Newly Diagnosed Multiple Myeloma Research Articles

Dynamic changes in γδT cells and bone resorption markers after zoledronic acid in multiple myeloma: A prospective study

We conducted a prospective evaluation for the dynamic change of γδT cells in peripheral blood (PB) and N-telopeptide of type I collagen in urine (uNTX) of patients diagnosed with multiple myeloma (MM) who underwent their initial treatment with zoledronic acid (ZOA; Zobonic®, TTY, Taiwan). Between March 2012 and November 2015, a total of 35 patients were enrolled, including 25 newly diagnosed MM (NDMM) patients. The percentage of γδT cells in PB was assessed at 20 days prior to the first ZOA infusion, then at day 8, day 64, and day 85 after the infusion. Simultaneously, uNTX levels were measured as well. Thirty-three patients who had received at least one dose of ZOA were included in subsequent analysis. We identified three dynamic change patterns for γδT cells: fluctuated pattern, continuously increasing pattern, and continuously decreasing pattern. Among NDMM patients, those exhibiting a continuously increasing pattern showed a significantly shorter overall survival compared to those with the other two patterns combined (4.7 months vs. 92.9 months, p = 0.037). For uNTX, which levels significantly decreased following ZOA treatment. In conclusion, our findings reveal three distinct dynamic change patterns for γδT cells after ZOA initiation, with continuously increasing pattern being associated with a poor prognosis. These findings prompt further inquiry into the role of γδT cells in MM patients and support the suppressive nature of γδT cells and their associated tumor microenvironment.

Comprehensive analysis of clinical outcomes, infectious complications and microbiological data in newly diagnosed multiple myeloma patients: a retrospective observational study of 92 subjects

Patients with multiple myeloma (MM) have an increased risk of sepsis due to underlying disease- and treatment-related immunosuppression. However, data on sepsis incidence, causative pathogens, and impact on outcomes in newly diagnosed MM (NDMM) are limited. We conducted a retrospective observational study of 92 NDMM patients who developed sepsis between 2022 and 2023 at a tertiary care center in Italy. Patient characteristics, sepsis criteria [Quick Sequential Organ Failure Assessment, Systemic Inflammatory Response Syndrome (SIRS)], microbiology results, and associations with progression-free survival (PFS) were analyzed. In this cohort of 92 critically-ill patients, pathogenic organisms were identified via microbiological culture in 74 cases. However, among the remaining 18 culture-negative patients, 9 exhibited a SIRS score of 2 and another 9 had a SIRS score of 4, suggestive of a clinical presentation consistent with sepsis despite negative cultures. Common comorbidities included renal failure (60%), anemia (71%), and bone disease (83%). Gram-negative (28%) and Gram-positive (23%) bacteria were frequent causative organisms, along with fungi (20%). Cox Univariate analyses for PFS showed statically significant HR in patients with albumin ≥ 3.5 vs < 3.5 (HR = 5.04, p < 0.001), Karnofsky performance status ≥ 80 vs < 80 (HR = 2.01, p = 0.002), and early-stage vs late-stage disease by International Staging System (HR = 4.76 and HR = 12.52, both p < 0.001) and Revised International Staging System (R-ISS III vs R-ISS I, HR = 7.38, p < 0.001). Sepsis is common in NDMM and associated with poor outcomes. Risk stratification incorporating sepsis severity, comorbidities, and disease stage may help guide preventive strategies and optimize MM management.

Percutaneous vertebroplasty/kyphoplasty contributes to the improved outcome in patients with newly diagnosed multiple myeloma: A single center cohort study

ObjectiveTo evaluate the efficacy and prognosis of percutaneous vertebroplasty/kyphoplasty (PVP/PKP) in patients with newly diagnosed multiple myeloma (NDMM). MethodsClinical data of NDMM patients who underwent PVP/PKP during front-line regimen at Peking Union Medical College Hospital from January 1, 2003, to June 30, 2023, were analyzed. Patients with comparable bone diseases not receiving orthopedic surgery were selected as controls. Visual analogue scale (VAS) score, progression-free survival (PFS), and overall survival (OS) were compared. ResultsBaseline characteristics were matched between the surgical group (n = 51 with 56 surgeries) and non-surgical group (n = 102), including demographics, tumor load, International Staging System (ISS), bone diseases, cytogenetic abnormalities, first-line treatment, and autologous stem-cell transplantation (ASCT). Bone lesions for PVP/PKP were located at thoracic vertebrae (53.6 %, 30/56) or lumbosacral vertebrae (46.4 %, 26/56). The postoperative VAS score was significantly improved (2.25 ± 0.81 vs 5.92 ± 1.05, P < 0.001). The median follow-up time was 51[38–70] months. Kaplan-Meier survival analysis suggested that both PFS (37[17–89] vs 23[12–61] months, HR 0.648, 95 %CI 0.431–0.973, P = 0.047) and OS (not reached vs 66[28-NR] months, HR 0.519, 95 %CI 0.296–0.910, P = 0.045) were significantly prolonged in the surgical group. COX multivariate analysis suggested that PVP/PKP was an independent prognostic factor for PFS (P = 0.021, HR 0.589, 95 %CI 0.376–0.922) and OS (P = 0.038, HR 0.496, 95 %CI 0.255–0.963). Subgroup analysis confirmed that patients with ISS II/III or non-ASCT achieved better PFS and OS in the surgical group (PFS: P = 0.033, P = 0.040; OS: P = 0.024, P = 0.018 respectively), while similar survival outcome was observed in patients with ISS I or ASCT between two groups. ConclusionFor NDMM patients, not only does PVP/PKP alleviate bone pain, meanwhile, it improves the PFS and OS in advanced subpopulation or non-transplant myeloma patients, which suggests that shortening the gap from symptom onset to diagnosis by orthopedic surgery favors clinical prognosis.

