysis of patients progressing up to 18 months after HDT/ASCT (n=1219) versus patients progressing in more than 18 months (n=935). The median OS was 41.5 versus 124.9 months, respectively. An analysis of the role of tandem HDT/ASCT in this real-world cohort will be presented at the conference.Conclusion: Globally as well as in the Czech Republic, HDT/ASCT is an important therapeutic approach in the first-line treatment of multiple myeloma. Our analysis of 2154 newly diagnosed transplant-eligible patients confirms high effectiveness - ORR of 92.8%, mPFS of 28.9 months, and long-term survival reaching mOS of 92.1 months. DisclosuresMinarik: Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Shingles Occurs in Only 0.5% of Myeloma Patients on Any Dose of Antiviral Prophylaxis

Background: CDC estimates that approximately 30% of persons in the U.S. will experience shingles during their lifetimes (http://www.cdc.gov/shingles/surveillance.html). The incidence among people 60 years of age and older is about 10 cases per 1,000 U.S. population annually. With a median age of 70 y.o. and frequent proteasome inhibitor use (Kim SJ et al, Clinical lymphoma & myeloma, 2008), multiple myeloma patients often receive scheduled prophylaxis for shingles with acyclovir or valacyclovir; however, there are currently no guidelines on the appropriate dosage for the prevention of shingles. Recent studies have used antiviral doses of acyclovir 2400mg/day to as low as acyclovir 200 mg/day to prevent shingles (Pour L et al., Clinical lymphoma & myeloma 2009; Kim SJ et al., Jpn J Clin Oncol 2011), but doses of 200-800 mg acyclovir per day are common in clinical practice. By reviewing all myeloma patients treated over the last 6 years, we hypothesized that a less than 1% failure rate can be achieved using the equivalent of acyclovir 400 mg twice daily in a patient with normal renal function. In addition, based on the findings of a recent study (Dosani T et al., Blood, 2017), which demonstrated that ALC/AMC ratio at time of multiple myeloma diagnosis can be used as an indicator of baseline immune status, we hypothesized in this present study that multiple myeloma patients who had shingles have a significantly lower ALC/AMC ratio on average than patients who did not have shingles.Methods: A retrospective chart review was conducted on 1,210 multiple myeloma patients treated at The Ohio State University Wexner Medical Center. In addition to demographic information on age, gender, age at multiple myeloma diagnosis, multiple myeloma stage and karyotype, and length of survival, information on the presence of shingles after the diagnosis of multiple myeloma, medication and dosage of prophylactic antivirals, and compliance to medication was also collected. For patients who developed shingles and were compliant with prescribed antiviral medication, their effective dose of antiviral was determined by dividing their dose of antiviral per day by their estimated GFR at the time of shingles diagnosis. Valacyclovir was converted to an equivalent dose of acyclovir (acyclovir 400 mg = valacyclovir 250 mg). GFR was determined by the CKD-EPI method, using serum creatinine and weight values taken near the time of shingles diagnosis. ALC/AMC ratios were estimated using ALC and AMC values taken near the time of multiple myeloma diagnosis. Patients with shingles were compared to an equal number of age- and gender-matched controls using a Wilcoxon rank-sum test, and patients with no ALC or AMC values taken near time of diagnosis were excluded from final comparison.Results: Demographic information on the patients included in this study can be found in Table 1. Out of 1210 multiple myeloma patients, 127 patients (10.5%) developed shingles after diagnosis, and of these, only 6 patients (0.5%) were both prescribed a prophylactic antiviral (acyclovir or valacyclovir) and were compliant with their antiviral medication (Figure 1). Most patients (77%) were not receiving antiviral prophylaxis, and even if antivirals were prescribed, only 21% were compliant. The average time from multiple myeloma diagnosis to shingles diagnosis was 1.7 years. For patients prescribed acyclovir prophylaxis, doses ranged 0-2400 mg/day, with most patients (62%) taking 800mg/day and 49% of patients taking 400mg/day (Table 2). Percentages do not add up to 100% since many patients had their doses changed over time. ALC/AMC ratios were not significantly different (p=0.78) between patients with shingles vs controls (Figure 2).Discussion: Shingles occurred in 10% of myeloma patients during the retrospective period. Only twenty percent of myeloma patients that suffered a shingles exacerbation were prescribed an antiviral, and, if they were prescribed an antiviral, only 6 of 127 (4.7%) patients who developed shingles were taking prophylactic antivirals as prescribed. Given a compliance rate of 20.7% among patients diagnosed with shingles, compliance more than dose should be emphasized in preventing shingles exacerbations. This highlights the value of patient education and compliance strategies to decrease patient morbidity in clinical practice (Bender BG, JAMA Pediatr, 2015). [Display omitted] DisclosuresHofmeister:Janssen: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding.

