Standard-risk Cytogenetics Research Articles

Therapeutic Outcomes of Relapsed-Refractory Multiple Myeloma Patients with 1q21+Treated with Daratumumab-Based Regimens: A Retrospective Analysis

Introduction: Gain/amplification of 1q21 (1q21+) is detected in approximately 40% of MM patients (pts) at diagnosis. There is emerging data that 1q21+ has a negative impact on prognosis in both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) pts even when treated with highly efficacious novel agents such as bortezomib (Bor), lenalidomide (Len), pomalidomide (Pom), carfilzomib (Car), and daratumumab (Dara). However, a recent pooled subgroup analysis of the phase 3 ICARIA-MM and IKEMA trials revealed that the addition of the isatuximab (Isa) to the backbone of Pom-dexamethasone (Dex) or Car-Dex, respectively, improved progression free survival (PFS) in RRMM pts with 1q21+. The benefit of Dara-based regimens in pts with RRMM harboring 1q21+ abnormalities is currently unknown. We evaluated the efficacy of Dara-based regimens in pts with RRMM harboring 1q21+. Methods: We identified consecutive MM pts who received a Dara-based regimen, between 1/2015 and 4/2019 at the Mayo Clinic Comprehensive Cancer Center's three sites (Rochester MN, Scottsdale AZ, Jacksonville FL). We included pts who had received any Dara-based regimen after 1-3 prior lines of therapy. 1q21+ abnormality was defined as gain of 1q21 [gain(1q21), 3 copies] and amplification (amp) of 1q21 [amp(1q21), ≥4 copies] on FISH. High-risk cytogenetics (HRCyto) was defined as FISH testing that was positive for t(4;14), t(14;16), t(14;20) or del(17p). Pt categories for analysis were: (1) with or without 1q21+, (2) standard-risk cytogenetics (SRCyto) vs. 1q21+ as the only cytogenetic abnormality, (3) HRCyto with or without 1q21+. Fisher's exact test was used to compare differences between categorial values and PFS was analyzed using Kaplan-Meier analysis. Results: 368 pts were identified, 278 had received a Dara-based regimen after 1-3 lines and 232 had FISH testing done and were included in the analysis. All pts received either Dara single agent, Dara-Len-Dex, Dara-Pom-Dex, or Dara-Bor-Dex. No pts received Dara-Car-Dex. Baseline characteristics are shown in Table 1. 1q21+ was noted in 57 pts (1q21 amp: 4, 1q21 gain: 53). The median follow-up time for the entire cohort was 35.7 months (m) (95% CI: 25.2-NR). The median PFS for 1q21+ pts treated with a Dara-based regimen was 24.6 m (95% CI: 19.9-29.4). The overall response rate (ORR) for pts with 1q+ treated with a Dara-based regimen was 57.9%; sCR: 1 (1.75%), CR: 3 (5.26%), VGPR: 9 (15.8%), and PR: 21 (36.8%). SD was noted in 16 (28%) pts. There were no PFS differences (p=0.956) or ORR differences (p=0.776) between the different Dara-based regimens used in pts with 1q21+. There were no PFS differences for pts with 1q21+ vs. pts without 1q21+; 24.5 m (95% CI: 18.6-29.4) vs. 23.5m (95% CI: 21.1-28.1), respectively; p=0.392. There were also no differences in ORR (p=0.09) for pts with 1q21+ vs. pts without 1q21+ treated with a Dara-based regimen. There were no PFS differences amongst pts with HRCyto without 1q21+ vs. pts with HRCyto and 1q21+; 23.5 m (95% CI: 20.7-NR) vs. 24.6 m (95% CI: 18.0-HR), respectively, p=0.507. Similarly, there were no ORR differences (p=0.127) between pts with HRCyto without 1q21+ vs. pts with HRCyto with 1q21+. Lastly, looking at pts with SRCyto vs. 1q21+ as the sole cytogenetic abnormality, there were no significant PFS differences [23.1 m (95% CI: 19.4-28.1), vs. 24.6 m (95% CI: 19.8-34.8), respectively, p=0.64] or ORR differences (p=0.075). Conclusion: Since 1q21+ is seen fairly frequently in pts with MM, its role as an independent prognostic marker as well as biomarker to guide treatment selection is being defined. While there is emerging data that Isa-based regimens can improve the PFS and ORR of patients with RRMM with 1q21+, we noted that for RRMM pts treated with Dara-based regimens, outcomes for pts with 1q21+ are similar to those with standard risk disease or other HRCyto markers. The lack of PFS and ORR differences seen regardless of 1q21+ status with Dara-based regimens could suggest that Dara-based treatment may abrogate the poor outcomes associated with the presence of 1q21+. To further explore the importance of 1q21+ as a therapeutic and prognostic biomarker in MM, existing data from large, randomized, prospective phase 3 trials needs to be pooled and analyzed to evaluate the role of anti-CD38 monoclonal antibodies in pts with 1q21+. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intravenous Immunoglobulin Prophylaxis Is Associated with Decreased Rate of Infection-Related Hospitalizations in Multiple Myeloma Patients