Low circulating tumor cell levels correlate with favorable outcomes and distinct biological features in multiple myeloma.

There is growing interest in multiple myeloma (MM) circulating tumor cells (CTCs), but their rareness in peripheral blood (PB) and inconsistency in cutoffs question their clinical utility. Herein, we applied next-generation flow cytometry in 550 bone marrow (BM) and matched PB samples to define an optimal CTC cutoff for both transplant-eligible and transplant-ineligible newly diagnosed MM (NDMM) patients. Deep phenotyping was performed to investigate unique microenvironmental features associated with CTC dissemination. CTCs were detected in 90% of patients (median 0.01%; range: 0.0002%-12.6%) and increased levels associated with adverse features. Correlations were observed between high CTC percentages and a diffused MRI pattern, a distinct BM composition characterized by altered B-cell differentiation together with an expansion of effector cells and tumor-associated macrophages, as well as a greater phenotypic dissimilarity between BM and PB clonal cells. Progression-free survival (PFS) and overall survival (OS) gradually worsened with each logarithmic increment of CTCs. Conversely, NDMM patients without CTCs showed unprecedented outcomes, with 5-year PFS and OS rates of 83% and 97%, respectively. A cutoff of 0.02% CTCs was independent of the ISS, LDH, and cytogenetics in a multivariate analysis of risk factors for PFS. The 0.02% CTC cutoff synergized with the MGUS-like phenotype and the R-ISS for improving the risk stratification systems. MRD negativity was less frequent if CTCs were ≥0.02% at diagnosis, but whenever achieved, the poor prognosis of these patients was abrogated. This study shows the clinical utility of CTC assessment in MM and provides evidence toward a consensus cutoff for risk stratification.

Trends in Outcomes After Upfront Autologous Transplant for Multiple Myeloma Over Three Decades

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.

Quality of life gains in frail and intermediate-fit patients with multiple Myeloma: Findings from the prospective HOVON123 clinical trial

BackgroundFrailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent. MethodsThe HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID). Results137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients. ConclusionHRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration.

Hallmarks of tumor-experienced T cells are absent in multiple myeloma patients from diagnosis through maintenance therapy.

Dysregulation of the bone marrow (BM) niche in multiple myeloma (MM) alters the composition and state of resident immune cells, potentially impeding anti-tumor immunity. One common mechanism of immune inhibition in solid tumors is the induction of exhaustion in tumor-specific T cells. However, the extent of T cell tumor recognition and exhaustion is not well-characterized in MM. As the specific mechanisms of immune evasion are critical for devising effective therapeutic strategies, we deeply profiled the CD8+ T cell compartment of newly-diagnosed MM (NDMM) patients for evidence of tumor reactivity and T cell exhaustion. We applied single-cell multi-omic sequencing and antigen-specific mass cytometry to longitudinal BM and peripheral blood (PB) samples taken from timepoints spanning from diagnosis through induction therapy, autologous stem cell transplant (ASCT), and maintenance therapy. We identified an exhausted-like population that lacked several canonical exhaustion markers, was not significantly enriched in NDMM patients, and consisted of small, nonpersistent clones. We also observed an activated population with increased frequency in the PB of NDMM patients exhibiting phenotypic and clonal features consistent with homeostatic, antigen-nonspecific activation. However, there was no evidence of "tumor-experienced" T cells displaying hallmarks of terminal exhaustion and/or tumor-specific activation/expansion in NDMM patients at any timepoint.

Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65–79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10−5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10−5 were reported in 35 patients (26%, 95% confidence interval (CI) 19–34) in IsaRd versus 71 (53%, 95% CI 44–61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89–5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10−5 and 10−6, and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10−5, the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877.

The Effect of Age and Other Patient Characteristics on Outcomes Among Nontransplanted Patients Who Were Treated With First-Line Lenalidomide, Bortezomib, and Dexamethasone: Results From the ConnectⓇ MM Registry