Targeted Next Generation Sequencing of Circulating Tumor DNA in Multiple Myeloma

Introduction: Immunophenotypic and chromosomal analysis among patients with multiple myeloma (MM) has traditionally been performed on plasma cells enriched from bone marrow aspirates. However, due to the patchy nature of MM, a bone marrow aspirate may not accurately represent the total body burden of disease nor does it reflect the true heterogeneity of the cancer cells. Additionally, since it is an invasive procedure, frequent resampling to monitor clonal evolution is infeasible. Next generation sequencing of circulating tumor DNA is a promising new approach that may address these shortcomings. Circulating tumor DNA, either from cell-free DNA or circulating tumor cells, originates from multiple different sites of disease and may be obtained from a single blood sample. This non-invasive approach may enable clinicians to detect early signs of resistance, monitor minimal residual disease, identify therapeutic targets, and provide prognostic information to help guide treatment decisions.Methods: Bone marrow mononuclear cells (BMMC), peripheral blood mononuclear cells (PBMC), and plasma samples were obtained from 45 patients treated at our center at the time of MM diagnosis, remission, or disease relapse. All samples were obtained through an Institutional Review Board approved protocol. DNA was extracted and library preparation for next generation sequencing was performed using unique molecular identifiers (UMI). The incorporation of UMIs allows for the identification and removal of errant base calls introduced during PCR amplification and Illumina sequencing thereby increasing the sensitivity of the assay to detect rare mutations. Target enrichment was performed using a panel of primers specific to exons of genes known to be significantly, recurrently mutated in MM as well as genes with predictive or prognostic value. Illumina sequencing was performed to a depth of 10,000X. Comparison of single nucleotide variants (SNV) and indels between matched BMMC, PBMC and plasma samples was determined. Correlation of clinical outcomes with mutation status and variant allele frequency was performed.Results: While good concordance was found between BMMC, PBMC, and plasma samples among the SNVs and indels detected, distinct variants unique to each tissue compartment were also identified. Indicating the assay may have utility for disease monitoring, variants detected in the blood pre-treatment were no longer detectable in post-treatment remission samples. Additionally, new variants in blood samples not present prior to initiation of therapy were detected at later time points providing evidence for clonal evolution. Finally, driver mutations were found in genes for which known targeted therapy is available or in genes that may theoretically confer drug resistance such as CUL4A that binds to Cereblon, a target of the immunomodulatory drug lenalidomide.Conclusions: While bone marrow biopsy represents the standard of care for diagnosis and disease monitoring in patients with multiple myeloma, the procedure is subject to sampling bias and frequent serial biopsies are impractical. A noninvasive approach using targeted next generation sequencing of circulating tumor cells is an appealing alternative. We demonstrate the feasibility of this technique in MM PBMC and plasma samples and find evidence that the assay may support clinical decision making. DisclosuresNo relevant conflicts of interest to declare.