Introduction: Infections are a significant cause of hospitalizations, morbidity, and mortality in multiple myeloma (MM) patients. The aim of this study was to determine the efficacy of intravenous immunoglobulin (IVIG) prophylaxis in reducing infection-related hospitalizations (IHs) in MM patients. Methods: This was a retrospective study of MM patients who received IVIG at Taussig Cancer Center between July 2009 and July 2021. IVIG was initiated at the discretion of the treating oncologist based upon serologic hypogammaglobulinemia (HGG) and recurrent infections. Patients received IVIG at doses of at least 0.4mg/kg every 30 to 60 days during periods of IVIG. The duration of each period of IVIG was determined by the treating oncologist based upon recovery of serum IgG levels. Patients could require multiple periods of IVIG and there could be intervals of months to years between periods of IVIG. Data was collected from 1 year prior to a patient's first IVIG period to 1 year after their last IVIG period. A patient's study period was divided into time "on-IVIG" and time "off-IVIG": the 60-days following a dose of IVIG was categorized as on-IVIG while all other time periods were categorized as off-IVIG. IHs were labeled as occurring on-IVIG or off-IVIG if the infection was initially diagnosed while the patient was on-IVIG or off-IVIG. Patients who did not have at least 60 days on-IVIG, 30 days off-IVIG and 1 IH during their study period were excluded. Data was collected on baseline patient characteristics, MM disease characteristics, treatment history, IVIG administration and infection characteristics. Severe HGG (sHGG) was defined as serum IgG levels <400 mg/dL. Patients were labeled as having a 1 year period of continuous IVIG if they received a dose of IVIG at least every 60 days for 365 days. Cytogenetic risk was defined using the International Myeloma Working Group criteria. The primary endpoint was the rate of IHs per patient-year on-IVIG vs. off-IVIG. Secondary endpoints were mean length of hospital stay and ICU stay for IHs on-IVIG vs. off-IVIG. Continuous and categorical variables were analyzed using paired t-test and chi-squared test respectively. Results: Of 395 patients who were screened, 108 were included. Novel agent exposure was broad and included proteasome inhibitors (106, 98.1%), immunomodulatory drugs (103, 95.4%) and monoclonal antibodies (63, 58.3%). Patients spent a total of 81,871 days on-IVIG and 71,303 days off-IVIG with each patient spending a median 758 days on-IVIG and 660 days off-IVIG. There were 271 total IHs in the study with 107 (39.5%) occurring on-IVIG and 164 (60.5%) occurring off-IVIG. Of the 271 total IHs, respiratory was the most common infectious source (158, 58.3%). 20 (18.7%) of the 107 IHs that occurred on-IVIG required intensive care unit (ICU) stay while 30 (18.3%) of the 164 IHs that occurred off-IVIG required ICU stay. There was a significant difference in the primary endpoint of rate of IHs per patient-year on-IVIG vs. off-IVIG in the overall study population (.81 vs. 1.08; Mean Difference [MD], -.27; 95% Confidence Interval [CI], -.57 to .03; P value [P] = .04). Subgroup analysis showed that patients with a 1 year period of continuous IVIG (49, 45.3%) had a significant reduction in IHs per patient-year while on-IVIG vs. off-IVIG (.48 vs. .78; MD, -.30; 95% CI, -.59 to .002; P = .03). The subgroup with standard-risk cytogenetics (54, 50.0%) and the subgroup with 2 or more IHs (67, 62.0%) also showed a significant reduction in IHs while on-IVIG vs. off-IVIG (.65 vs. 1.01; MD, -.36; 95% CI, -.71 to -.01; P = .02) and (1.04 vs 1.43; MD, -.39; 95% CI, -.82 to .05; P = .04) respectively. The subgroup with sHGG (87, 80.6%) and the subgroup with high-risk cytogenetics (20, 18.5%) did not show a significant reduction in IHs while on-IVIG vs. off-IVIG (.79 vs. 1.05; MD, -.26; 95% CI, -.60 to .07; P = .06) and (1.17 vs. 1.01; MD, .16; 95% CI, -.75 to 1.07; P = .64) respectively. For the secondary endpoints of mean length of hospital stay and ICU stay, there was no significant difference between IHs occurring on-IVIG vs. off-IVIG (6.4 days vs. 6.3 days; MD, .10; 95% CI, -1.2 to 1.4; P = .55) and (4.3 days vs. 5.2 days; MD -.90, 95% CI, -3.0 to 1.1; P = .18) respectively. Conclusion: IVIG showed significant benefit in reducing infection-related hospitalizations in the overall population and in multiple subgroups. IVIG should be considered in certain cohorts of MM patients to prevent infection-related hospitalizations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hypercalcemia: A Risk Factor for Early Disease Progression and Poor Survival in Cytogenetically Standard-Risk Multiple Myeloma

Introduction The advent of novel therapies over the last decade, including proteasome inhibitors, immunomodulators, and monoclonal antibodies, has drastically improved the outcomes in patients with Multiple Myeloma (MM). It is common in both clinical practice and design of clinical trials to risk stratify patients to determine poor-prognosis based on known high-risk cytogenetics and baseline health status. Despite efforts to unify and refine the definition of high-risk disease, significant heterogeneity exists within risk strata and the majority of MM patients do not harbor high-risk cytogenetics. Many patients with ostensibly standard-risk disease progress rapidly, exhibiting a clinical presentation that aligns more closely with high-risk disease biology. We retrospectively evaluated outcomes within an institutional database to determine whether variation in prognosis among patients with standard risk MM may be predicted by clinical and biochemical features that are measurable at the point of care. Methods This retrospective cohort study included patients diagnosed with MM at the Cleveland Clinic in Cleveland, OH between 1/1/2008 - 12/31/2015 who had relapsed or died prior to initiation of the study. Patients with conventional high-risk cytogenetic features including: del(17p), t(4;14), t(14,20) or t(14;16) by fluorescence in situ hybridization (FISH) were excluded. Multiple variables at diagnosis were included in the analysis: race, gender, age, serum calcium (Ca), B-2-microglobulin, albumin, kidney function, hemoglobin, involved: uninvolved serum free light chain ratio, lactate dehydrogenase (LDH), serum monoclonal (M) protein, International Staging System (ISS) stage, Eastern Cooperative Oncology Group (ECOG) score, and the presence of extramedullary disease. Hypercalcemia (HCa) was defined using 3 groups - Group 1: Ca <10.0, Group 2: 10.1 - 12.5, and Group 3: > 12.5 mg/dL. Time to event analysis was conducted using the Kaplan Meier method. The impact of clinical and biochemical features at presentation on PFS and OS was quantified using a Cox Proportional Hazard on a univariate and multivariate basis in order to determine risk factors for early relapse among this cohort of patients with standard-risk cytogenetics. Results A total of 264 NDMM patients were screened for high-risk cytogenetics and the 18 patients excluded. An additional 99 patients were excluded from our analysis due unavailable FISH data at diagnosis. Twenty-one patients did not have serum calcium levels available at the time of diagnosis and were excluded, resulting in a study population of 126. Among these patients, the median age was 61.5 years old, 77.6% (n=97) of patients were Caucasian, and 47.6% (n=60) were male. The median time to follow up was 5.2 (2.9-7.0) years. A total of 13.6% had extramedullary disease (n=17) and 25.4% had a frontline autologous stem cell transplant (ASCT) (n=32). Stratification was conducted utilizing ISS stage: 34.4% Stage 1 (n=42), 31.1% (n-38) Stage II, and 34.4% (n=42) and ECOG score: 34.4% (n=42) Score 1, 38% (n=38) Score 2, and 42% (n=34.4) Score 3. The three hypercalcemia groups were similar with regard to demographics, ECOG, and laboratory data; however, ISS stage (23%, 47%, and 73%, p=0.002) and serum creatinine (median 0.96, 1.4, and 2.3 mg/dL, p=0.001) were positively correlated with calcium level at time of diagnosis. There was a statistically significant difference in 2-year PFS among the HCa groups (54.4%, 36.1%, and 9.1%, p = 0.002 and p <0.001, respectively) (Figure 1). There was also a statistically significant difference in OS among the HCa groups (Median OS years/5-year OS: 6.1/65.3%, 4.5/46.9%, 2.4/9.1%, p=0.032 and p <0.001, respectively) as well (Figure 2). Differences in PFS and OS remained significant after adjusting for age, race, ISS stage, extramedullary disease, ECOG. and frontline ASCT. Conclusion Our results showed that serum calcium level predicted disease progression and survival in a large cohort of patients without high-risk cytogenetic features. Variation in outcomes among MM patients who do not harbor high risk cytogenetics has not been fully explained. These results may help to inform clinical decision making, refine current risk stratification models, and identify a subpopulation with the strata of standard risk for correlative studies to evaluate disease genomics and biology. 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

The Role of Corrected Dlco in Predicting Relapse and Mortality Post Autologous Hematopoietic Cell Transplantation in Multiple Myeloma