BackgroundLenalidomide (R), bortezomib (V), and dexamethasone (d) is a standard-of-care regimen in newly diagnosed multiple myeloma (NDMM); however, characteristics and outcomes for nontransplanted patients receiving frontline RVd are not well understood. PatientsThe ConnectⓇ MM Registry is a large, US, multicenter, prospective observational cohort study of NDMM patients. MethodsThis analysis investigated characteristics and outcomes of patients who received RVd alone or followed by Rd or R (RVd ± Rd/R) who did not undergo frontline autologous stem cell transplantation. ResultsAs of August 2021, 314 of 1979 nontransplanted patients received RVd ± Rd/R as initial therapy. Of these, 135 were aged ≤ 65 years and 179 were > 65 years. 108 patients had time to relapse (TTR) of ≤ 12 months and 182 had TTR > 12 months. Baseline characteristics were comparable regardless of TTR and age group except renal function, which was more commonly impaired in older patients. Among patients aged ≤ 65 and > 65 years, median duration of first-line treatment was 6.3 and 9.0 months, median time to next line for those who received second-line therapy was 15.5 and 15.2 months, median progression-free survival (PFS) was 19.3 and 23.0 months, and median overall survival was 60.0 and 59.1 months, respectively. High-risk disease (per IMWG criteria) and high serum calcium were associated with higher hazard of progression or death; the adjusted PFS hazard ratio with respect to age (≤ 65 vs. > 65 years) based on multivariable analysis was 1.18 (0.89-1.57; P = .25). ConclusionThese results indicate RVd is active across age groups and provide a better understanding of outcomes with RVd in NDMM.

Clinical Significance of Serum ADA Combined with GLB, CREA, β2-MG and HGB in Newly Diagnosed Multiple Myeloma

To investigate the role of serum adenosine deaminase (ADA) combined with globulin (GLB), creatinine (CREA), β2-microglobulin (β2-MG) and hemoglobin (HGB) in the initial screening of multiple myeloma (MM), in order to reduce missed diagnosis and misdiagnosis of MM. A retrospective analysis was performed on 62 newly diagnosed multiple myeloma (NDMM) patients who were admitted to the Department of Hematology of the First Affiliated Hospital of Chengdu Medical College from April 2018 to December 2021, and 33 patients with benign hematologic diseases and 30 healthy subjects were selected as the control group. The expression of ADA in pan-cancer was analyzed using TCGA and GTEx databases. The general data and laboratory indicators of the subjects were collected, and the differences of ADA activity and other laboratory indicators in each group were compared. The relationship between serum ADA activity and clinical data of NDMM patients was analyzed. The changes of ADA activity before and after chemotherapy in NDMM patients and the differences of ADA activity in NDMM patients with different DS and ISS stages were compared. Multivariate logistic regression was used to analyze the risk factors of NDMM. The receiver operating characteristic(ROC) curve was used to evaluate the diagnostic efficacy of ADA and other laboratory indicators in MM. Bioinformatics method was used to analyze the co-expression networks and enrichment pathways of ADA. ADA level was significantly upregulated in tissues of 14 types of cancer in TCGA database, and ADA was highly expressed in 11 types of cancer in TCGA combined with GTEx databases. The serum levels of ADA, GLB, uric acid (UA), cystatin C (CysC) and β2-MG in the NDMM group were significantly higher than those in benign hematologic disease group and healthy control group ( P < 0.05), while the levels of ALB and the value of albumin to globulin ratio (A∶G) in the NDMM group were significantly lower than those in the other two groups ( P < 0.001). There were significant differences in DS stage (P =0.036), ISS stage (P =0.019) and the levels of CREA (P =0.036), UA (P =0.034), β2-MG (P =0.019) in NDMM patients with different ADA activity levels. After primary chemotherapy, ADA activity and β2-MG concentration were decreased in NDMM patients ( P < 0.01). The comparison results of patients in different stages showed that ADA activity of patients in DS stage I+II was significantly lower than that of patients in DS stage III (P <0.05), and ADA activity of patiens in ISS stage I+II was significantly lower than that of patients in ISS stage III ( P < 0.01). Multivariate logistic regression analysis showed that increased GLB, increased ADA activity, increased CREA, increased β2-MG and decreased HGB were independent risk factors for NDMM. The area under the curve (AUC) of ADA in the diagnosis of MM was 0.847, and the AUC of ADA combined with GLB, CREA, β2-MG and HGB in the diagnosis of MM was 0.940. The results of co-expression network and enrichment pathway analysis showed that ADA bounded to 20 proteins and it was significantly associated with the metabolic pathways of purine, pyrimidine, nicotinate and nicotinamide. The detection of ADA activity in serum is of positive significance for the auxiliary diagnosis, therapeutic evaluation and monitoring the progress of NDMM patients. ADA combined with GLB, CREA, β2-MG and HGB can improve the detection rate of MM, and reduce missed diagnosis and misdiagnosis to a certain extent.

Safety results from the phase 3 MajesTEC-7 study in patients (pts) with transplant ineligible/not intended newly diagnosed multiple myeloma (NDMM).