Time from First Symptom Onset to the Final Diagnosis of Multiple Myeloma — Possible Risks and Future Solutions: Large Retrospective and Confirmatory Prospective ‘Deutsche Studiengruppe Multiples Myelom’ (DSMM) Analysis

Introduction: Since Multiple Myeloma (MM) has seen major advances in the understanding and management of the disease, among them revised disease definitions and recognition of early diagnosis-defining events, early diagnosis and treatment initiation, especially of symptomatic patients (pts), have been advocated by the international and European MM working groups. As a consequence, prompt recognition of MM is essential. However, since MM represents a frequently insidious developing malignancy and may appear with unspecific symptoms, e.g. bone pain or anemia symptoms, this can obscure diagnosis finding and result in substantial delays until the correct diagnosis is made. Objective literature and larger group analyses are lacking and potential risks, which may lead to delayed MM recognition, remain as yet undetermined. This ongoing DSMM project addressed this aspect with the aim to optimize prompt diagnosis finding and to consequently further improve the quality of MM care.Methods: We performed an initially retrospective analysis in 101 MM pts, followed by a prospective study in 176 pts using a structured MM-specific questionnaire, which was developed within our MM research group, with our comprehensive cancer center and statisticians. The questionnaire consists of 9 items and was initially tested in 10 healthy volunteers in 5 successive rounds, until utmost comprehensibility and perfection were achieved. For both analyses, all available pt medical reports on the duration and type of the initial symptoms leading to the diagnosis of MM were assessed and putative risks for possible delays were determined. The subsequent prospective study was complemented with this questionnaire. This included assessment of pts' satisfaction with the diagnostic process and their suggestions, how it could be improved in the future. The trial protocol and MM-questionnaire were approved by the ethics committee. All pts provided written informed consent and all procedures were conducted in accordance with the Declaration of Helsinki and GCP guidelines.Results: The retro- and prospective MM cohorts showed comparable pt characteristics with typical age and MM features for tertiary centers.The median time from pts' first symptoms to the final MM diagnosis was 4 months (ms; 0.5-120) in the retrospective cohort, and similar in the prospective group with 6 ms (0.5-60). Both analyses showed substantial variations of prompt to much longer latencies (Fig.1A). Of note, 20% in the retrospective analysis and 35% in the prospective study showed a prolonged duration of ≥12ms from symptom onset until the diagnosis of MM was made (Fig.1A). Frequencies of MM-related pathologic bone fractures, renal and infectious complications, occurring before the initial MM diagnosis, were substantial with 41%, 35% and 16%, respectively. 34% of pts had none of these complications at the time of MM diagnosis, 43% had one, 20% two and 3% three complications. Although the most frequent symptom was bone pain, occurring in 73% of MM pts before the final MM diagnosis was made, only 6% of MM diagnoses were first suspected by orthopedists, whereas by nephrologists in 16%, although renal impairment was less frequent (Fig.1B). The final diagnosis of MM was most often made by tertiary centers (81%), followed by outpts' hematologist/oncologist practices (10%) and general practitioners (5%). Of interest, 61% of pts were completely or rather satisfied with the diagnostic process, whereas 39% were less satisfied (Fig.1C). Many more pts than the latter group with 39%, namely 58% of pts, believed that their disease could have been diagnosed more expeditiously (Fig.1D). Those pts, who criticized the longer diagnostic process vs. those that did not, showed a much longer median time interval from symptom onset to their final MM diagnosis of 9 vs. 3 ms. Risks for delays in diagnosis finding were light-chain-only MM, prior orthopedic and rheumatologic comorbidities disguising MM, longer distance to referral centers and pts' residence in smaller rural areas.Conclusions: Considerable latencies in diagnosis finding of ≥12 ms may occur in MM pts showing unspecific symptoms like bone pain and/or anemia. Longer time intervals from the onset of first symptoms to the MM diagnosis substantially influence pts' coping with their disease and their satisfaction with their MM center. Subsequent analyses aim to generate further insights, how prompt MM diagnosis can be achieved. [Display omitted] DisclosuresEngelhardt:German Cancer Aid (#11424): Other: Educational Grant; Janssen Cilag GmbH: Other: Educational Grant; Celgene GmbH: Other: Educational Grant; Amgen GmbH: Other: Educational Grant.