Introduction: Autologous Hematopoietic Cell Transplantation (AHCT) remains the standard of care for multiple myeloma (MM) patients who achieve at least a partial response to prior chemotherapy. Survival post AHCT is associated with disease risk and patient comorbidities, including lung diseases indicated by pulmonary function. The corrected diffusing capacity for carbon monoxide (DLCOc) is usually assessed in transplant candidates in order to determine AHCT eligibility, although precise DLCOc cut-offs are yet to be standardized. Recent studies suggested that a DLCOc ≤60% possesses a prognostic value in predicting relapse and mortality post AHCT. Hence, we aimed to validate the role of DLCOc ≤60% in predicting post-AHCT outcomes at our institution. Methods: We did a retrospective review of MM patients who underwent AHCT at Cleveland Clinic between January 1st, 2011 and January 15th 2021. The patients were categorized based on their corrected DLCO into two groups: DLCOc ≤60% and DLCOc >60% of the predicted value. Baseline characteristics, including patient, disease, and transplant factors were compared between the two groups. The collected data were analyzed using SPSS and GraphPad Prim by means of Chi square, ANOVA, and Kaplan Meier survival analysis. Results: A total of 466 patients with available DLCOc data were included in our study, of which 38 patients had a DLCOc ≤60% and 428 had a DLCOc >60% of the predicted value. Our cohort had a median follow up of 31.9 months post-AHCT. Patient and disease characteristics were similar between the 2 groups, including age (median 59.1 vs 60.3 years, P= 0.407), sex (Males 65.8 vs 58.2%, P=0.361), standard risk (81.5 vs 66.4%) and high risk (18.5 vs 33.6%) cytogenetic profiles (P=0.107), as well as history of smoking (23 vs 38.2%, P=0.1). In addition, both groups had a similar distribution across the International Staging System (ISS) stages (37.9, 37.9, 24.2% vs 38.3, 38.9, 22.8% for stages I, II and III, P= 0.987) and received similar preparative regimens (92.1, 7.9, 0% vs 96.3, 3, 0.7% for Melphalan 200 mg/m2, Melphalan 140 mg/m2 and Busulfan + Cyclophosphamide, P=0.25). Kaplan-Meier survival analysis showed that the DLCOc ≤60% group survived for a significantly shorter period with median overall survival (mOS) of 27.3 vs 91.7 months (P<0.0001) (Fig 1A). In addition, the DLCOc ≤60% group had earlier relapses with median progression free survival (mPFS) of 21.2 vs 38.7 months (P=0.0115) (Fig 1B). Subgroup analysis confirmed that mOS was significantly shorter in the DLCOc ≤60% group irrespective of relapse, with mOS of 25.4 vs 79.6 months (P<0.0001) in relapsed MM of DLCOc ≤60% (n=18) and DLCOc >60% (n=193) patients, respectively. Similarly, non-relapse survival was also shorter (medians unreached) in the non-relapsed DLCOc ≤60% group (n=20) compared to the non-relapsed DLCOc >60% group (n=235) (P<0.0001). When selecting patients of standard risk cytogenetics from both groups, the significant difference in mOS and mPFS was retained with mOS 51.7 vs unreached months (P<0.0001) and mPFS 21.2 vs 67.7 months (P=0.0051) for DLCOc ≤60% group (n=22) and DLCOc >60% (n=225), respectively. Likewise, matching for melphalan 200 mg/m2 regimen patients further maintained the remarkable gap in mOS 25.4 vs 91.7 months (P<0.0001) and mPFS 20 vs 40 months (P=0.0013) for DLCOc ≤60% group (n=35) and DLCOc >60% (n=413), respectively. Conclusion: The pre-AHCT DLCOc level possesses a useful prognostic value that can predict disease relapse as well as both relapse- and non-relapse related mortality post AHCT. This was demonstrated when using a cut-off value of ≤60% vs >60%. Our findings were supported by the fact that both groups had similar clinical and cytogenetic characteristics, thus reducing the risk of confounding effects. Our findings were also validated when controlling for cytogenetic risks and melphalan dosage. Large, prospective trials are warranted to determine whether DLCOc ≤60% can serve AHCT eligibility criterion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Maintenance Therapy Cessation for Sustained MRD Negative Multiple Myeloma Patients

Introduction Maintenance therapy with lenalidomide (len) and other drugs is a cornerstone therapeutic strategy for sustaining deep durable remissions in multiple myeloma (MM). However, indefinite treatment, as currently recommended, may lead to financial, emotional, and physical toxicity. Current guidelines lack data on optimal duration of maintenance in MM patients (pts) who have achieved sustained negative minimal residual disease (MRD) status. Here, we present the first pre-planned interim results from a phase II study evaluating maintenance cessation in patients with sustained MRD negative status for at least 3 years at the time of enrollment on study. Methods The current two-stage designed study of fifty MM pts, having already demonstrated >3 years of durable MRD negative responses, will be evaluated for MRD negative sustainability after ceasing maintenance therapy. Enrolled pts stop maintenance therapy and undergo active surveillance for three years, including serum protein testing every 3 months, bone marrow MRD testing by multiparametric flow cytometry (single 10-color tube with limit of detection of at least 6x106 (6 cells in 1 million) every 6 months, and annual PET-CTs. Primary endpoint includes sustained MRD negative rate after 1 year. Secondary endpoints include sustained MRD negative rate 3 years of cessation, re-treatment responses, microbiome and immune studies, health-related quality of life outcomes (HRQoL), and progression-free survival (PFS). The first stage includes 15 pts, and if 8 or more remain MRD negative at the end of 1 year, study enrollment continues to stage two (n=35). Results At data cutoff, on July 31, 2022, twenty-three pts (15 - stage 1; 8 - stage 2) have been enrolled on study. Median follow-up was 14.8 months (95% LL-UL: 11.1 - 25.1) after study enrollment, included 17(74%) male and 6(26%) female; 19(83%) ISS-stage 1, 2(9%) ISS-stage 2, and 2(9%) ISS-stage 3; and 4(17.3%) pts with high-risk cytogenetics [1 - t(4,14) and t(14,16); 1 - t(4,14) and +1q21gain; 2 - +1q21gain]. All pts enrolled onto study were receiving lenalidomide maintenance at the time. For stage 1, 13/15 (87%) remained MRD negative at 12 months of stopping maintenance therapy, and study accrual is ongoing with enrollment of 8 additional pts onto second stage. Overall, MRD negative sustained rates at 6 months and 12 months are 17/18 (94%) (95% CI: 73%-99%) and 14/16 (88%) (95% CI: 62%-98%), respectively. Progression free survival at 12 months was 94% (95% CI: 83%-100%). Two pts converted from MRD negative to MRD positive disease states while meeting clinical progression criteria with new FDG avid bone lesions. These pts have transitioned to new regimens: Pt 13 initiated carfilzomib, pomalidomide, and dexamethasone with VGPR; Pt 2 with a plan to initiate daratumamab-based therapy locally. Pt 10 converted to MRD positivity without clinical progression and opted to restart maintenance therapy with repeat MRD testing pending. Among the three MRD converters, one pt demonstrated standard risk cytogenetics and two pts had unknown risk cytogenetics. Additional HRQoL outcome data will be presented at the time of the meeting. Conclusions Initial first stage results of stopping maintenance in sustained MRD negative patients (>3 years) warrants further investigation and study continuation. This study and similar ones, such as MRD2STOP (NCT04108624), set a benchmark for future trials investigating maintenance cessation. One such trial includes SWOG 1803, which randomizes maintenance continuation vs. discontinuation in two-year MRD negative sustained patients. While maintenance therapy demonstrates clear benefit for MM patients, feasibility of treatment-free periods remain an unanswered critical question in the field. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Standard Cytogenetic Risk Stratification Is Not Predictive of CD19 CAR Outcomes and Impact of Disease Burden Varies between Cytogenetic Risk Groups