7506 Background: Despite recent advances in the treatment (tx) of transplant ineligible/not intended NDMM, most pts still relapse and require alternative txs, highlighting a need for new frontline tx options with new mechanisms of action to improve pt outcomes. Teclistamab (tec) demonstrated rapid, deep, and durable responses in the MajesTEC-1 trial (NCT03145181/NCT04557098). Preliminary data from the MajesTEC-2 trial (NCT04722146) demonstrated that tec, daratumumab (dara), and lenalidomide (len) combination (tec + DR) is tolerable, with promising efficacy in pts with relapsed/refractory MM and NDMM. The phase 3 MajesTEC-7 (NCT05552222) study will compare tec + DR vs DR + dexamethasone (dex) in pts with NDMM who are ineligible/not intended for ASCT as initial tx. We report the results of the first safety run-in (SRI) from MajesTEC-7. Methods: Eligible patients were aged ≥18 yrs with NDMM and ineligible/not intended for ASCT as initial tx, with measurable disease and an ECOG performance status (PS) score 0–2. Pts in the SRI received tec (step-up dose [cycle 1], QW [cycle 2], Q2W [cycle 3–6], and Q4W [cycle 7+]) + DR (as SOC) until progression, unacceptable toxicity, or death. Response assessments were based on IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Prophylactic immunoglobulin replacement was highly recommended. Results: As of Nov 27, 2023, 26 pts had received tec + DR (median, 11 cycles; range, 2–14) and 24 pts (92.3%) remained on tx. Median follow-up was 10.2 mo (range, 2–12). At baseline, median age was 72.5 yrs, 11.5% had an ECOG PS score of 2, and 15.4% had ≥1 soft-tissue plasmacytoma. 4 pts (15.4%) deferred transplant. Treatment-emergent AEs (TEAEs) occurred in 100% of pts (grade [gr] 3/4, 22 pts [84.6%]). Infections occurred in 25 pts (96.2%; gr 3/4, 8 pts [30.8%]). CRS occurred in 16 pts (61.5%; all gr 1). ICANS occurred in 1 pt (gr 1). Gr 3/4 TEAEs occurring in ≥3 pts were neutropenia (13 [50%]), febrile neutropenia (5 [19.2%]), thrombocytopenia (4 [15.4%]), COVID-19 (3 [11.5%]), maculo-papular rash (3 [11.5%]), and hypertension (3 [11.5%]). 1 pt discontinued tec + DR due to withdrawal of consent. 2 discontinued len due to TEAEs (gr 3 maculo-papular rash and gr 4 neutropenia). There was 1 death due to a TEAE in cycle 3 (pneumonia influenza). Overall response rate was 92.3% (complete response or better, 73.1%; very good partial response or better, 92.3%). Conclusions: These results from the first SRI of MajesTEC-7 demonstrate a manageable safety profile with early efficacy of tec + DR in NDMM. Two additional SRIs are ongoing investigating tec (less frequent dosing) + DR and talquetamab + DR. Clinical trial information: NCT05552222 .

Efficacy and safety of ciltacabtagene autoleucel ± lenalidomide maintenance in newly diagnosed multiple myeloma with suboptimal response to frontline autologous stem cell transplant: CARTITUDE-2 cohort D.

7505 Background: CARTITUDE-2 is a phase 2 multicohort study evaluating ciltacabtagene autoleucel (cilta-cel) across various clinical settings. Cohort D is evaluating cilta-cel ± lenalidomide (len) maintenance in patients (pts) with newly diagnosed multiple myeloma (NDMM) who achieved less than complete response (CR) after autologous stem cell transplant (ASCT) frontline therapy (tx). We report efficacy and safety for this cohort. Methods: Adults with NDMM per IMWG criteria, best response of &lt;CR and ≥stable disease after 4–8 cycles of initial tx, including induction, high-dose chemotherapy and ASCT ± consolidation, and without exposure to CAR-T or anti-BCMA tx received a single cilta-cel infusion (target dose, 0.75×106 CAR+ viable T cells/kg) 5–7 d after the start of lymphodepletion. Per protocol, safety was assessed in the first 5 pts with cilta-cel only; subsequently, 12 pts initiated continuous len maintenance ≥21 d post cilta-cel for ≤2 yrs. Primary endpoint was minimal residual disease negativity (MRD neg) at 10–5 based on next-generation sequencing or flow. Results: As of Sept 5, 2023 (median follow-up, 22 mo [range, 5–39]), 17 pts received cilta-cel (with len, n=12; without len, n=5). Median age was 54 yrs; 6% had high-risk cytogenetics; and 100% were International Staging System stage I at baseline. Of 15 MRD-evaluable pts, 12 (80%) achieved MRD neg at 10–5; median time to MRD neg was 1 mo (range, 1–6). Overall response rate was 94% (n=16/17; ≥CR, 94%). Median duration of response was not reached, and median time to first response was 1 mo. Progression-free survival (investigator-assessed) and overall survival rates at 18 mo were 94% each. CAR+ T cells peaked in blood at a median of 12 d post infusion (mean, 2187 cells/µL; SD, 2102 cells/µL) and remained detectable for a median of 43 d (range, 26–209). All pts had grade (gr) 3/4 TEAEs. Hematologic TEAEs included neutropenia (94%), lymphopenia (65%), thrombocytopenia (47%), and leukopenia (41%). Infections occurred in 12 (71%) pts (gr 3/4, 29%). CRS occurred in 14 (82%) pts, and median time to onset was 8 d. All CRS events were gr 1/2 and recovered in a median of 3 d. ICANS occurred in 1 pt (gr 1); median time to onset was 7 d and recovery was 1 d. Other neurotoxicities occurred in 6 pts (gr 1, n=1; gr 2, n=4; gr 3, n=1); median time to onset was 21 d and recovery was 70 d (n=4). No MNTs/parkinsonism occurred. 1 pt had a secondary malignancy of gr 3 MDS with an onset on d 353 that was not treatment related per investigator assessment. Conclusions: In pts with NDMM and &lt;CR after frontline ASCT, a single cilta-cel infusion ± len maintenance demonstrated deep responses that were durable. TEAEs were consistent with the known safety profile of cilta-cel. These data show promising efficacy and safety with cilta-cel ± len maintenance in pts with NDMM who achieved &lt;CR after ASCT frontline tx. Clinical trial information: NCT04133636 .