Real World Outcomes of Newly Diagnosed High-Risk Multiple Myeloma Patients Treated at Princess Margaret Cancer Centre: A Retrospective Chart Review

Background: In the era prior to the availability of novel agents, we have previously reported that the median progression-free survival (PFS) and overall survival (OS) of high-risk (HR) multiple myeloma (MM) patients (pts) undergoing a single autologous stem cell transplant (ASCT) was only 9.9 and 18.3 months, respectively (Chang H et al., Bone Marrow Transplant, 36 (2005), 793). The current study expands our experience in newly diagnosed HR pts and focuses on the outcomes in pts treated with single or tandem ASCT.Methods: A retrospective chart review of myeloma pts was conducted based on pt information retrieved from the Princess Margaret Myeloma Database. 245 pts with HR MM diagnosed and treated in our centre from Oct 1998 to Dec 2016 were identified. Survival rates were calculated using the Kaplan-Meier product-limit method and the log rank-statistic was used for comparison of survival curves.Results: Pts were considered HR based on the presence of any one of the cytogenetic features: t(4:14) (71%), t(14:16) (36%), and chromosome 17p deletion (42%). Characteristics at the time of MM diagnosis of the 245 pts identified as HR are summarized in Table 1. The median age was 60.9 years. First-line therapy included the following: tandem ASCT in 86 pts (35%), single ASCT in 84 pts (34%), and no ASCT in 75 pts (31%). Of the 170 pts who underwent single or tandem ASCT, 119 (70%) received maintenance therapy post-ASCT, including 84% of the tandem ASCT pts and 56% of the single ASCT pts.Median follow-up was 29.3 months (range 1.1-123.7). The median PFS from date of diagnosis of all HR pts was 33.1 months [95% CI 29.3-37.0 months], while the median OS was 79.2 months [95% CI 58.3-90.9 months]. Both PFS (p= 0.0003) and OS (p= 0.0011) were significantly affected by first-line therapy with a median PFS of 53.1 vs 32.9 vs 21.8 months and median OS of 88.5 vs 71.9 vs 55.0 months in pts treated with tandem ASCT, single ASCT and no ASCT, respectively. Tandem ASCT pts had improved PFS and OS survival at 1, 2, and 5-years compared to single and non-transplant pts (Fig. 1A & B). Age at diagnosis significantly affected the PFS (p= 0.0003) and marginally affected the OS (p= 0.0748), likely due in part to our policy for the preferential use of fixed-duration non-ASCT as first-line therapy in older individuals (typically ≥70 years of age). On the other hand, serum beta 2- microglobulin levels correlated significantly with OS (p= 0.0023) while the association with PFS was not significant. Among ASCT pts, those who received tandem ASCTs vs single ASCT demonstrated a significantly better PFS (p= 0.0039) and showed a trend for improved OS (p= 0.0707). Amongst pts who received single ASCT, those with maintenance vs no maintenance demonstrated significantly better PFS (p=0.0082). Finally, pts with both t(4:14) and 17p deletion (28 pts) had a significantly decreased PFS (p= 0.0414) and a trend for decreased OS (p= 0.0621) compared to those with only one abnormality (Fig. 1C & D).Conclusions: Although adverse factors such as older age and co-morbidities likely affected the ability to perform 1 or 2 autografts and likely introduced bias into our analysis, our data nevertheless suggest that tandem ASCT is an effective approach in extending PFS and OS among HR MM pts when compared to single transplants or none at all in the real-world setting. Multivariate analysis is underway to further delineate the factors contributing to PFS and OS in HR pts. As in other transplant studies, the PFS is improved in pts who receive maintenance therapy after single ASCT. Efforts should be made to offer newly diagnosed HR MM pts a program that includes tandem transplantation, if feasible, as well as maintenance therapy post-transplant. Pts with “ultra HR” MM, i.e., those with both t(4;14) and 17p deletion, require new innovative approaches. [Display omitted] DisclosuresReece:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Paid expert testimony, Research Funding, Speakers Bureau; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Paid expert testimony, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka: Research Funding. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria; Amgen: Honoraria. Kukreti:Celgene: Honoraria; Amgen: Honoraria. Prica:Janssen: Honoraria; Celgene: Honoraria. Tiedemann:BMS Canada: Honoraria; Celgene: Honoraria; Takeda Oncology: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Trudel:Janssen: Research Funding; Amgen: Consultancy, Honoraria; Astellas: Research Funding; Celgene: Consultancy, Honoraria; Takeda: Honoraria; GlaxoSmithKline: Research Funding.