Standard Cytogenetic Risk Stratification Is Not Predictive of CD19 CAR Outcomes and Impact of Disease Burden Varies between Cytogenetic Risk Groups

Real-World Multiple Myeloma Risk Factors and Outcomes By Race/Ethnicity in the United States

Introduction: Age-adjusted incidence and mortality rates for multiple myeloma (MM) have been higher among Blacks/African Americans (AAs) than Whites in the United States. Yet several prospective and real-world retrospective studies have suggested similar, or even improved, outcomes among Blacks/AAs, particularly when there is equal access to care. Real-world (RW) evidence can provide important insight into factors that impact patient (pt) outcomes in everyday practice. This retrospective, observational cohort study sought to describe associations between pt, disease, and treatment characteristics and survival outcomes by race/ethnicity. Methods: This study used the nationwide Flatiron Health electronic health record-derived, de-identified database of MM pts treated in the United States. During the study period of January 1, 2016, to January 31, 2022, pts whose first-line treatment was initiated after the study start date and whose race/ethnicity was categorized as either non-Hispanic (NH) White or NH Black/AA were included. Pts with evidence of treatment >14 days prior to their diagnosis date were excluded. We examined pt, disease, and treatment characteristics by race/ethnicity. We also examined RW progression free-survival (rwPFS) and overall survival (rwOS), indexed to first line of therapy (LOT). rwPFS was defined as the time from start of first LOT to the date of first progression event (informed by International Myeloma Working Group criteria and incorporating both abstracted M spike values and structured free light chain values) or death. rwOS was defined as the time from start of first LOT to the date of death. Differences in rwPFS and rwOS were assessed using the Kaplan-Meier method. Multivariable (MV) Cox proportional hazards models were used to examine associations between pt, disease, and treatment characteristics and outcomes by race/ethnicity. Results: At the time of data cutoff, 4387 pts had initiated first LOT; 1017 (23.2%) were Black/AA and 3370 (76.8%) were White. The median age at both MM diagnosis and start of first LOT was 68 years among Black/AAs and 71 years in Whites. Black/AAs were more likely than Whites to be female (53.0% vs 43.6%) and from the Southern United States (64.1% vs 36.3%). Rates of high-risk cytogenetics and 1q21 amplification were similar between races/ethnicities, as was median time from MM diagnosis to start of first LOT. Most Blacks/AAs (53.6%) and Whites (53.4%) received a proteasome inhibitor/immunomodulatory drug-based regimen as first LOT; Black/AA pts were less likely to receive stem-cell transplant than Whites (16.7% vs 21.8%). In unadjusted analyses indexed to first LOT, median rwPFS (25.4 vs 26.7 months) and median rwOS (64.6 vs 59.7 months) were similar for the overall populations of Black/AAs and Whites, respectively. MV-adjusted analyses examining associations between selected variables and outcomes by race/ethnicity are shown in Figure 1 (rwPFS) and Figure 2 (rwOS). Age of ≥75 at start of first LOT (compared to age of <65 years), Eastern Cooperative Oncology Group Performance Status (PS) of 2 (compared to PS of 0) and International Staging System Stage II or III disease at diagnosis (compared to Stage I disease at diagnosis) were associated with statistically inferior rwPFS and rwOS for both Black/AAs and Whites. The presence of high-risk cytogenetics or 1q21 amplification (compared to standard-risk cytogenetics or absence of 1q21 amplification, respectively) were similarly associated with worse rwPFS among both Black/AAs and Whites, though were only statistically significant among Whites. The presence of high-risk cytogenetics was significantly associated with worse rwOS among both races/ethnicities. 1q21 amplification was similarly associated with worse rwOS in both subgroups but was not statistically significant among Black/AAs. Conclusions: Among RW pts with MM from the Flatiron Health database, unadjusted rwPFS and rwOS were similar between NH Black/AA pts and NH White pts, as previously reported. In general, associations between risk factors for rwPFS and rwOS were consistent between races/ethnicities. Findings from this study compliment knowledge gained from earlier prospective and RW retrospective studies, helping to inform clinicians about the impact of race/ethnicity on disease characteristics and treatment patterns in the United States as well as MM outcomes within diverse populations. Funding: Sanofi. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of High-Risk Disease on Outcome after CAR-T Cell Therapy for Multiple Myeloma: A Meta-Analysis of 759 Patients

Background Chimeric antigen receptor (CAR-) T cell therapy showed enormously promising results in patients with relapsed/refractory multiple myeloma (rrMM), leading to approval of the first 2 products by FDA/EMA. Patients with rrMM who receive CAR-T cell therapy may have received several lines of prior therapy and experienced multiple relapses. Therefore, patient selection is especially important for CAR-T cell therapy, a very complex and expensive treatment, which recently showed risks for treatment delay or even cancellation due to long turnaround times of apheresis and infusion. Here, we summarized the current body of evidence on the role of CAR-T cell therapy for rrMM and high-risk disease, to identify patients who may benefit and those who may not. Methods We performed a systematic literature review to identify all fully published prospective trials. We searched Medline, EMBASE, Cochrane trials registry, and www.clinicaltrials.gov. A conventional meta-analysis was conducted using R statistical software. Risk ratios (RR) and 95% confidence intervals (CI) were calculated within a random-effects framework. Main efficacy outcomes were overall response (ORR), complete response, minimal residual disease, survival, and relapse. High-risk disease features were defined as presence of the following at time of CAR-T cell infusion: cytogenetic high-risk (presence of at least either del(17p) or t(4;14)), presence of extramedullary disease (EMD), Revised International Staging System (R-ISS) stage III. Results 19 trials comprising a total of 759 patients with heavily pretreated rrMM were included in quantitative analyses. Patients received a median of seven prior treatment lines (such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies), including autologous stem cell transplantation in 80% of patients. The median age of patients was 60 years. Age and number of prior lines of therapy was significantly affected by trial origin. Median age and lines of therapy were 61 and 7 lines in US-based trials versus 57 years and 5 lines in China-based trials. The most frequent single target was B cell maturation antigen (BCMA). 4 trials used tandem CARs, including 2 trials targeting both BCMA and CD38 and 2 trials targeting both BCMA and CD19. 1 trial only targeted CD19. Costimulatory domain was 4-1BB designs in most trials, and fludarabine and cyclophosphamide was the most common lymphodepletion regimen. In terms of response, high-risk cytogenetic profile was significantly associated with worse ORR, showing RR of 0.86 (95% CI, 0.76-0.97) in favor of standard-risk cytogenetics (P=0.01; Figure). Results for complete response and measurable residual disease were in line with these results and all in favor of standard-risk cytogenetics, showing 30% and 40% increased risk for worse outcome (P<0.001, respectively). Regarding disease risk, EMD was not significantly associated with worse ORR, showing RR of 0.97 (95% CI, 0.92-1.02; P=0.26; Figure). No significant associated with complete response and measurable residual disease were seen. R-ISS stage III was significantly associated with worse ORR, complete response, and measurable residual disease (P<0.001, respectively). In terms of relapse, high-risk cytogenetics and EMD were significantly associated with worse outcome, showing RRs of 0.70 (95% CI, 0.58-0.83; P<0.001) and 0.88 (95% CI, 0.78-0.98; P=0.02). This translated into significant associations with worse progression-free survival. Overall survival could not be sufficiently assessed due to missing reports, although 2 trials suggested worse outcomes at least for EMD. Conclusion High-risk cytogenetics were significantly associated with worse outcomes after CAR-T cell therapy for rrMM. Although EMD was not associated with significantly different ORR, risk for relapse and worse survival was significantly increased. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-world patient characteristics and treatment outcomes among nontransplanted multiple myeloma patients who received Bortezomib in combination with Lenalidomide and Dexamethasone as first line of therapy in the United States