Effects of socioeconomic status (SES) and healthcare resource (HCR) availability on survival in Black patients (pts) versus (vs) White pts with multiple myeloma (MM): A SEER Medicare analysis.

e13678 Background: In MM, disparities exist for overall survival (OS) by race, and many factors may contribute to these differences. This study evaluates whether SES and HCR availability impacts OS in older pts with newly diagnosed MM (NDMM) based on race. Methods: This retrospective study used linked SEER-Medicare claims (diagnosis [Dx] 6/1/2013–12/31/2017) and Area Health Resource Files (AHRFs; from 2018) to identify non-Hispanic White and non-Hispanic Black pts aged ≥66 years with NDMM. AHRFs included county-level HCR availability data (e.g. number of long-term hospital beds, medical doctors [MDs]). Continuous Medicare A and B enrollment until 12/31/2019 or preceding death was required. Pts with other cancers, Dx from death data, missing county information and enrollment in health maintenance organizations or clinical trials were excluded. Kaplan-Meier was used for unadjusted median OS and Cox proportional hazards for OS risk by race. Age, sex, race, Charlson Comorbidity Index (CCI), poverty, education, and HCR availability were included in the adjusted mixed effects Cox model. Results: We identified 6,609 pts with NDMM; 15.6% were Black. For Black pts vs White pts, median age at Dx was 76 vs 77 years, 57.1% vs 46.0% were female, and mean CCI was 2.1 vs 1.4 (p&lt;.001 for all). Within census tracts, mean percentage of pts living under the poverty line and received &lt;12 years of education was 21.2% vs 11.3% (p&lt;.001) and 19.0% vs 11.3% (p&lt;.001) for Black pts vs White pts, respectively. Unadjusted median OS for Black pts vs White pts was 2.76 vs 3.01 years (hazard ratio [HR]: 1.08; p=.063). In the adjusted model, several SES and HCR availability factors were significant. OS HR by race reversed directionality when adjusted for demographics, SES and HCR availability, but this was not significant (HR: 0.92; p=.12; Table). Conclusions: We found that Black pts with NDMM in SEER-Medicare claims were younger, had higher CCI, completed less education, and were more likely to live in census tracts with higher poverty percentages vs White pts. Several factors relating to SES and HCR availability significantly influenced OS and may drive disparities in care. Further research on larger datasets is needed to better understand these disparities. [Table: see text]

Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial.

7502 Background: In the primary analysis of the phase 3 PERSEUS study, subcutaneous DARA (DARA SC) + VRd (D-VRd) induction/consolidation (ind/consol) and D-R maintenance improved progression-free survival (PFS) and increased depth of response (complete response or better [≥CR] and MRD negativity [neg]) compared to VRd ind/consol and R maintenance for TE NDMM. Here, we report further results on deepening of response and MRD neg during maintenance. Methods: TE pts with NDMM were randomized 1:1 to D-VRd or VRd. Pts in both arms received up to six 28-day cycles (4 pre-ASCT ind, 2 post-ASCT consol) of VRd (V 1.3 mg/m2 SC on Days [D] 1, 4, 8, 11; R 25 mg PO on D 1-21; d 40 mg PO/IV on D 1-4, 9-12) followed by R maintenance (10 mg PO on D 1-28 until progressive disease [PD]). Pts in the D-VRd arm also received DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W during maintenance until PD. MRD-neg rate (clonoSEQ) was defined as the proportion of ITT pts who achieved both ≥CR and MRD neg. Results: In the 709 pts randomized (D-VRd, n=355; VRd, n=354), responses deepened over time with D-VRd vs VRd, including rates of ≥CR (end of consol: 44.5% vs 34.7%; P= 0.0078 and overall: 87.9% vs 70.1%; P&lt;0.0001). MRD-neg rates increased over time and were higher with D-VRd vs VRd at 12, 24, and 36 mo after Cycle 1 Day 1 (all P&lt;0.0001; Table). Rates of sustained MRD neg for ≥12 mo were higher for D-VRd vs VRd (10–5: 64.8% vs 29.7%; P&lt;0.0001; 10–6: 47.3% vs 18.6%; P&lt;0.0001); results were consistent across prespecified clinically relevant subgroups. Among pts who were MRD positive (pos) at end of consol, significantly higher proportions of pts in the D-VRd group vs the VRd group achieved MRDneg during maintenance at 10−5 (60.2% vs 40.5%; P= 0.0049) and 10−6 (56.7% vs 25.2%; P&lt;0.0001) and sustained MRD neg for ≥12 mo at 10−5 (38.6% vs 17.4%; P= 0.0006) and 10−6 (31.3% vs 10.3%; P&lt;0.0001). End of consol and overall MRD neg at both 10–5 and 10–6 were associated with improved PFS. Additional data on response rates in different study phases and sustained MRD neg will be presented. Conclusions: During maintenance, a greater proportion of pts with MRD-pos status achieved MRD neg with D-R vs R. The higher rates of deep (10–6) and sustained MRD neg achieved with D-VRd ind/consol and D-R maintenance vs VRd ind/consol and R maintenance translated to a clinically meaningful benefit of improved PFS. These data further support D-VRd and D-R maintenance as a new standard of care for TE pts with NDMM and highlight the benefit of DARA SC in maintenance. Clinical trial information: NCT03710603 . [Table: see text]

Navigating High-Risk and Ultrahigh-Risk Multiple Myeloma: Challenges and Emerging Strategies.

Despite significant improvement in the outcomes of patients with newly diagnosed multiple myeloma (NDMM) with novel therapies, there is still an underserved high-risk (HR) population that experiences early disease progression and death. With the median survival crossing 10 years, we defined ultrahigh-risk (uHR)MM as MM leading to death within 24-36 months of diagnosis and HRMM as MM leading to death within 36-60 months. Several features have emerged as markers of uHRMM: the co-occurrence of two or more high-risk cytogenetic abnormalities, extramedullary disease, plasma cell leukemia and a high-risk gene expression profiling signature. The heterogeneous risk definition across trials, the few trials available designed for HR patients, and the small HR subgroups in all-comers trials make it difficult to generate recommendations with high levels of evidence. Nevertheless, regardless of treatment administered, several studies consistently showed that achieving and maintaining measurable residual disease negativity is now considered the main factor able to mitigate the adverse prognosis related to baseline features. For fit patients with HR transplant-eligible (TE) NDMM, quadruplet induction/consolidation treatment with anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors and dexamethasone, and autologous stem-cell transplant and maintenance with, if available, at least a doublet combination could be considered the option of choice. For non-TE NDMM, considering the recent data generated and carefully reviewing those upcoming, quadruplet treatment consisting of anti-CD38 monoclonal antibodies, immunomodulatory agents, proteasome inhibitors, and dexamethasone should also be considered. Future trials integrating BCMA-directed novel generation immunotherapies hold great potential for further advancing the treatment landscape in all NDMM patients with HR disease.

Myc rearrangement redefines the stratification of high-risk multiple myeloma.

Myc rearrangement (Myc-R) is a controversial factor linked to adverse outcomes in newly diagnosed multiple myeloma (NDMM). This study aimed to evaluate the impact of Myc-R on the prognosis of NDMM patients and its role in risk stratification compared with traditional high-risk cytogenetic abnormalities (HRCAs). A total of 417 NDMM patients enrolled from May 2009 to September 2022 were included. Fluorescence insitu hybridization (FISH) was used to detect Myc-R and other Myc abnormalities (Myc-OA). Median progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and log-rank tests. Multivariate Cox regression analysis was used to identify independent risk factors. Myc-R was identified in 13.7% of patients, while 14.6% had Myc-OA. Patients with Myc-R had significantly shorter median PFS (15.9 months) and OS (25.1 months) compared with those with Myc-OA (24.5 months PFS; 29.8 months OS) and Myc-negative (Myc-N) status (29.8 months PFS, 29.8 months OS). Myc-R was independently associated with worse PFS and OS compared to Myc-OA. Patients with Myc-R alone had inferior median PFS (15.9 months vs. 28.1 months, p = 0.032) and OS (25.1 months vs. 61.2 months, p = 0.04) compared to those with traditional single HRCA. The study suggests that traditional single HRCA may not significantly impact survival in NDMM patients. However, incorporating Myc rearrangement or traditional double/triple-hit HRCAs into the risk stratification model improves its predictive value, highlighting the importance of Myc rearrangement in risk assessment. Myc rearrangement is an independent adverse prognostic factor in NDMM. The incorporation of Myc rearrangement or multiple HRCAs into risk stratification models improves their prognostic value, providing a novel perspective on high-risk factors in NDMM.

Effect of daratumumab on light chain reduction in newly diagnosed multiple myeloma with light chain cast nephropathy.

