Hayman, Suzanne R.

Abstract Patient-reported outcomes (PROs) are associated with treatment outcomes in multiple myeloma (MM) in the clinical trial setting. However, most PRO tools are time consuming, which hinders use in routine practice. Our institution incorporated a “Hematology Patient-Reported Symptom Screen” (HPRSS), a 3-item questionnaire for fatigue, pain, and quality of life (QOL). The main objective of this study was to evaluate the impact of these symptoms on progression-free survival (PFS) and overall survival (OS) in a real-world cohort of patients with newly diagnosed MM. This retrospective study included patients with MM diagnosed between April 2011 and December 2017, seen at Mayo Clinic (Rochester, MN), who completed the HPRSS. Patients rated their symptoms on a scale from 0 to 10. Clinically relevant symptoms were defined as scores ≥5 for pain and fatigue, and ≤5 for QOL. At diagnosis, 735 patients had scores for all domains. The median follow-up was 8.1 years. Age was associated with increased odds of fatigue and decreased QOL. Female sex and comorbidities were associated with fatigue and pain. Higher disease stage, anemia, lytic lesions, and increased plasma cell burden were associated with fatigue, pain, and decreased QOL. Clinically relevant fatigue, pain, and decreased QOL were associated with decreased PFS and OS. On multivariate analysis including age, International Staging System III, high-risk cytogenetics, and postinduction transplantation, fatigue and decreased QOL were independently associated with decreased OS. A composite HPRSS score stratified patients into 3 groups with distinct OS. Patient-reported symptoms are prognostic in patients with newly diagnosed MM. The prognostic values of fatigue and decreased QOL are independent of age, disease stage, and transplant status.

Abstract As patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (>28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P < .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (>46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment.

7558 Background: Survival in patients with multiple myeloma (MM) continues to improve with the newer therapies, but there is no clear evidence of a cure and patients continue to relapse. However, most patients have the most extended period without progression with their first-line therapy, and subsequent therapies often provide a shorter duration of response due to the use of drugs with overlapping mechanisms of action and, more importantly, a shorter first remission, pointing toward more aggressive disease biology. With newer immunotherapies being used at 1st relapse, this may change. We designed this study to explore the natural history of MM after the 1st relapse and define the predictors of outcome after the initial relapse. Methods: We identified all patients in the Mayo Clinic database diagnosed between Jan 2004-June 2019 who had had initial disease progression. The study cohort included 2005 patients. We explored the overall survival (OS) from the time of documented disease progression or the start of second-line treatment in patients who had not met IMWG criteria before second-line therapy. Front-line therapy was grouped into those with either an IMiD or PI, both IMiD and PI, daratumumab with IMiD and PI, and none of these agents. The IMiD and PI were always used with dexamethasone with or without an alkylator. Results: The median age was 63 (range 24-95) years and 60% were male. The median estimated follow-up from diagnosis for all patients was 86 mos. (95% CI; 82, 88) and the median time to progression from the start of therapy was 25 mos. (95% CI; 24, 26). The median OS from the first progression was 45 mos. (95% CI; 42, 50), 36 mos. for those diagnosed before 2009, and 52-53 mos. for those diagnosed later. On univariate analysis, age <70 at 1st relapse, RISS I, novel agents in initial therapy, CR in the first line, diagnosis after 2009, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse (Table). On multivariate analysis, age <70, RISS I, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse. Conclusions: The study provides an estimate of the outcomes and significant predictors of outcomes after 1st relapse in patients with MM. These factors should be taken into consideration when designing clinical trials in this patient population. In particular, these factors identify a high-risk group of patients not always identified by baseline characteristics and should be the focus of future trials. [Table: see text]

7520 Background: There are 2 CAR-T products and 3 bispecific antibodies (BsAbs) that are FDA-approved for patients (pts) with relapsed, refractory multiple myeloma (MM). Clinical trials experience to date suggests that clinical response of BsAb is less impacted after CAR-T therapy. We examined the outcome of pts who received BsAb in standard-of-care (SOC) practice at Mayo Clinic Rochester. Methods: Retrospective analysis of MM patients who received FDA-approved BsAb at Mayo Clinic, Rochester between 12/2022- 1/2024. IMWG criteria was used for clinical response. Results: Sixty-two patients received BsAbs: 77% (48/62) received teclistamab, and 23% (14/62) received talquetamab. Median age was 62 years (range: 33-81), 60% (37/62) were males, and 45% (28/62) received prior CAR-T. Patients who had prior CAR-T therapy had more prior lines of therapy compared to those who did not. Overall, ORR to teclistamab was 61%, which is comparable to previous studies and other real-world reports. ORR and ≥CR rates were comparable between patients with and without prior CAR-T (Table). Of the 28 pts who received CAR-T before BsAbs, 61% (17/28) received idecabtagene vicleucel, 10% (3/28) were ciltacabtagene autoleucel, and 29% (8/28) on clinical trial. We then compared outcome of BsAb between pts who had relapsed from CAR-T within 1 year (n=21, median PFS: 8.84 months (range, 1.12, 10.84)) or after 1 year (n=7, median PFS: 16.62 months (range, 13.30, 36.20)). At the time of BsAb infusion, pts with who relapsed < 1 year vs ≥1 year post CAR-T had comparable blood counts, ALC, M-protein and involved FLC levels, CRP, ferritin and LDH. BsAb CR/sCR rate was significantly higher in pts with disease relapse ≥1 year compared to <1 year post CAR-T (57% vs 14%, p=0.02). Conclusions: Irrespective of prior CAR-T exposure, BsAb have clinical activity in SOC practice in pts with MM. Our preliminary data suggest that responses to BsAbs are better in pts with late compared to early relapse post CAR-T. Longer follow-up is needed to understand the duration of response. Larger, multi-center studies with longer follow-up will help identify factors that impact BsAb response post CAR-T.[Table: see text]