BackgroundThere is limited real-world evidence that describes patients with newly diagnosed multiple myeloma (NDMM) treated with the bortezomib, lenalidomide, and dexamethasone (VRd) triplet regimen. We evaluated patient characteristics and treatment outcomes among nontransplanted NDMM patients who received VRd as their first line of therapy (LOT) in US oncology practice settings.MethodsThis retrospective observational cohort study evaluated patients from the Flatiron MM Core Registry who received VRd as first LOT between November 1, 2015, and February 28, 2021. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Associations between patient demographic and clinical characteristics and PFS were evaluated using a multivariable Cox proportional hazards model.ResultsA total of 2342 eligible patients with VRd as first LOT were identified (mean age, 67.0 years). Among all identified patients, 64.3% were ≥ 65 years of age, 25.5% were elderly (≥75 years), and 47.9% were frail. Among patients with available data, 21.2% had high-risk cytogenetics, and the majority had International Staging System (ISS) stage I/II disease (71.8%), and Eastern Cooperative Oncology Group performance status (ECOG PS) score 0/1 (81.2%). Median duration of therapy was 5.5 months. With median follow-up of 21.0 months, median PFS and time-to-next-treatment were 26.5 and 16.1 months, respectively. Higher risk of disease progression or death was seen in patients categorized as elderly (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.13-1.66 vs patients < 65 years), having high-risk cytogenetics (HR = 1.44; 95% CI: 1.19-1.75 vs standard risk), having ISS disease stages II and III (HR = 1.31; 95% CI: 1.06-1.63 and HR = 1.37; 95% CI: 1.10-1.70 versus stage I, respectively), and having worse ECOG PS score (≥2) (HR = 1.49; 95% CI: 1.22-1.81 versus functionally active patients).ConclusionsThe majority of patients treated with VRd in this study were ≥ 65 years of age, were ISS stage I/II, had an ECOG PS score of 0/1, and had standard cytogenetic risk. Median PFS observed in real-world practice was notably shorter than that observed in the SWOG S0777 clinical trial. In nontransplanted patients treated with VRd as first LOT, a higher risk of disease progression or death was associated with older age, having high-risk cytogenetics, worse disease stage, and worse ECOG PS score.

Exploring the current molecular landscape and management of multiple myeloma patients with the t(11;14) translocation.

Multiple myeloma (MM) is a genetically complex disease. The key myeloma-initiating genetic events are hyperdiploidy and translocations involving the immunoglobulin heavy chain (IgH) enhancer on chromosome 14, which leads to the activation of oncogenes (e.g., CCND1, CCND3, MAF, and MMSET). The t(11;14) translocation is the most common in MM (15%–20%) and results in cyclin D1 (CCND1) upregulation, which leads to kinase activation and tumor cell proliferation. Notably, t(11;14) occurs at a higher rate in patients with plasma cell leukemia (40%) and light chain amyloidosis (50%). Patients with myeloma who harbor the t(11;14) translocation have high levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL2). Multiple studies demonstrated that the presence of t(11;14) was predictive of BCL2 dependency, suggesting that BCL2 could be a target in this subtype of myeloma. Venetoclax, an oral BCL2 inhibitor, has shown remarkable activity in treating relapsed/refractory MM patients with t(11;14) and BCL2 overexpression, either as monotherapy or in combination with other anti-myeloma agents. In this review, we describe the molecular defects associated with the t(11;14), bring into question the standard cytogenetic risk of myeloma patients harboring t(11;14), summarize current efficacy and safety data of targeted venetoclax-based therapies, and discuss the future of individualized or precision medicine for this unique myeloma subgroup, which will guide optimal treatment.

Retrospective analysis of responses to second-line treatments of multiple myeloma after disease progression in patients who underwent ASCT.

e20004 Background: Most Multiple Myeloma (MM) patients who respond to initial treatment ultimately progress. Data regarding 2nd line treatment remains scarce, but in general treatment relies on whether the disease is refractory to Lenalidomide (R) or not. Here, we report responses to 2nd line treatments of MM patients in with disease progression (PD) following Autologous Stem Cell Transplant (ASCT). Methods: We retrospectively reviewed MM patients with PD after ASCT at Cleveland Clinic during the period of April 1, 2016 till December 31, 2021. Baseline demographic, clinical and cytogenetic features were obtained from electronic records. Patients who had PD after ASCT, as defined by IMWG criteria, were divided into two smaller subcohorts: R-refractory and R-sensitive. Outcomes were compared among treatment groups within each subcohort. Continuous variables are reported as means with standard deviations, while categorical variables are presented as percentages. Categorical variables were compared using the chi-squared test while the t test and ANOVA were used for continuous variables. Results: 127 patients who had PD following ASCT were identified (Table). Most common cytogenetic aberrancies were del(13) (RB) 34.6%, t(11;14) 18.9% and gain(1q) 15%. Pre-PD maintenance included R 58.3%, Bortezomib (V) 7.1%, RV combination 8.7% and other R-based regimens 9.4%, with no difference in time to disease progression (TTPD) between them (p = 0.82), and an average of 15.5 months TTPD among all patients. ISS III patients were likely to progress earlier than ISS II or I (10.91 vs 14.56 vs 20.33 months; p = 0.008), while high and standard-risk cytogenetics did not predict TTPD (12.62 vs 16.85 months; p = 0.092). Patient who achieved CR either pre or post-ASCT were less likely to progress compared to others with weaker responses (p = 0.032; p = 0.002). Patients who did not achieve CR post-ASCT progressed earlier than those with CR (12.37 vs 16.53 months; p = 0.041). In R-sensitive patients (n = 25), PD was not significantly different in patients on 2nd line Daratumumab (D), R and dexamethasone (d) vs RVd (45.5% vs 60%; p = 0.505). In R-refractory patients (n = 57), PD was also not significantly different in DVd, Dd with Pomalidomide, or Carfilzomib (C)-based regimens (81.3% vs 68.2% vs 60%; p = 0.426). Time to 2nd PD was significantly longer in DRd vs RVd (12.4 vs 3 months; p = 0.026) but similar in DVd vs DPd vs C-based regimens (6.75 vs 8 vs 5.89 months; p = 0.711). Conclusions: TTPD in MM post-ASCT is determined by the ISS stage and achieving CR but not by cytogenetic risk or maintenance choice. Current regimens used as 2nd line in R-refractory patients are statistically indifferent, but DRd delays further PD compared to RVd in R-sensitive patients.[Table: see text]

Impact of high-dose melphalan followed by autologous stem cell transplant in producing MRD negative complete response in newly diagnosed multiple myeloma.