7554 Background: Light chain cast nephropathy (LCCN) is present in 16-31% of patients (pts) in newly diagnosed multiple myeloma (NDMM). In pts with an involved serum free light chain (iFLC) &gt;150mg/dL and predominant LC proteinuria, the probability of LCCN is high enough for a clinical diagnosis without the need for kidney biopsy. Early mortality is higher in pts with renal impairment (RI) who did not achieve a renal response (RR), and a rapid reduction in iFLC may predict RR. While the use of bortezomib and dexamethasone (Vd) in upfront therapy has led to marked improvements in outcomes, the optimal regimen is unclear. Methods: We included pts with NDMM and RI (creatinine &gt;2 mg/dL or eGFR &lt;40 ml/min/1.73m2) and a diagnosis of LCCN (iFLC &gt;150mg/dL and light chain proteinuria) at a single center from 2005-2023. Pts with &gt;10% albuminuria or a diagnosis of MGRS or amyloidosis were excluded. Primary outcome was FLC response (iFLC &lt;50mg/dL and &gt;90% reduction, FLC-R) at day 30 (d30). Other outcomes included hematologic response (partial response or better) at d30 and RR (minimal response or better) at d90, based on International Myeloma Working Group criteria. Results: We included 51 pts with characteristics depicted in the table. All pts received therapy with Vd, adding cyclophosphamide (VCd) in 26 (51%), daratumumab (dara, DVd) in 13 (25%), both (DVCd) in 6 (12%) and alone in 6 (12%). At d30, 11 pts (58%) in dara-containing regimens (DVd, DVCd) and 10 pts (31%) in non-dara-containing regimens (Vd, VCd) achieved a FLC-R (p=0.08); dara was associated with higher odds of achieving a FLC-R at d30 (OR 2.9, p=0.03) after adjusting for age, stage and eGFR at diagnosis. At d90, pts receiving dara had a higher rate of RR than those who did not (69% vs 58%, p=0.5); dara was associated with higher odds of a RR at d90 (OR 1.6, p=0.5). After adjusting for age, stage and eGFR at diagnosis, achieving a FLC-R at d30 was associated with higher odds of a RR at d90 (OR 8.9, p=0.02). Conclusions: Prompt reduction of iFLC is an important objective during the early treatment of LCCN in order to achieve a RR, and dara increases the odds of achieving a FLC-R. The use of dara led to higher odds of a RR at d90, but not statistically significant. We confirmed that achieving a FLC-R at d30 was associated with achieving a RR at d90. Our results suggest that the role of a dara should be explored in prospective studies for the upfront treatment of LCCN in NDMM. [Table: see text]

Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ).

7500 Background: The first line of treatment (tx) is important for patients (pts) with newly diagnosed multiple myeloma (NDMM) as pts may not have a chance for subsequent therapy. VRd is currently a standard of care (SOC) in NDMM. Isa is an approved anti-CD38 monoclonal antibody (mAb) inducing myeloma cell death through multiple mechanisms. In the Phase 3 IMROZ study (NCT03319667), we investigate the efficacy and safety of Isa-VRd vs VRd in transplant-ineligible NDMM pts. Methods: IMROZ is a global, prospective, randomized, open-label study done at 102 study sites in 21 countries. Included pts had active, measurable NDMM not considered for transplant due to elderly age or comorbidities. Pts aged ≥80 were excluded. Pts were randomized 3:2 and stratified by age, R-ISS stage and China vs non-China, to receive Isa-VRd or VRd. Isa-VRd arm pts received Isa (10 mg/kg IV); both arms received V (1.3 mg/m2 SC), R (25 mg PO) and d (20 mg IV/PO). The primary endpoint was progression-free survival (PFS). Key secondary endpoints were complete response (CR), minimal residual disease negativity (MRD-) (10-5 by NGS) in pts with CR, very good partial response or better and overall survival. Adverse events (AEs) and laboratory parameters were graded with NCI CTCAE v4.03. Results: 446 pts (265 Isa-VRd, 181 VRd) were randomized; pt characteristics were well balanced. At data cutoff (26 Sep 2023), 125 (47.2%) and 44 (24.3%) pts in Isa-VRd and VRd arms were still on tx, respectively. Median (mdn) tx duration was 53.2 (Isa-VRd) vs 31.3 (VRd) mo; addition of Isa did not significantly affect relative dose intensity of VRd. At mdn follow-up of 59.7 mo, mdn PFS was not reached (Isa-VRd) vs 54.3 mo (VRd); HR 0.596 (98.5% CI 0.406–0.876), log-rank p=0.0005. From the current trend, projected Isa-VRd mdn PFS will reach ~90 mo. PFS benefit was consistent across subgroups and maintained through subsequent line of therapy (PFS2 HR 0.697; 95% CI: 0.51-0.952). Isa-VRd led to deep and sustained responses and was well-tolerated (Table). Exposure-adjusted Grade 5 TEAE rate was 0.03 (Isa-VRd) vs 0.02 (VRd). Conclusions: IMROZ is the first Phase 3 study of an anti-CD38 mAb with SOC VRd in this pt population to show a significantly reduced risk of progression or death by 40.4% vs VRd while providing deep and sustained responses. The safety profile was consistent with addition of Isa to VRd. Numerical differences in TEAEs are largely explained by longer exposure in the Isa-VRd arm. These results support Isa-VRd as a potential new SOC in pts not intended for transplant. Clinical trial information: NCT03319667 . [Table: see text]

Effect of maintenance therapy (MT) on real-world outcomes (RWO) of patients (pts) with newly diagnosed multiple myeloma (NDMM) post stem cell transplant (SCT).