7516 Background: Immune effector cell hemophagocytic lymphohistiocytosis IEC-HS is a complication of CAR T cell therapy (CART). This study aims to look at the outcomes of CART patients who develop IEC-HS. Methods: Patients who developed IEC-HS after receiving CART and patients who developed IEC-HS without (nonCART) between December 2020 and March 2022 were included. Results: The 20 CART patients were older than the 25 nonCART patients. Peak ferritin, fibrinogen, CRP, serum creatinine and transaminases were similar between the 2 group. CART patients had lower white blood cell count and platelets and bilirubin than the nonCART patients. CART patients were more like to have markedly elevated IL-6 levels (> 315 mg/ml), higher IL-18, higher MCP-1, and suppressed IL-1β and GMCSF than nonCART patients (Table). Treatment of IEC-HS included tocilizumab (n = 19), anakinra (n = 18) siltuximab (n = 4) and basiliximab (n = 4), dexamethasone (n = 18) methylprednisolone (n = 6), etoposide (n = 1) and ruxolitinib (n = 1). A significant response defined by a 90% reduction or normalization of the cytokine was observed with IL-10 and IFN-ϒ in 92.3% and 84.6% of the CART patients respectively. An intermediate response was noted with TNF, IL-6, MCP-1 and MIP-1 in 38.4%, 30.8% and 61.6% and 38.5% of the patients respectively. No patient had a significant response in IL-2Rα or IL-1β and only 7.7% had a significant response in IL-18. Of the 5 patients who had a MIP-1 response, 4 were on basiliximab +/- high flow continuous venovenous hemofiltration and the only patient that had an IL-18 response was on both modalities. The 100-day mortality after IEC-HS in the CART patients was 40% and was associated with higher peak and lower best ferritin but not the percentage reduction (Table). Higher TNF (90.3 pg/ml vs 37.2 pg/ml, p = 0.05), markedly elevated levels of IL-6 (92% vs 50%, p = 0.03) and IL-10 (33% vs 0%) and an IL-6 response (44.4% vs 0%) were associated with survival at day 100. IL-6 responders had lower peak ferritin vs IL-6 nonresponders (14066 mcg/L vs 45051 mcg/L, p = 0.08). Enterococcus faecium bacteremia developed in 75% of the nonsurvivors vs 16.6% of the 100-day survivors (p = 0.009). Survivors cleared the enterococcus bacteremia within days while nonsurvivors had protracted bacteremia. Conclusions: IEC-HS is devastating complication of CART. Anti-cytokine therapy can reduce some cytokines and ferritin but overimmunosuppression may lead infectious complication, in particular with E. faecium. Better biomarkers are needed to finetune immunosuppressive therapy in order to avoid over-immunosuppression. [Table: see text]