e20001 Background: High dose melphalan followed by autologous stem cell transplant (HDM-ASCT) remains the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) despite advances in treatments. Achievement of complete response (CR) is associated with improved overall survival (OS) and progression-free survival (PFS); Minimal Residual Disease (MRD) negativity (-) using next generation flow cytometry with a sensitivity of 10-5 is strongly associated with improved PFS and OS. We investigated the rates of conversion to MRD(-), especially MRD(-) CR following HDM-ASCT in patients with NDMM. Methods: We retrospectively reviewed patients with NDMM who underwent early HDM-ASCT at Mayo Clinic Rochester from May 2018 to July 2019. Response assessment was conducted after induction and within 100 days post-ASCT based on 2016 IMWG criteria, except for using Mass-Fix instead of immunofixation. MRD was assessed in bone marrow using the established Euro Flow protocol with sensitivity of 10-5. The FISH assay was used to risk-stratify patients as high-risk (HR) and standard risk (SR) cytogenetics as per the mSMART guidelines. Primary outcome measure was the conversion to MRD(-) CR after ASCT. Secondary outcomes include the overall conversion to MRD(-) irrespective of IMWG response, the impact of HR cytogenetics and pre-ASCT IMWG response on conversion to MRD(-) CR. Results: Two-hundred and ten patients were included; 126 (60%) were male and median age 62 years (range 32–77 years). There were 78 (44%) patients with HR cytogenetics. Pre-ASCT, 23 patients (11%) achieved MRD(-) CR, and 66 (31%) patients achieved MRD(-) CR post ASCT. Of 187 patients not in MRD(-) CR pre-ASCT, 45 (24%) converted to MRD(-) CR. Table provides a breakdown of the conversion rate of pre-ASCT IMWG response category to MRD(-) CR post ASCT and patients with MRD(+) CR had the highest rate (78%) of conversion. The presence of HR cytogenetics did not impact rates of MRD(-) CR achievement post ASCT irrespective of pre-ASCT IMWG response (p = 1.0). Overall, irrespective of IMWG response, 43 (20%) patients were MRD(-) pre-ASCT (19 in VGPR, 24 in CR or better) and 102 (49%) patients were MRD(-) post-ASCT (36 in VGPR, 66 in CR or better). Among 85 patients in VGPR post-ASCT, 36 were MRD(-) of which 8 (22%) progressed, while 49 were MRD(+) of which 24 (49%) progressed (p = 0.014). Conclusions: Upfront HDM-ASCT in patients with NDMM leads to deeper responses with 24% converting to MRD(-) CR and more than doubling of the total rate of MRD(-) irrespective of IMWG response. [Table: see text]

Prognostic Significance of the Stage at Which an MRD-Negative Status Is Achieved for Patients With Multiple Myeloma Who Received ASCT.

ObjectiveTo explore the prognostic significance of the stage at which a minimal residual disease (MRD)-negative status is achieved for patients with newly diagnosed multiple myeloma (NDMM) who received autologous hematopoietic stem cell transplantation (ASCT).Cases and MethodsA retrospective analysis of 186 NDMM patients who received “induction therapy-ASCT-maintenance therapy” in our center and achieved an MRD-negative status was performed. Patients were divided into three groups, A (induction therapy), B (3 months after ASCT), and C (maintenance therapy), according to the stage at which an MRD-negative status was achieved.ResultsThe median time to progression (TTP) of 186 patients was not reached; the median overall survival (OS) was 113.8 months. The median TTP of the patients in three groups was not reached (P=0.013), and the median OS of the patients in three groups was not reached, not reached, and 71.2 months, respectively (P=0.026). Among patients with standard-risk cytogenetics, the median TTP of those in all three groups was not reached (P=0.121), and the median OS of the patients in three groups was not reached, not reached, and 99.6 months, respectively (P=0.091). Among patients with high-risk cytogenetics, the median TTP of those in three groups was not reached, 53.9 months, and 35.8 months (P=0.060), and the median OS was not reached, 71.2 months, and 60.2 months, respectively (P=0.625). Among patients with R-ISS stage I-II, the median TTP of those in three groups was not reached (P=0.174), and the median OS of the patients in three groups was not reached, not reached, and 99.6 months, respectively (P=0.186). Among the 29 patients with R-ISS stage III, the median TTP of those in the 3 groups were unreached, unreached, and 35.1 months (P<0.001), and the median OS was unreached, unreached, and 48.5 months, respectively (P=0.020). In all enrolled patients, the stage of reaching MRD-negative was an independent prognostic factor for TTP, rather than a prognostic factor for OS. The stage of reaching MRD-negative in patients with R-ISS III was an independent prognostic factor for OS.ConclusionFor the same patients who are MRD-negative, the prognoses of those who achieve an MRD-negative status at different groups are different. The stage at which an MRD-negative status is achieved can predict the prognosis of patients with R-ISS stage III.

P26: EXTRAMEDULLARY MULTIPLE MYELOMA: A MONOCENTRIC RETROSPECTIVE OBSERVATIONAL STUDY

Extramedullary Multiple Myeloma (EMM) is a distinctive sub-entity of Multiple Myeloma, characterized by clonal plasma-cells proliferation outside the bone marrow; it can be diagnosed either as a tissue growing in contiguity with bone marrow (paraskeletal) or in distant organs (extramedullary). This subset of patients, especially the latter ones, have a poor prognosis, and there are not EMM-specific therapy schedules. The aim of our observational study was to describe patients that presented both type of EMM in order to report which common therapeutic approaches were used and to identify which disease characteristics mostly affected overall survival. We retrospectively analyzed 111 patients (pts) with EMM disease referred to the Hematology Department of Sapienza University of Rome between 2004 and 2021: 64 presented EMM at the onset of disease and 37 at relapse. Sixty-one pts were male and 50 were female (55% vs 45%); 60 pts (54.1%) were ISS-1 and the most common isotype was IgG (62.2%), followed by IgA (22.5%) and light chain myeloma (11.7%). Cytogenetics data were available for 37 patients: among them, 8 patients showed a high-risk cytogenetics profile: the most frequent findings were del13q (40.5%), amp/gain1q (24.3%) and t(4;14) (13.5%). Out of these 37 pts, 11 (30%) presented 2 or more cytogenetics alterations, while 4 pts (11%) presented a complex karyotype. Ninety-eight pts (88%) presented a paraskeletal localization, while 13 pts (12%) showed extramedullary localizations; the most frequent organs involved were soft tissues (5/13), followed by nervous central system, lymph nodes and orbit (2/13). Regarding the therapeutic approaches, 47% of pts with EMM at diagnosis received regimens containing a proteasome inhibitor (PI) and immunomodulatory drugs (IMiDs); 38% of pts underwent autologous stem cell transplantation (ASCT). At relapse, the most used regimens (30% of pts) were combinations containing monoclonal antibodies or IMiDs monotherapy. In both groups, one-third of patients underwent radiotherapy to reduce the local symptoms. After a median follow-up of 52 months for pts with EMM at diagnosis and 20 months for pts at relapse, the median OS was 147 months (mo) in first group and 32 mo in the second group (p<0.001). Among pts with EMM at diagnosis, pts who underwent ASCT showed a better median OS compared to other pts (NR vs 87.6 mo, p=0.004). Analyzing the type of EMM, we showed that pts with an extramedullary localization had a worse outcome compared to pts with paraskeletal disease (median OS 43.4 vs 147 months, p=0.011). Despite the limit of our cohort, pts with EMM at diagnosis and high-risk cytogenetics had a worse outcome compared to those with standard-risk cytogenetics (median OS: 33.2 months vs NR, p=0.041). Multivariate analysis showed that the ASCT and obtaining at least a very good partial response after therapy were independent factors associated with better progression free survival (PFS). Regarding OS, obtaining at least a partial response and a previous therapy with a PI were independent factors associated with better OS. Despite the limits of the retrospective study, our data demonstrated that specific therapy based on PIs and ASCT could overcome the poor prognostic factor of EMM, according to the previous published data. Further studies are warranted to assess the optimal strategies for pts with extramedullary EMM, whose prognosis is still poor.