7562 Background: SCT followed by MT is the standard of care for pts with transplant-eligible (TE) NDMM. Five randomized clinical trials (RCTs) comparing lenalidomide MT versus no MT showed improved progression free survival (PFS), but no overall survival (OS) benefit except for one by McCarthy et al. that allowed pt crossover between treatment arms. Use of MT has also been associated with an increased risk of second primary malignancies and an inferior quality of life. We report RWO post SCT with and without MT in TE NDMM. Methods: We performed a multi-center, retrospective, observational study using the de-identified COTA real-world database derived from the EMRs of US centers. Pts with NDMM from 1/1/2012 to 1/1/23 were included in the study. Kaplan-Meier method was used to evaluate time to next treatment (TTNT), OS, follow-up time (reverse OS endpoint), and report log-rank test p-values. TTNT was defined in two ways: time from SCT to the earliest of initiation of next line of therapy (LOT) or death (TTNT1) and the time from 2nd LOT post-SCT to the earliest of initiation of next LOT or death (TTNT2). A propensity score (PS) matched analysis was used to compare study cohorts and report hazard ratios (HRs) using the Cox proportional hazards method. High risk cytogenetic abnormalities (HRCA) were defined as pts with 17p(-), t(4;14), t(14;16), t(14;20) and 1q+. Results: 1928 ptsmet the study criteria: 957 pts received SCT with MT (M) and 971 pts received no MT (NM). Median age at Dx was 61 y, 57% were male, 70% were White, and 31.2% had HRCA with a median follow-up of 64 months (mos) (95% CI: 61.6, 66.7). In the M vs NM arms, 29.6% and 32.7% pts had HRCA, respectively. Median TTNT1 for M vs NM was 51 vs 36 months (mos), (p&lt;0.001), respectively. Median TTNT2 for M vs NM was 11.7 vs 21.6 mos, (p&lt;0.001), respectively. Median OS for M vs NM was 108.8 mos vs 126.3 mos, (p=0.08), respectively. In the PS model, the NM group had significantly lower hazard of TTNT2 and OS events (HRs 0.65 and 0.85, p&lt;0.001 and p=0.08, respectively). Conclusions: Our study demonstrates improved TTNT2 outcomes with the NM approach. M therapy did not have an impact on OS in this cohort. Both results indicate an absence of long-term benefit with the use of M therapy. OS is a difficult primary outcome to achieve in MM RCTs where survival may have to be collected for decades. Thus, our large study of RWO with long-term follow-up is valuable. [Table: see text]

Efficacy of carfilzomib-based regimens as induction/consolidation therapy in newly diagnosed multiple myeloma: A meta-analysis.

e19535 Background: Carfilzomib (K) is a 2nd generation selective and irreversible proteosome inhibitor. It has shown encouraging results in newly diagnosed multiple myeloma (NDMM) patients. However, no direct comparisons were made among different regimens. This analysis aims to compare efficacy with different K-based regimens in NDMM. Methods: A literature search was done on PubMed and Embase with keywords for “Carfilzomib” and “multiple myeloma” till 1/1/2024. 25 articles (N = 3221) were included after screening 2800 articles. Data was collected for overall response rate (ORR), complete response (CR), minimal residual disease negativity (MRD-), 2-year progression free survival (PFS), and 2-year overall survival (OS). Survival data was extracted from visualization of Kaplan-Meier curve if not provided in text. R software was used for the meta-analysis. Results: In one trial (N = 72), ORR and CR were 90% and 7%, respectively in patients with K and dexamethasone (d). In one trial (N = 111), ORR, CR, PFS, and OS were 93%, 18%, 74%, and 96%, respectively with Kd and thalidomide (T). In six trials (N = 844), ORR, CR, MRD-, PFS, and OS were 92%, 43%, 38%, 78%, and 88%, respectively with Kd and lenalidomide (R). In one trial (N = 22), ORR, CR, and MRD-, were 100%, 64%, and 23%, respectively with Kd and Bendamustine (B). In three trials (N = 576), ORR, CR, MRD-, PFS, and OS were 82%, 23%, 16%, 48%, and 82%, respectively with Kd, and melphalan (M). In three trials (N = 189), ORR, CR, MRD-, PFS, and OS were 89%, 24%, 30%, 71%, and 89%, respectively with Kd and cyclophosphamide (Cy). In two trials (N = 63), ORR, CR, MRD-, PFS, and OS were 97%, 86%, 55%, 95%, and 100%, respectively with KRd and daratumumab (D). In one trial (N = 64), ORR, CR, PFS, and OS were 91%, 8%, 77%, and 95%, respectively with KCyTd. In one trial (N = 46), ORR, CR, MRD-, PFS, and OS were 96%, 70%, 65%, 80%, and 89%, respectively with KRd and elotuzumab (E). In one trial (N = 125), ORR, CR, MRD-, PFS, and OS were 94%, 70%, 79%, 70%, and 78%, respectively with KRd and isatuximab (I). In one trial (N = 526), ORR, CR, MRD-, and PFS were 90%, 18%, 17%, and 78%, respectively with KCyRd. In three trials (N = 280), ORR, CR, MRD-, PFS, and OS were 97%, 66%, 60%, 87%, and 94%, respectively with KRd and stem cell transplant (SCT). In two trials (N = 180), ORR, CR, MRD-, PFS, and OS were 91%, 55%, 43%, 70%, and 85%, respectively with KCyd-SCT. In one trial (N = 123), ORR, CR, MRD-, PFS, and OS were 98%, 86%, 80%, 87%, and 94%, respectively with KRDd-SCT. Conclusions: Among K based regimens, the highest response and 2-year-survival rates were achieved with KRDd, IKRd and were comparable to regimens with SCT. Highest MRD negativity was achieved with KRDd-SCT and IKRd. Hence, four drug regimens can be considered in NDMM to achieve high response and survival rates instead of SCT especially in patients who cannot tolerate or chose not to undergo SCT. Long-term results are needed to confirm these results.