7515 Background: BCMA directed CAR T cells, antibody drug conjugates (ADCs), and T cell engagers (TCEs) each have distinct strengths and weaknesses. While these agents have shown unprecedented response rates and survival outcomes, no head-head comparisons exist. We assessed the relative efficacy of different BCMA-therapies in relapsed myeloma, with a focus on high-risk subgroups. Methods: Retrospective study of MM patients treated at Mayo Clinic with commercial or investigational BCMA targeted therapies between April 2018-June 2023. Results: 385 patients (ADC=59, TCE=134, CAR T=192) with a median follow up of 20-months. The median time from diagnosis was 6.1 years. The table shows disease, and treatment characteristics. Amongst ADCs and TCEs recipients, the median treatment duration was 1.9 and 3.5 months respectively, disease progression (64% and 79%) and intolerance (22% and 10%) were the most common reasons for discontinuation. The overall response rates were 27, 50, and 86% for ADCs, TCEs and CAR T, respectively. Compared to ADCs, CAR T was associated with improved PFS (adjusted HRPFS=0.29, 95%CI=0.20-0.43) and OS (aHROS=0.28, 95%CI=0.18-0.44) when adjusting for age, R-ISS, double hit high risk cytogenetic abnormalities (HRCAs), extramedullary disease (EMD, excluding paraskeletal plasmacytomas), triple class refractoriness, and the number of lines of therapy (LOTs) received in the preceding 1 year. Likewise compared to ADCs, TCEs were associated with superior PFS (aHRPFS=0.59, 95%CI=0.40-0.86) and OS (aHROS=0.60, 95%CI=0.39-0.93). Amongst patients with plasma cell leukemia (PCL) or EMD at the time of BCMA therapy (n=123), median PFS was poor irrespective of the therapeutic class at 1.3, 1.7 and 6.1 months for ADCs, TCEs and CAR T, respectively. Equally, for patients previously treated with BCMA therapy (n=58), median PFS was poor regardless of class at 1.9, 2.4 and 3 months for ADCs, TCEs and CAR T, respectively. Of 229 relapses the mode of relapse was known in 192 cases (84%), with 101 (52%) having EMD at relapse. Conclusions: While contingent on myriad other factors, patients able to receive BCMA-directed CAR T therapy experience superior survival compared to ADC and TCEs. EMD, PCL and BCMA-exposed populations are recalcitrant to BCMA-directed immunotherapy, and EMD is a common means of relapse. [Table: see text]

e14535 Background: Cytokine release syndrome (CRS) is the most common complication of chimeric antigen receptor T cells (CAR-T) for hematologic malignancies. We hypothesized that patients undergoing CAR-T therapy who are on metformin will experience a lower incidence or severity of CRS than patients not on this medication. Methods: We evaluated all patients treated with CAR-T at Mayo Clinic Rochester between 1/1/2018 and 1/31/2023, and abstracted relevant clinical and laboratory characteristics to determine the incidence and severity of CRS, PFS as well as OS in patients who were, or were not, on metformin before and during CAR-T therapy for Type 2 diabetes mellitus. We used the Chi-Square test, Mann-Whitney test and the Kaplan-Meier method to analyze data. Results: In the 5-year interval under consideration 237 patients received CAR-T, 168 for non-Hodgkin lymphoma (NHL), and 69 for multiple myeloma (MM). 23 patients (15 NHL and 8 MM) were on metformin at the time of CAR-T. 15 patient developed CRS while on metformin and 175 patients not on metformin (p=0.05). Grade 3 or 4 CRS incidence was 4% in both groups (p=0.41). Of the 153 patients with NHL not on metformin, 121 developed any grade of CRS, while 10 of 15 patients on metformin developed CRS (p=0.268). 4 NHL patients developed CRS Grade ≥3 or higher, while 0 of 15 on metformin developed Grade ≥3 CRS (p=0.237). For the MM patients, the incidence of CRS was 49 patients not on metformin and 5 patients on metformin (p<0.001). 3 MM patients developed CRS Grade ≥3 or higher, while 0 of 8 on metformin developed Grade ≥3 CRS (p=0.346). 12 of 15 patients on metformin with NHL achieved CR compared to 92 of 153 patients not on metformin (p=0.1305). 3 of 8 patients with MM on metformin compared to 24 of 61 patients with MM not on metformin achieved CR or better post CAR-T (p=0.92). Tocilizumab was used in 40% of patients on metformin but in 66% of patients not on metformin (p=0.0016). In NHL patients, PFS from CAR-T infusion was not reached (range: 6.3 to NR) for patients on metformin versus 9.9 months (range: 6.3–19.5) in patients not on metformin (p = 0.3332). In the MM patients, progression-free survival (PFS) from CAR-T infusion was 8.4 months (95% CI: 7.9–not reached [NR]) for patients on metformin and 22.6 months (13.7–NR) for those not on metformin (p = 0.07). Median OS for NHL patients on metformin was not reached (9.766–NR) versus 32.6 months (18.6–NR) for patients not on metformin (p = 0.7022). Median OS was 17 months (95% CI: 8.3 to NR) for patients with MM on metformin vs NR (95% CI: 9.4 to NR) for patients not on metformin (p = 0.2559). Conclusions: In this retrospective study, the co-administration of metformin during CAR-T cell therapy for NHL and MM appears to be associated with a numerically reduced incidence of CRS. The effect appears to be particularly marked in patients with multiple myeloma. Metformin therapy did not seem to affect the response to CAR-T therapy in either NHL or MM.

AbstractSeveral tools exist for assessing frailty in multiple myeloma (MM), but most are based on clinical trial datasets. In this study, we evaluate the prognostic impact of frailty based on the cumulative deficit frailty index (FI), and the prognostic impact of relationship and socioeconomic status (SES) in newly diagnosed MM patients. This is a retrospective study including 515 patients with MM seen at Mayo Clinic (Rochester, MN) at diagnosis between 2005–2018. The FI was calculated using patient-reported data on activities of daily living and comorbidity data. Items were scored as 0/0.5/1, with 1 indicating deficit. The FI was calculated by adding individual scores and dividing that by the number of non-missing items. Frailty was defined as FI ≥ 0.15; 61% were non-frail and 39% were frail. Frailty and non-married/relationship status were associated with higher disease stage, decreased likelihood of early transplantation, and independently associated with decreased survival. SES was not independently associated with survival. Frail patients reported worse scores for fatigue, pain, and quality of life. In conclusion, a cumulative deficit FI was associated with higher symptom burden and decreased survival in a real-world cohort of newly diagnosed MM patients. Social support has prognostic value and should be assessed in clinical practice.

Abstract Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018–2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20–0.43) and TCEs (aHR = 0.62, 95%CI = 0.43–0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18–0.44) and TCEs (aHR = 0.60, 95%CI = 0.39–0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable.

Background: GLUT4 inhibition via the use of a protease inhibitor, such as nelfinavir (NEL), is an attractive therapeutic option in multiple myeloma (MM), given the dependence of MM cells on glucose. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor, such as metformin (MET), may counter the possibility of therapeutic resistance to GLUT4 inhibition in MM cells, showing synergistic promise (Dalva-Aydemir et al., Clin Can Res 2015). In addition to GLUT4 inhibition, NEL also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (BOR) (Driessen et al., Blood 2018). Thus, this study evaluated the safety and tolerability of repurposing MET and NEL, in combination with BOR for the treatment of relapsed/refractory MM (RRMM) that had progressed on all standard of care (SOC) therapies. Methods: This trial utilized a 3+3 dose escalation design with 3 dose levels planned for up to a maximum of six (21-day) cycles. MET was administered for 14/21 days and started at a dose of 500 mg BID with plans to be investigated at a maximum dose of 1000 mg BID. NEL was administered for 14/21 days and started at a dose of 1250 mg BID with plans to be investigated to a maximum dose of 2500 mg BID. SubQ BOR was administered on days 1, 8, and 15 of a 21-day cycle at a dose of 1.3 mg/m 2 to a portion of patients. Patients with RRMM were required to have had 2 prior lines of therapy and prior exposure to proteasome inhibitors (PIs), immunomodulators (IMiDs), and Anti-CD38 monoclonal antibodies. The primary objective was to determine the maximal tolerated dose (MTD) of this combination. The secondary objective was to evaluate the safety as well as the overall response rate (ORR) of this combination. This trial was funded by the Helen Diller Family Foundation. Results: From 4/2019 until 9/2022, nine patients were accrued with a median age of 65 (range: 42-81) that received a median of 7 prior lines of therapy (Range: 6-13). All but one patient had a prior autologous stem cell transplant. Only one patient was not triple-class refractory, and 2/3 rd (n = 6) also had prior anti-BCMA therapy. The first three patients received only MET (500 mg BID) and NEL (1250 mg BID) at the first dose level for up to one cycle before experiencing progressive disease and coming off the study. Given the limited activity of MET and NEL in the initial treatment of these three patients, two subsequent amendments to the protocol allowed for the upfront addition of BOR 1.3 mg/m2 to the original combination, as well as shortened the DLT evaluation period from two cycles to just one. Thus, the following six patients received MET (500 mg BID) and NEL (1250 mg BID) at the first dose level in addition to weekly BOR at 1.3 mg/m2. Four (44%) patients experienced grade 3+ hematological AEs and six (67%) experienced grade 3+ non-hematological AEs. The most common hematologic grade 3+ AE observed was anemia (44%). The nonhematologic grade 3+ AEs observed were dyspnea, fatigue, nausea, and vomiting (11% each). None of the AEs were possibly related to treatment, suggesting good overall safety of the combination. While eight of nine patients have since died of progressive disease, no deaths were attributable to the treatment. All six patients who received BOR upfront with MET and NEL were previously refractory to BOR in prior lines of therapy; however, none had received BOR as their last line of therapy prior to accrual to this study. Four of these six patients had progressive disease after one cycle of therapy and went off study. However, the remaining two were able to receive 2 or more cycles of therapy, with one experiencing an unconfirmed minor response (MR) in the first cycle and the other experiencing stable disease (SD) for all six cycles. The patient who experienced SD was safely able to transition to a subsequent clinical trial utilizing an anti-BCMA bispecific antibody therapy and remains alive at the time of this analysis. The study was closed before accrual to the next dose level was started. Conclusions: This is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of RRMM. While no ORR was observed, identification of biomarkers used for selection of patients with no other SOC options who could experience at least SD responses may be beneficial in allowing this combination to slow or stabilize the disease progression until other novel therapies or clinical trials are available.