Early Infection Risk in Newly Diagnosed Multiple Myeloma Patients in the Modern Era

Background:Multiple myeloma (MM) is the second most common hematologic malignancy, with an estimated 30,000 new cases in the United States annually. Advances in management of MM over the past 20 years have significantly improved outcomes, but MM continues to be an incurable disease. Infections continue to be a major cause of morbidity and mortality, with a high proportion of MM patient developing infections within the first 3 months of diagnosis. There have been limited data on infection rates in MM patients in community-based oncology setting over the past two decades. This study looked to define infection rates and associated risk factors in newly diagnosed MM patients within 90 days of initial diagnosis.Methods:A retrospective, observational study was conducted on MM patients ages 18-89 newly diagnosed January 1, 2010-December 31, 2018 within Kaiser Permanente Northern California. Patients were required to have a minimum of one year of membership prior to MM diagnosis. SEER data was used to identify MM patients, and clinical data were extracted from the electronic health record. Bacterial, viral, and fungal infections were identified using ICD9/ICD10 codes. Baseline demographic and clinical characteristics from visit notes, laboratory and pathology results, and transplant data from utilization and claims data were analyzed to assess infection risks. High-risk cytogenetics was defined as notation of the following in pathology reports or oncology notes: add 1q, t(4:14), t(14:16), t(14:20), deletion of 17p. Bivariate analyses were conducted to assess differences across groups using the chi-squared test and the Wilcoxon-Mann-Whitney nonparametric test.Results:A total of 2030 newly diagnosed MM patients identified for this study. Median age at diagnosis was and n=828 (40.8%) of patients were female. Among this cohort, 522 (25.7%) had an infection within 90 days of MM diagnosis. The median age of patients having infections was 71 years (IQR 63-80), and the median age of those not having infections was 68 years (IQR 60-76, p<0.001). The median Charlson Comorbidity Index (CCI) of patients having infections was 3 (IQR 1-5) and the median CCI of those not having infections was 2 (IQR 1-4, p<0.001). Patients having hemoglobin <10.0 g/dl were more likely to have infection than those having hemoglobin >10.0 g/dl (30.4% vs. 23.6% respectively, p=0.011). Similarly, patients presenting with hypercalcemia (calcium >11.0 mg/dL) were more likely to have infection (37.4% vs. 24.6% in patients having calcium <11.0 mg/dL, p<0.001) as were patients with creatinine clearance <60.0 mL/min of those having <60.0 mL/min vs. 20.7% of those having >60.0 mL/min, p<0.001). Patients having indicators of high-risk cytogenetics were less likely to have infections within 90 days of diagnosis compared to those with standard risk cytogenetics (21.1% vs 26.2% respectively, p=0.031). We did not detect significant differences across transplant eligible status within the first year after diagnosis (22.1% infection among transplant eligible vs. 26.6% among those who were not transplant eligible, p=0.059) nor across sex (27.3% among females vs. 24.6% among males, p=0.176). Additionally, no significant differences in infection were detected across race and ethnicity (24.0% infection among Asian patients, 26.4% among Black patients, 27.7% among Hispanic patients, 25.5% among White patients, and 14.3% among patients having unknown or other race and ethnicity, p=0.741).Conclusions:In this community-based oncology study, infection within 90 days of diagnosis continues to be a significant complication of multiple myeloma and these results are comparable to previous studies. Risk factors for infection include age, CCI, standard risk cytogenetics, anemia, hypercalcemia, and renal failure. Stem cell transplant, sex and ethnicity were not associated with increased risk for infection. Future analysis will include assessments of hospitalization and mortality associated with infection. This study illustrates the importance of further research looking at decreasing infection rates in multiple myeloma patients. DisclosuresNo relevant conflicts of interest to declare.

Effects of Cytogenetic Risk on Outcomes in Multiple Myeloma Treated with Selinexor, Bortezomib, and Dexamethasone (XVd)

Effects of Cytogenetic Risk on Outcomes in Multiple Myeloma Treated with Selinexor, Bortezomib, and Dexamethasone (XVd)

Daratumumab, Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: Pooled Analysis of Octans and Alcyone

Daratumumab, Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: Pooled Analysis of Octans and Alcyone

Characteristics and Outcomes of Non-Transplanted Patients with Newly Diagnosed Multiple Myeloma (NDMM) Initiating Treatment with Bortezomib, Lenalidomide, and Dexamethasone (VRd) As First-Line of Therapy

Introduction: In the US, bortezomib, lenalidomide, and dexamethasone (VRd) is one of the preferred treatment regimens in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) based on the results from the phase 3 Southwest Oncology Group (SWOG) S0777 study. Although the efficacy of VRd in transplant-ineligible or -deferred NDMM patients was demonstrated in SWOG S0777, clinical trials have strict eligibility criteria that may not translate to the real-world. There is limited real-world data on the characteristics and outcomes of non-transplanted patients with NDMM treated with VRd, especially in older, frail patients with comorbidities. This study aimed to address these knowledge gaps by evaluating the characteristics and outcomes of patients with NDMM who received VRd as first-line of therapy (LOT) in US oncology practice.Methods: This retrospective observational study included patients from the Flatiron Multiple Myeloma Core Registry who received VRd as first LOT between November 1, 2015 and February 28, 2021. The index date was defined as the first observed record of the VRd regimen. Non-transplanted patients were defined as those who did not receive a stem cell transplant (SCT) from the diagnosis date to the index date. Patients were excluded if they were <18 years of age on index date; were enrolled in a clinical trial; had other malignancies prior to the index date; had a diagnosis of amyloid light-chain amyloidosis prior to the index date; or had a SCT prior to index date. Demographics, clinical characteristics, and outcomes were assessed in the overall study cohort and among specific subgroups: older adults (≥75 years of age on index date); frail patients (frailty score ≥2, calculated using age on index date, Charlson Comorbidity Index during the pre-index period, and Eastern Cooperative Oncology Group performance status [ECOG PS] score on the closest date to the index date ≤90 days prior to and ≤7 days after the index date, patients with missing ECOG were not excluded); patients with high-risk cytogenetics, and patients with acute renal impairment ([RI], serum creatinine >2 mg/dL on the closest date to the index date or having diagnosis codes of ICD-9-CM 584.5-584.9, ICD-9-CM 586, ICD-10-CM N17.0-2, N17.8-9, and N19, measured ≤90 days prior to and ≤7 days after the index date). Duration of therapy was measured as the time between the index date and end of the LOT. Progression-free survival (PFS) was measured as time between the index date and disease progression or death, whichever occurred first. PFS did not account for treatment discontinuation for reasons other than progression or death. Disease progression was defined as a clinically meaningful increase in serum M-protein, urine M-protein, or the free light chain ratio according to the International Myeloma Working Group criteria. PFS was analyzed using the Kaplan-Meier method.Results: A total of 2342 eligible NDMM patients treated with VRd as first LOT were identified, with a median follow-up of 21.0 months. A majority of patients were ≥65 years (64.3%), with the mean (SD) age at index date being 67 (±10) years. Most patients were male (53.3%), had International Staging System [ISS] stage I/II (48.4%; 33% missing) and the ECOG PS score 0/1 (63.5%; 22% missing). Of the 2342 patients, 597 (25.5%) patients were categorized as older adults (≥75 years of age); 1122 (47.9%) as frail; 374 (16.0%) as patients with high-risk cytogenetics; and 250 (10.7%) as patients with RI. About 28% of the patients received a SCT within 1-year of the index date. The median duration of therapy was 5.6 months. The median PFS for the overall study group was 33.2 months. Median PFS was substantially shorter for patients who were ≥75 years of age (22.8 months), were frail (28.7 months), had high-risk cytogenetics (25.1 months), or had RI (25.1 months) (Figure).Conclusions: The majority of patients with NDMM treated with VRd in the real-world setting were aged ≥65 years, were ISS stage I or II, had an ECOG PS score of 0 or 1, and had standard-risk cytogenetics. Median PFS observed in the real-world setting was shorter than that observed in the SWOG S0777 clinical trial. Patients who were ≥75 years of age, were frail, had high-risk cytogenetics, or had RI demonstrated shorter median PFS than patients in the overall study population. Alternate treatment options with demonstrated efficacy in the older, frail, and transplant ineligible patients are available. [Display omitted] DisclosuresMedhekar: Janssen: Current Employment. Ran: Janssen Scientific Affairs, LLC: Current Employment. Fu: Janssen: Current Employment. Patel: Janssen: Current Employment. Kaila: Janssen Scientific Affairs, LLC: Current Employment. OffLabel Disclosure:Bortezomib, and lenalidomide are both FDA approved agents for treating multiple myeloma. The combination of bortezomib, lenalidomide, and dexamethasone is commonly used in clinical practice and is listed as a preferred regimen in NCCN guidelines.

Post-Induction Undetectable Minimal Residual Disease at 10 -5 Sensitivity Level within Marrow and/or Stem Cell Graft Overrides Cytogenetic High Risk

Introduction: Post-induction minimal residual disease (MRD) within but not outside (peripheral blood/stem cell graft) of marrow among transplant eligible patients with multiple myeloma (MM) is currently recognized as poor-prognostic. Emerging number of studies are evaluating MRD within the context of cytogenetic risk. In this study we aimed to quantify circulating plasma cells (PCs) by flow in apheresis products (graft=gMRD) and compare with marrow MRD(mMRD) and outcome according to cytogenetics.Patients & Methods: Four hundred eleven subsequent newly diagnosed multiple myeloma (NDMM) patients transplanted (AHCT) between September 2006 - June 2021 were included prospectively. Standard-risk cytogenetics(SR) is defined as t(11;14), t(6;14), or a normal karyotype , whereas del(17p13), t(4;14), t(14;16), t(14;20), + 1q21 and complex findings are high-risk cytogenetics (HR). In the sample drawn for HPSC quantification of the graft and bone marrow, the number of clonal PCs were quantified by Flow. CD27 PC7 orCD27 A750, CD56 A700, CD19 ECD, CD38 FITC orCD38 A750, CD138 APC, CD45 KO, CD81 PE, CD117 PC7, polyclonal Rabbit Anti-Human Kappa or Lambda Chains /FITC antibodies and acquisition of at least 10 5 cells per tube Analysis was performed using the Navios Flow Cytometer (3L10C, Beckman Coulter) using the Kaluza software (Beckman Coulter, USA) according to the criteria defined by Montero et al and also abnormal distribution of kappa vs. Lambda expression. Undetectable MRD was defined as absence of clonal PCs at a sensitivity of 10 -4 prior to 2017(n=217) and 10 -5 after 2017(n=131). MRD assessment is similar in the graft and marrow. Impact of postinduction MRD analysis was performed in 131 patients with MRD data of 10 -5 sensitivity level. Results were reported in the intention-to-treat (ITT) population for mMRD.Results: Median follow-up after AHCT was 61.5 months (range:3.2-168) (prior to 2017) and 17.7 months (range: 3-47.4) (after 2017). Induction regimen consisted of bortezomib without or with immunomodulatory drug (IMID) 78.8%, 2.8% (prior to 2017) and 74.1%, 22.9% (after 2017). Consolidation 18% (n=39/217), 22.1% (n=29/131) (prior and after 2017) and maintenance 21.2% (n=46/217), 35.1% (n=46/131) (prior and after 2017) were administered based on the response to AHCT. Cytogenetically HR was observed 14.1% (n=47) (among total cohort) and 15.8% (n=19) (after 2017 cohort). Post-induction biochemical response distribution among patients with undetectable MRD are shown in Table-1. MRD assessments were performed at a sensitivity of 10 -4 and 10 -5 in graft (n=147 and 76), marrow (n=18 and 4) or both (n=52 and 51). A statistically significant correlation was detected between marrow and graft MRD only at sensitivity level 10 -5 (SE: 0.638, p<0.001). Additionally, correlations between CR and gMRD (Kappa coefficient (SE): -0.284, p=0.03); CR and mMRD (SE: -0.452, p:0.001) were found. Since marrow and graft MRD results are correlated, all graft and marrow results were merged for the multivariate analysis (MVA) (Table-2). Having undetectable vs detectable MRD in either graft or marrow estimates a 2 years-PFS of 83.6% vs 46.5% (p=0.007). Among 42 MRD(-) patients, only four (two with HR)have relapsed. There is a tendency for better two year probability of PFS with undetectable mMRD vs gMRD at 10-5 ( not reached vs 84.7% ; ns)(Figure 1). The patients (after 2017) are divided into four groups according to MRD status and cytogenetic risk stratification: MRD(-)SR (n=35; 29.2%), MRD(-)HR (n=7; 5.8%), MRD(+)SR (n=66; 55%), MRD(+)HR (n=12; 10%). Kaplan-Meier curves revealed significant differences in PFS among these groups (p=0.03) (Figure-2).Conclusion: Our real-world triplet drug induction-based experience shows for the first-time post-induction mMRD and MRD to be correlated with each other and with PFS. PFS with MRD(-) at 10 -5 results have displayed a better outcome compared to 10 -4. MVA showed MRD and age to determine PFS, independent from post-induction CR, ISS and cytogenetic risk. Although observed less frequently, achieving post-induction MRD(-) either in graft or marrow may ameliorate the poor prognosis of HR. With improvement in induction it may be possible to achieve more frequent MRD(-) and thus analyze the impact of each cytogenetics risk group ie 1q amplification separately. Furthermore, MRD in graft may be a non-invasive therapeutic efficacy tool which is subject to less sampling variation. [Display omitted] DisclosuresBeksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau.