Anti-myeloma Therapy Research Articles

Response to daratumumab-retreatment in patients with multiple myeloma

AbstractDaratumumab is an effective therapy in multiple myeloma (MM). We assessed whether daratumumab retreatment may re-induce significant responses and which patients do benefit the most. We hypothesized, that there is effective synergism between daratumumab and alternating antimyeloma drug combinations during retreatment and that retreatment is safe and effective. Here, we analyzed 293 consecutive MM patients receiving daratumumab at our institution from 2016 until 2023 retrospectively, and compared responses, side effects and survival of the first daratumumab treatment line and its retreatment. We identified 22/293 (8%) patients with daratumumab retreatment. These patients showed an advanced age and ISS/R-ISS stages, and ≥ 3 lines of prior antimyeloma therapy in 91%. Of note, the median durations of the first and subsequent daratumumab treatment were similarly long. We confirmed a therapy break between daratumumab lines as advantageous. Daratumumab retreatment was effective, with responses declining only gradually from its first use to subsequent first and second retreatment with 64%, 46% and 43%, respectively. Interestingly, comparable progression free survival rates were observed with 11.5, 12 months and not reached, respectively. Consistently, adverse events per daratumumab line did not increase. Our findings suggest that well-selected daratumumab-exposed MM patients may show rewarding responses to daratumumab retreatment, the more with alternating antimyeloma combinations, initial good response and CD38-antibody-treatment pauses, thereby proving CD38-antibody-retreatment as feasible, effective and non-toxic. Confirmatory studies are required to further validate our results.

Central nervous system multiple myeloma: A real-world multi-institutional study of the Greek Myeloma Study Group.

Central nervous system (CNS) involvement is a rare and aggressive complication of multiple myeloma (MM). We identified 54/4352 MM patients (1.2%), who developed CNS-MM between 2000 and 2022. A matched-control group of MM patients without CNS-MM was used for comparisons. Median age was 63 years. Median time to CNS-MM was 28 months; 6/54 experienced CNS-MM at MM diagnosis. Abnormal lactate dehydrogenase (LDH), high-risk cytogenetics, and extramedullary involvement (EMI), that is, soft tissue plasmacytomas and/or plasma cell leukemia (PCL), were more frequent in CNS-MM versus controls (p < .05); 13/54 had PCL at CNS-MM. The majority had leptomeningeal infiltration (LMI) (66%); 26% had CNS-MM without systemic myeloma; EMI was the strongest predictor for CNS-MM (OR: 6.3). Median overall survival (OS) of CNS-MM patients versus controls was 43 months (95% CI: 32-54) versus 60 months (95% CI: 38-82) (p < .001); treatment of CNS-MM included mainly bortezomib/thalidomide/chemotherapy whereas 20% received novel drugs/immunotherapy combinations; 28 patients underwent cerebrospinal fluid infusions; EMI was the strongest negative predictor for post CNS-MM OS (p = .005; HR: 2.9). Treatment after 2016 predicted significantly for OS (p = .002; HR: 0.27). Median post CNS-MM OS was 4 months (95% CI: 2.6-5.4); in patients treated after 2016 median OS was 12 months. In conclusion, we have demonstrated in this large real-world series that survival of CNS-MM remains poor; however, there is a positive impact of treatment after 2016, related to the efficacy of modern anti-myeloma therapy; EMI significantly increases the probability to develop CNS-MM and the risk of post CNS-MM death, indicating a potential need for CNS prophylaxis for those patients.

Phase I study of TQB3602, an oral proteasome inhibitor, in relapsed and refractory multiple myeloma.

TQB3602 is a novel orally bioavailable proteasome inhibitor. This study is thefirst-in-human phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of TQB3602 in relapsed/refractory multiple myeloma (RRMM). This is a multicenter phase I clinical trial consisting of the 3+3 dose-escalation phase and dose expansion phase. Patients with MM who have received ≥2 prior antimyeloma therapies were enrolled. TQB3602 is administered at a dose of 0.5~7mg on days 1, 8, 15 in 28-day cycle. Twenty-five RRMM patients who relapsed or failed ≥2 lines of therapies were enrolled in the dose escalation phase. Two patients in the 7.0 mg dose group developed dose-limiting toxicity events (one with grade 2 peripheral neuropathy [PN] complicated by pain and one with diarrhea and abdominal pain), leading to a maximum tolerated dose of 6.0 mg. Any-grade adverse events (AEs) occurred in 24 (96.0%) patients, while grade ≥3 AEs occurred in 13 (52.0%). The most common grade ≥3 AEs was anemia (6, 24.0%). The incidence rate of PN was 16% with no grade ≥3 PN occurred. TQB3602 was rapidly absorbed, resulting in a time-to-plasma peak concentration of 0.8-1.5 h. The mean half-life was approximately 82 h. The AUClast and Cmax were approximately 1.9 times higher on day 15 than on day 1. Among 22 response-evaluable patients, 63.7% achieved stable disease or better. TQB3602 is well tolerated, with a favorable neurotoxicity profile, and has shown preliminary efficacy in patients with RRMM. The anticipated therapeutic dose was 6 mg and was adopted for an ongoing dose-expansion phase.

The Interplay between the DNA Damage Response (DDR) Network and the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Multiple Myeloma.

The DNA damage response (DDR) network and the mitogen-activated protein kinase (MAPK) signaling pathway are crucial mechanisms for the survival of all living beings. An accumulating body of evidence suggests that there is crosstalk between these two systems, thus favoring the appropriate functioning of multi-cellular organisms. On the other hand, aberrations within these mechanisms are thought to play a vital role in the onset and progression of several diseases, including cancer, as well as in the emergence of drug resistance. Here, we provide an overview of the current knowledge regarding alterations in the DDR machinery and the MAPK signaling pathway as well as abnormalities in the DDR/MAPK functional crosstalk in multiple myeloma, the second most common hematologic malignancy. We also present the latest advances in the development of anti-myeloma drugs targeting crucial DDR- and MAPK-associated molecular components. These data could potentially be exploited to discover new therapeutic targets and effective biomarkers as well as for the design of novel clinical trials. Interestingly, they might provide a new approach to increase the efficacy of anti-myeloma therapy by combining drugs targeting the DDR network and the MAPK signaling pathway.

Analysis of real-world (RW) pomalidomide (pom) dosing patterns in patients (pts) with multiple myeloma (MM) from the Flatiron database.

e19508 Background: Pom is an immunomodulatory drug commonly used in combination with other antimyeloma therapies for the treatment (tx) of pts with MM. However, there is a paucity of data on RW dosing patterns with pom and associated tx outcomes. We report RW pom dosing patterns and effectiveness using RW data to inform potential pom dosing strategies as part of combination tx regimens. Methods: RW pom data in pts with MM were derived from the US Flatiron Health deidentified electronic health record (EHR) database (Jan 2011–Nov 2021). Pom starting dose (1, 2, 3, or 4 mg) and line of therapy (LOT) were identified from EHRs. Tx patterns were captured per LOT; pts could receive &gt;1 pom-containing tx regimen/LOT. Pts receiving pom were followed until Dec 2023 for outcome analysis. Overall survival (OS) and time to next tx (TTNT) were estimated using the Kaplan-Meier method and analyzed by log-rank testing. Results: Of 15,378 pts with MM, 2,034 had an order for pom, of whom 1,344 received pom and 880 had LOT data. The most common initial pom dose was 4 mg (50%), followed by 2 mg (30%), 3 mg (16%), and 1 mg (4%). The most common pom-containing tx regimens were: daratumumab + pom + dexamethasone (d; 29%), pom + d (18%), and carfilzomib + pom + d (14%); 6% of pts received pom monotherapy. Retreatment with pom was infrequent, with 84% of pts receiving only 1 pom-containing LOT. Most pts (n=652, 74%) remained on the initial pom dose received; of these, 367 pts remained on an initial dose of 4 mg. Among pts who changed dose (n=227, 26%), 36% changed from 2 mg and 36% changed from 4 mg. Of pts who received an initial dose of 4 mg and changed dose (n=81), 43%, 51%, and 6% reduced to 3, 2, and 1 mg, respectively. Of pts who received an initial dose of 2 mg and changed dose (n=82), 17% reduced to 1 mg. Among pts who received an initial dose of &lt;4 mg and changed dose, dose escalation was common (67% of pts with a 3 mg initial dose increased to 4 mg; 33% and 50% of pts with a 2 mg initial dose increased to 3 and 4 mg, respectively). Outcome analysis of pts with LOT and available follow-up data suggest that initial pom dose had no impact on OS and TTNT (Table). Log-rank analysis of OS and TTNT between the initial doses of 2 and 4 mg showed no significant difference among all pts ( P=0.32) or in pts who changed dose ( P=0.29). Conclusions: RW analyses show that most pts remain on the initial pom dose received, but some pts changed doses. Pom, most commonly used in combination regimens, can be used across an initial dose range with no impact on efficacy in pts with MM. Optimal pom dosing may vary across pts and combination regimens; pom dosing should be tailored to pt needs per disease and tx factors. [Table: see text]

Early Chimeric Antigen Receptor T Cell Expansion Is Associated with Prolonged Progression-Free Survival for Patients with Relapsed/Refractory Multiple Myeloma Treated with Ide-Cel: A Retrospective Monocentric Study

The outcomes of patients with relapsed and refractory multiple myeloma (RRMM) previously treated with the 3 main classes of myeloma therapy-immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies-remain poor. Recently, based on the phase II pivotal KarMMa trial showing prolonged overall survival (OS) and progression-free survival (PFS) in heavily treated patients, idecabtagene vicleucel (ide-cel), a B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) product, was approved in the United States for the treatment of RRMM. In France, since June 2021, an early access program has authorized the use of ide-cel in the setting of RRMM (defined as progressive myeloma after at least 3 previous regimens, including the 3 main antimyeloma therapies). We report the first French experience through this early access program in a retrospective study of 24 consecutive patients treated with ide-cel at our institution. The patients were evaluated according to International Myeloma Working Group criteria and by positron emission tomography computed tomography (PET-CT) at 1, 3, 6, 9, and 12 months after ide-cel infusion. Most patients had adverse cytogenetic abnormalities, and RRMM with triple-refractory drugs were seen in 79%. Bridging therapy was required for 19 of 24 patients. Before CAR-T cell infusion, lymphodepletion with fludarabine and cyclophosphamide was systematically performed. The median follow-up was 15.2 months. At 3 months after ide-cel infusion, 92% of patients achieved at least a partial response, and 50% achieved a complete response or better (≥CR). At 6 months, 70% of patients had a persistent ≥CR. At 3 and 6 months, bone marrow minimal residual disease (10-6 level) was undetectable in 79% and 75% of patients, respectively. At 6 months, CR as assessed by PET-CT was achieved in 15 of 20 patients (75%). The median PFS was 14.8 months, and median OS was not reached. Notably, an expansion of circulating CAR-T cells to >180/mm3 after infusion was strongly associated with prolonged PFS. Additionally, the level of soluble BCMA measured before infusion was identified as a prognostic factor for PFS, likely correlated to the tumor burden. Grade 1-2 cytokine release syndrome (CRS) occurred in 22 of 24 patients (92%). Only 1 patient (4%) experienced grade ≥3 CRS. The occurrence of neurologic toxicity was infrequent (12.5%) and reversible in all cases. Hematologic toxicity was relatively common, and secondary hypogammaglobulinemia occurred in most patients. Infections (mostly viral) were frequent but most often nonsevere. This study echoes the promising results of the KarMMa trial and identifies possible prognostic indicators in RRMM patients treated with ide-cel, potentially refining treatment strategies and improving outcomes in this challenging context.

FHND004 inhibits malignant proliferation of multiple myeloma by targeting PDZ-binding kinase in MAPK pathway.

Inhibitors of Epidermal growth factor receptor tyrosine kinase (EGFR-TKIs) are producing impressive benefits to responsive types of cancers but challenged with drug resistances. FHND drugs are newly modified small molecule inhibitors based on the third-generation EGFR-TKI AZD9291 (Osimertinib) that are mainly for targeting the mutant-selective EGFR, particularly for the non-small cell lung cancer (NSCLC). Successful applications of EGFR-TKIs to other cancers are less certain, thus the present pre-clinical study aims to explore the anticancer effect and downstream targets of FHND in multiple myeloma (MM), which is an incurable hematological malignancy and reported to be insensitive to first/second generation EGFR-TKIs (Gefitinib/Afatinib). Cell-based assays revealed that FHND004 and FHND008 significantly inhibited MM cell proliferation and promoted apoptosis. The RNA-seq identified the involvement of the MAPK signaling pathway. The protein chip screened PDZ-binding kinase (PBK) as a potential drug target. The interaction between PBK and FHND004 was verified by molecular docking and microscale thermophoresis (MST) assay with site mutation (N124/D125). Moreover, the public clinical datasets showed high expression of PBK was associated with poor clinical outcomes. PBK overexpression evidently promoted the proliferation of two MM cell lines, whereas the FHND004 treatment significantly inhibited survival of 5TMM3VT cell-derived model mice and growth of patient-derived xenograft (PDX) tumors. The mechanistic study showed that FHND004 downregulated PBK expression, thus mediating ERK1/2 phosphorylation in the MAPK pathway. Our study not only demonstrates PBK as a promising novel target of FHND004 to inhibit MM cell proliferation, but also expands the EGFR kinase-independent direction for developing anti-myeloma therapy.

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long-term outcomes in the Phase 3 IKEMA study.

Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2months in 1q21+ patients and 38.2 versus 16.2months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM.

Renal outcome in multiple myeloma patients with cast nephropathy: a retrospective analysis of potential predictive values on clinical and renal outcome

ABSTRACT Objective Cast nephropathy (CN) is the leading cause of acute kidney injury (AKI) in multiple myeloma (MM). Since it is sparsely documented why some patients with CN do achieve a renal response while others do not, we describe a single-center cohort of patients with multiple myeloma and biopsy-confirmed CN to evaluate potential markers of renal response. Methods The data was collected as a retrospective, single-center analysis of CN-patients treated at the Medical University Vienna between 01/01/2004 and 01/01/2022. Baseline parameters and clinical outcome was compared between renal responders and non-responders. Results Among 28 patients with CN, n = 23 were assessed for renal response (14 responders; 9 non-responders). Renal responders were younger (median age: 61 years; 77 years, p = 0.039), showed higher overall survival (153months; 58months, p = 0.044) and achieved hematologic response (≥PR) to first-line therapy (p = 0.029), and complete hematologic response (CR) at any time (p = 0.025) significantly more often. Further, we could show that rapid initiation of anti-myeloma therapy after initial presentation correlated significantly with renal response (median 9 days; 27 days, p = 0.016). Analyses of kidney biopsy specimens revealed that patients with a high IF/TA score showed end stage renal disease (dialysis ≥ 3 months) significantly more often (p = <0.001). Discussion In summary, our data suggests, that a rapid start with systemic hematologic treatment in patients with MM and CN is crucial and achieving an early hematologic response is important for renal recovery. Moreover, achieving a deep hematologic response and subsequent renal recovery improves clinical outcome as reflected by an overall survival benefit.

Soluble B-cell maturation antigen in multiple myeloma.

B-cell maturation antigen (BCMA) has emerged as a promising immunotherapeutic target in multiple myeloma (MM) management, with the successive approval of antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapies directed to this membrane receptor. Soluble BCMA (sBCMA), a truncated version produced through gamma-secretase cleavage, can be quantified in serum/plasma samples from patients with MM via electrochemiluminescence, fluorescence, or enzyme-linked immunosorbent assays, as well as through mass spectrometry-based proteomics. Besides its short serum half-life and independence from kidney function, sBCMA represents a reliable and convenient tool for MM monitoring in patients with nonsecretory or oligosecretory disease. Numerous studies have suggested a potential utility of this bioanalyte in the risk stratification of premalignant plasma cell disorders, diagnosis and prognostication of MM, and response evaluation following anti-myeloma therapies. In short, sBCMA might be the "Swiss army knife" of MM laboratory testing, but is it ready for prime time?

Low Erythropoietin to Albumin Ratio in the Serum Predicts Less Reversibility of Renal Impairment with Poorer Prognosis in Multiple Myeloma

Background: Renal impairment (RI) is one of the most common clinical presentations in patients with multiple myeloma (MM) and contributes to its morbidity and mortality. In consistent with this, renal injury is an important factor considered high risk for MM in recently updated NCCN clinical practice guideline. It has been demonstrated that RI is reversible in about half the patients with MM and reversal of renal dysfunction significantly affects the prognosis of MM (Blood Cancer J. 2014 Aug 1;4(8):e235). Because reversibility of RI was a more important prognostic factor than response to anti-myeloma therapy in patients with MM with RI (Clin Lymphoma Myeloma Leuk. 2022 Aug;22(8):626-634; Eur J Haematol. 2000 Sep;65(3):175-81), identification of accurate non-invasive predictive markers for differentiating reversible / irreversible RI in MM patients treated with anti-myeloma therapy is undoubtedly needed. Methods: We conducted a retrospective study to evaluate the predicting value of serum erythropoietin (EPO) to albumin ratio (EPO/albumin) of MM patients treated with anti-myeloma therapy for reversibility of RI and overall survival (OS). RI was defined as an estimated glomerular filtration rate (eGFR) that was measured before treatment ≦50 ml/min per 1.73 m 2 by the simplified Modification of Diet in Renal Disease formula, and the definition of the reversibility of RI were also based on eGFR measurements, as previous publications described (J Clin Oncol. 2010 Nov 20;28(33):4976-84). Renal complete response (CRrenal) was defined as a sustained improvement from an eGFR baseline value of lower than 50 to ≥60 mL/min/1.73 m 2. Partial renal response (PRrenal) was defined as a sustained recovery of eGFR at the time of diagnosis of less than 15 to 30-59 mL/min/1.73 m 2; when achieved CRrenal or PRrenal, the MM patients with RI is defined as the renal responder group, otherwise, the MM patients with RI is defined as the renal non-responder group. Total 52 newly diagnosed MM patients with RI were analyzed in this study, 27 cases in the renal responder group and 25 cases in the renal non-responder group. Bortezomib with high-dose dexamethasone were used as the treatment of choice for such patients. Serum EPO levels were determined using chemiluminescence immunoassay. In our research, mean ± standard deviation (SD) was used to describe the normally distributed variables data while median with interquartile range (IQR) was used to describe the nonparametric variables data. P&amp;lt;0.05 was taken to indicate significance in all analyses. Results: There were significant differences in serum EPO and albumin, hemoglobin and RDW between the renal responder group and the non-responder group. The renal responder group had higher EPO [median: 44.06 (IQR: 160.96) vs 13.58(26.49)] and RDW [median:53(IQR:15) vs 48(9)], lower serum albumin (mean:30.21±SD: 7.78 vs 35.79±6.01) and hemoglobin. (mean:66.56±SD:16.42 vs 78.76±19.79), compared with the non-responder group. Of note, there were no significant differences in serum β2-Microglobulin, creatinine and eGFR at baseline between the two groups. As expected, serum EPO was negatively correlated with serum albumin (r = -0.257, P = 0.033). Likewise, EPO/albumin was negatively correlated with albumin (r = -0.42, P = 0.002); In contrast, EPO/albumin was positively correlated with serum EPO (r = 0.98, P &amp;lt; 0.001). Importantly, our study showed that EPO/albumin were independent predictor of the reversal of RI in MM patients. The optimal cutoff for EPO/albumin was determined via ROC analysis and was determined to be 1.77 U/g. The area under the curve was 0.784. According to the optimal cutoff value, low and high EPO/albumin groups were defined. The data confirmed that the group (n=36) with low EPO/albumin in the serum had shorter OS in MM with RI, compared with the group (n=16) with high EPO/albumin. Conclusions: Our findings demonstrated that low EPO/albumin in the serum predicts less reversibility of RI with poorer prognosis in MM, it is a reliable biomarker for predicting reversibility of RI in MM patients before anti-myeloma therapy. Figure 1

French Early Nationwide Idecabtagene Vicleucel (Ide-Cel) Chimeric Antigen Receptor (CAR) T-Cell Therapy Experience in Patients with Relapsed/Refractory Multiple Myeloma (FENIX): Update of the IFM Study from the Descar-T Registry

Introduction Prognosis of patients with relapsed/refractory multiple myeloma (RRMM) is poor, particularly in triple-class refractory patients (refractory to a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody). Idecabtagene vicleucel (Ide-Cel) is the first chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen (BCMA) approved by both the European Medicines Agency and the US FDA and the only one available in France through the Early Access Program for treatment (≥ 3 lines) of RRMM. Here we present an update of characteristics and outcome of patients enrolled in this program. Methods We conducted a multicenter, retrospective, observational study that included all consecutive patients with RRMM registered in the DESCAR-T database of patients treated with CAR T therapy, who underwent apheresis up to November 2022 to be treated by commercial Ide-Cel in France. The main objective was to analyze efficacy in terms of response rates, progression free survival (PFS) and overall survival (OS). Secondary objectives included evaluation of safety in terms of cytokine release syndrome (CRS), neurotoxicity, cytopenia, infections and management of relapse including subsequent anti myeloma therapies (sAMT). Results From June 2021 to November 2022, 207 patients were registered in DESCAR-T and underwent leukapheresis to be treated with Ide-cel, 164 (79%) were infused; 43 were not infused: 13 due to rapidly progressive disease or death and 5 due to manufacturing failure. Fifty seven (28%) patients did not meet KarMMa inclusion criteria: cytopenia (n=23), kidney failure (n=13), performance score (PS) &amp;gt;1 (n=15), prior anti BCMA drug conjugate antibody (n=8), prior allograft (n=5). Median age of the 164 patients was 60.5 years (range 34-82), 59% were male, median number of prior treatment lines was 4 (range 2-12) including prior autologous stem cell transplantation in 147 (90%); 130 (80%) were triple-refractory, 47 (29%) were penta-refractory. At diagnosis, 12 (16%) patients had R-ISS stage III disease (89 missing). High tumor burden (&amp;gt; 30% BMPCs) was present in 71 patients (54%) (33 missing). High risk cytogenetic abnormalities defined by del(17p) or t(4;14) were present in 63 patients (58%) (56 missing) and 15 (23%) had extramedullary disease (EMD) (98 missing). One hundred and forty-two (87%) received bridging therapy of which 39 (27%) responded: 25 had partial response (PR); 8 very good partial response (VGPR); 6 complete response (CR). Median time from apheresis to infusion was 62 days. Median follow-up after infusion was 6.2 months. In the first 3 months, overall response rate was 82% (n=134), best achieved response was CR, VGPR and PR in 60 (38%), 36 (23%) and 38 (24%) respectively. Median PFS was 11.6 months (95% CI (7.1; NA)). The 12-month OS was 73% (95% CI (64; 84)). In the first 6 months post-infusion, MRD was analyzed for 45 patients and reached negativity rate in 77%. In univariate analysis, only EMD had a significant impact on PFS: median PFS was 6.3 months (95% CI (3; NA)) for patients with EMD (p = 0.003; HR 3.5, 95% CI (1.55; 7.9)). CRS occurred in 146 (89%) patients, with only 3 cases (2%) of grade ≥ 3. Neurotoxicity occurred in 19 (12%) patients (5 with grade ≥ 3). Ninety-eight (60%) patients received tocilizumab, and 37 (23%) received steroids. Persistent grade ≥ 3 thrombocytopenia, anemia and neutropenia at M1 were observed in 55 (34%), 20 (12%) and 90 (55%) patients, respectively. Forty (24%) patients presented infections grade ≥ 3 in the first six months after infusion. Fifty-two patients progressed during follow-up. 34/52 patients (65%) received a sAMT. Median time from relapse to first administration of sAMT was 0.6 months. Eighteen received bispecific antibodies including 12 anti-BCMA and 6 anti-GPRC5D. Among these 34 patients, a total of 13 (38%) died. Overall, at data cut-off, 26 patients had died, including 9 after disease progression, 4 of acute toxicity and 2 of sepsis. Conclusion This updated study confirms safety and efficacy of Ide-cel in patients with RRMM in real world settings. Response rates and safety were comparable to those reported in the registration trial (Munshi et al., 2021) and American real world study (Hansen et al., 2023). Importantly, patients with EMD had a significant lower PFS. Prognosis data at relapse following ide-cel require a longer follow up and will be presented at ASH.

Daratumumab, Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) Alone in Transplant-Ineligible Asian Patients with Newly Diagnosed Multiple Myeloma: Final Analysis of the Phase 3 Octans Study

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action and has shown clinical efficacy for the treatment of multiple myeloma (MM). In an updated analysis of the global phase 3 ALCYONE study, D-VMP demonstrated a significant progression-free survival (PFS) benefit compared to VMP in transplant-ineligible patients with newly diagnosed MM (NDMM). A prior analysis of the phase 3 OCTANS study (median follow-up, 12.3 months) also showed a favorable clinical benefit/risk profile for D-VMP versus VMP in transplant-ineligible Asian patients with NDMM. Here, we report results from the final analysis of OCTANS, with a median follow-up of &amp;gt;3 years. Methods: The randomized, phase 3 OCTANS study (NCT03217812) enrolled Asian patients with NDMM who were ineligible for autologous stem-cell transplant due to age or presence of comorbidities. Patients were randomized 1:2 (VMP:D-VMP) to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 weeks in Cycles 2-9, and every 4 weeks thereafter until disease progression). Per a protocol amendment, patients receiving daratumumab IV were permitted to switch to daratumumab SC 1,800 mg (same schedule as IV) on Day 1 of any cycle. The primary endpoint was achievement of a very good partial response (VGPR) or better. Results: A total of 220 patients were randomized to D-VMP (n = 146) or VMP (n = 74). At the time of the final analysis, with a median follow-up of 41.2 months, the rate of VGPR or better was significantly higher with D-VMP versus VMP (80.1% vs 47.3%; P &amp;lt;0.0001; Table). The rate of measurable residual disease negativity (10 -5) was also higher with D-VMP versus VMP (40.4% vs 10.8%; P &amp;lt;0.0001). D-VMP continued to show a significant improvement in PFS versus VMP (median, 38.7 vs 19.2 months; HR, 0.35; 95% CI, 0.23-0.52; P &amp;lt;0.0001; Table, Figure), as well as a longer time to subsequent antimyeloma therapy (median, 46.8 vs 20.6 months; HR, 0.31; 95% CI, 0.20-0.47; P &amp;lt;0.0001). However, median overall survival was not yet reached for either group. The overall safety profile of D-VMP was consistent with that observed for the primary analysis. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported for 133 (92.4%) patients who received D-VMP and 60 (84.5%) patients who received VMP and were primarily hematologic events; nonhematologic grade 3/4 TEAEs in ≥10% of patients included pneumonia (D-VMP, 31.3% vs VMP, 18.3%), hypokalemia (15.3% vs 4.2%), and hypertension (13.2% vs 8.5%). Grade 3/4 infection TEAEs were reported for 67 (46.5%) and 22 (31.0%) patients who received D-VMP or VMP, respectively. Serious TEAEs were reported for 75 (52.1%) and 28 (39.4%) patients in the D-VMP and VMP groups, respectively, and TEAEs led to treatment discontinuation in 6 (4.2%) and 4 (5.6%) patients, respectively. The incidence of infusion-related reaction TEAEs in the D-VMP group was 33.3%, which is consistent with that previously reported for daratumumab; most events were of grade 1 or 2 severity. The risk of immunogenicity to daratumumab was low, with 1 of 130 evaluable patients testing positive for daratumumab antibodies. Within the D-VMP group, 76 patients switched from daratumumab IV to SC administration. Among these patients, 64 (84.2%) patients preferred SC administration, 7 (9.2%) preferred IV administration, and 15 (19.7%) had no preference on ≥1 of 2 surveys. Of the 64 patients who preferred SC administration, primary reasons included treatment administration time (84.4%), more comfortable administration process (57.8%), less caregiver burden (31.2%), and fewer administration-related reactions (26.6%). Conclusions: With a median follow-up of &amp;gt;3 years, this final analysis of OCTANS demonstrated a continued clinical benefit with D-VMP versus VMP in Asian patients, with PFS improvement comparable to that observed in the global ALCYONE study (HR, 0.35 vs 0.42, respectively). No new safety concerns were identified for D-VMP with extended follow-up. In addition, daratumumab SC administration was preferred by the majority of patients who switched from daratumumab IV. These results further support the use of daratumumab IV or SC in combination with VMP in transplant-ineligible Asian patients with NDMM.

A Phase II Study of Isatuximab in Combination with Pomalidomide and Dexamethasone in Patients with Multiple Myeloma Progressing on or after One Line of Lenalidomide-Containing Therapy

Introduction Relapse in patients (pts) with multiple myeloma (MM) is a common occurrence, resulting in a continued need for novel treatment approaches. Isatuximab (Isa), a monoclonal antibody (mAb), combined with pomalidomide (Pom) and dexamethasone (Dex), is indicated for the treatment of pts with relapsed/refractory multiple myeloma who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy. The current study aims to evaluate the efficacy and safety of IsaPomDex in pts with MM relapsing for the first time after one line of treatment containing lenalidomide (Len). Methods EAE115 (NCT05298683) is an ongoing, investigator-initiated, phase II, prospective, open-label, multicenter study aiming to enroll 108 pts. Eligible pts are adults with documented MM who have evidence of progressive disease, by the International Myeloma Working Group criteria, on or after treatment with only one prior line of anti-myeloma therapy with lenalidomide (≥2 cycles, alone or in combination) and a proteasome inhibitor. Pts must also have adequate bone marrow and hepatic function and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Excluded are pts with previous anti-myeloma therapy with any anti-CD38 mAb, pomalidomide, or stem cell transplant within 12 weeks before treatment initiation. Pts receive six 28-day cycles of Isa 10 mg/kg (once weekly [QW] by intravenous [IV] infusion on days 1, 8, 15, and 22 in cycle 1 and days 1 and 15 in subsequent cycles), Pom 4 mg (per Os on days 1-21, each cycle), and Dex 40 mg or 20 mg for pts ≥75 years old (per Os or IV on days 1, 8, 15 and 22, each cycle). Fifteen to 60 minutes before Isa infusions, patients receive pre-medications to mitigate potential infusion-related adverse reactions. Following initial 6 cycles, pts achieving at least very good partial response (VGPR) are randomized 1:1 to receive Isa (Q2W or Q4W) plus PomDex, and pts achieving &amp;lt;VGPR continue treatment with Isa (Q2W) plus PomDex. Treatment is given until progressive disease, death, unacceptable adverse events (AEs), lost to follow-up, or consent withdrawal. The study primarily evaluates the overall response rate (ORR; defined as partial response [PR] or better) to IsaPomDex therapy at six months. Adverse events are classified using the Medical Dictionary for Regulatory Activities. Herein, we present safety and efficacy data for all treated patients (cut-off date 15/05/23. Results Twenty pts had received at least one dose by the cut-off date, of whom 16 (80.0%) were continuing with IsaPomDex treatment; four (20.0%) pts had discontinued due to physician or pt decision or progressive disease or death. At baseline (cycle 1, day 1), pts had a median age of 72.0 years (range: 60.0-85.0), 10 (50.0%) were male, and 13 (65.0%) had ECOG PS 0. Eleven (55.0%) pts were at stage II by the revised International Staging System, 9 (45.0%) pts had lytic bone lesions, 5 (25.0%) pts had high-risk cytogenetics, and 1 (5.0%) pt had soft-tissue plasmacytomas (Table 1). Regarding previous treatment outcomes, 14 (70.0%) pts had achieved ≥VGPR (stringent complete response, 2 [10.0%] pts; complete response, 2 [10.0%] pts; VGPR, 10 [50%] pts). Five (25%) and 1 (5.0%) pts achieved partial and minimal response, respectively. Six (30.0%) pts had received ASCT in the prior line. At a median follow-up of 3.4 (range: 0.6-6.1) months, the median number of IsaPomDex cycles received was 3.0 (range: 1.0-7.0); one (5.0%) pt received six treatment cycles. Of the 18 (90.0%) response evaluable pts (2 pts were ongoing without 2 efficacy assessments) VGPR and PR were achieved by 4/18 (22.2%) and 9/18 (50.0%) pts, respectively. ORR was achieved by 13/18 (72.2%) pts, and the median (range) time from IsaPomDex study dose to first response (≥PR) was 1.0 (range: 0.9-1.3) months. Thirteen (65.0%) pts had ≥1 treatment-emergent adverse events (TEAE). Of these pts, 10 (50.0%) had a ≥1 grade (gr)≥3 TEAE and 4 (15.0%) had ≥1 gr ≥3 serious TEAE. The most common TEAEs were neutropenia in 9 pts (45.0%), anaemia in 3 pts (15.0%) and fatigue in 3 pts (15.0%). The most common gr ≥3 TEAE was neutropenia in 7 pts (35.0%) (Table 2). Conclusions Second-line treatment with IsaPomDex in pts with MM who have progressed on or after one Len-containing line of treatment appears to be effective, although longer follow-up is needed to assess its efficacy. No new safety signals were observed with the combination.

The Impact of Isatuximab Regimens on Hypogammaglobulinemia Occurrence, Recovery, and Associated Infections in Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Isatuximab (Isa) is an immunoglobulin (Ig)G1 monoclonal antibody targeting a CD38 transmembrane glycoprotein in multiple myeloma (MM). Isa is approved for use in multiple countries to treat adults with relapsed/refractory MM (RRMM) when given in combination with either pomalidomide-dexamethasone (Pd) or carfilzomib-dexamethasone (Kd). Hypogammaglobulinemia (HGG; polyclonal IgG &amp;lt;4 g/L) and the associated infection risk is a potential complication for patients (pts) with MM treated with immunotherapies. High infection and HGG rates have been reported during treatment (tx) with antimyeloma therapies, and in particular, recently, with anti-B cell maturation antigen-directed therapies. 1,2 Here, we explore the impact of Isa monotherapy on Ig levels, and of approved Isa combinations (Isa-Pd and Isa-Kd) on Ig levels and the incidence, severity, and clinical significance of HGG, including the incidence of infections depending on concomitance of HGG or not, in pts with RRMM. Methods: Pts with RRMM with central lab Ig data from 3 monotherapy studies were pooled (across dose levels, most &amp;gt;10 mg/kg) to retrospectively explore Ig levels throughout tx with Isa monotherapy until disease progression, intolerable toxicity, or withdrawal.We performed a side-by-side analysis of pts from the Phase 3 ICARIA-MM (Isa-Pd vs Pd) and IKEMA (Isa-Kd vs Kd) studies with/without HGG at baseline and concomitance of HGG with infections. Pts were analyzed overall and according to the heavy chain of the monoclonal protein at study entry, where IgG consisted of monoclonal IgG (M-spike in g/dL *1000) subtracted from total quantitative IgG (mg/dL) to obtain the true polyclonal IgG level, and non-IgG consisted of other Ig or light chain subtypes. Recovery was defined as &amp;gt;6 g/L (complete) or ≥4 g/L (partial) after having &amp;lt;4 g/L at any time. Results: Isa monotherapy analyses revealed a fast decrease in non-involved IgA levels after 1 month, followed by stabilization, which has also been reported with daratumumab monotherapy. Isa monotherapy did not induce decreased IgG levels. In ICARIA-MM, more pts with non-IgG vs IgG MM at study entry had HGG during tx (54.0% vs 14.4%, Isa-Pd; 39.6% vs 12.7%, Pd), whereas incidences were similar in IKEMA (11.7% vs 8.9%, Isa-Kd; 15.5% vs 11.4%, Kd). A smaller proportion of pts with HGG vs without HGG at any time during the study had definitive tx discontinuation in both ICARIA-MM and IKEMA; discontinuations related to adverse events (AEs) were less frequent in pts with HGG vs without HGG (Table). Of these AEs, infections led to discontinuation in 33.3% to 46.2% of patients with HGG at any time, regardless of tx (Table). In ICARIA-MM, 70.9% (Isa-Pd) and 55.5% (Pd) of pts without HGG at baseline developed HGG post-baseline; in IKEMA, 90.6% (Isa-Kd) and 82.0% (Kd) developed HGG post-baseline. Among pts who received Isa-Pd, those who had IgG MM at study entry experienced a larger proportion of recovery (9.1%, complete; 26.0%, partial) than those with non-IgG MM (6.8%, complete; 15.9%, partial); similar results were seen with Pd in pts with (21.9%, complete; 40.6%, partial) and without IgG MM (4.8%, complete; 19.0%, partial). Pts who had IgG MM at study entry and received Isa-Kd experienced a larger proportion of recovery (17.0%, complete; 33.0%, partial) than those with non-IgG MM (3.8%, complete; 7.5%, partial); similar results were seen with Kd in pts with (14.7%, complete; 25.3%, partial) and without IgG MM (3.1%, complete; 3.1%, partial). Infections of any grade concomitant with HGG were reported in 28.2% of pts in ICARIA-MM and 59.2% in IKEMA, with a larger proportion of pts receiving Isa combinations reporting infections of any grade and Grade ≥3 (Table). Respiratory infections of any grade concomitant with HGG were more frequent in pts receiving Isa-Pd vs Pd and Isa-Kd vs Kd (Table). There were low proportions of pts with Grade ≥3 respiratory infections concomitant with HGG regardless of tx arm (Table). Conclusions: Monotherapy with Isa had little impact on Ig levels. Among pts treated with Isa monotherapy, there is an early drop in non-involved IgA levels, followed by stabilization. In ICARIA-MM and IKEMA, HGG did not contribute to increased Grade ≥3 infections. Isa added to backbone tx is safe with a low rate of Grade ≥3 infections despite the decrease in Ig levels. Funding: Sanofi.

LGL in MGUS or MGUS in LGL? Lessons of Nature and Their Clinical Implications

Associations between seemingly unrelated entities often reveal important lessons of nature, instructive for the understanding of mutual pathogenic roots. While investigating the clinical features of T-cell large granular lymphocytic leukemia (LGL), we noted the frequent presence of plasma cell dyscrasias/monoclonal gammopathies (MGs), chiefly MGUS. There are several potential explanations for this co-occurrence: 1) similar demographics (both conditions mostly presenting in the elderly); 2) the possibility that the two precursors originate from an initial polyclonal immune response to a common target; and 3) as alternative, that monoclonal plasma cells or the Ig product may be the targets of cytotoxic T-LGL cells in a context of tumor surveillance reaction. For instance, clonal TCR may recognize the M protein idiotype or vice versacausing aberrant activations. In addition, while MGUS should not be associated with cytopenias, responses to anti-myeloma therapies have been observed in LGL with MGUS refractory to traditional immunosuppressive therapies. We hypothesized that the study of clinical and epidemiologic features of MGs and LGL may be helpful to elucidate some of these fundamental questions. To address this, a dual approach was applied: 1) MG-forward strategy: screening of LGL in 2348 individuals with documented diagnosis of MGs and available bone marrow exam; 2) LGL-forward strategy: search of MGs in 235 LGL cases with M protein assessment. Overall, among 2348 cases with MGs, we identified 42 cases (1.8%) with concurrent evidence of LGL. We then selected an exploratory cohort of 787 MG patients with clinical annotations for further phenotypic dissection and comparative analyses. Within 533 patients with non-active MGs (i.e., MGUS or smoldering myeloma -SM), 144 (27%) had cytopenias of any type and grade, which could not be attributable to plasma cell infiltration. Screening for comorbid conditions explaining cytopenias left 32 cases (22%) presumed to be idiopathic. LGL was overrepresented in MGUS-SM with cytopenias (6 vs 0.3% in cases without counts alterations, p&amp;lt; .001). This frequency was higher when considering only cases with idiopathic cytopenias (22 vs 1.8% in cases with cytopenias of other causes, p&amp;lt; .001) ( FigA). Reverse analysis of the LGL cohort demonstrated that 71 (30%) LGL cases had M proteins. Overall, the MG/LGL dyad was more frequently associated with concurrent autoimmune conditions (54%), as well as monoclonal B-cell lymphocytosis and other B-cell lymphoid neoplasms (19%). Next, we compared cases with MG/LGL vs those with MGs (N = 775) or LGL (N = 157) exclusively. When compared to the MGs cohort, MG/LGL cases presented a younger age (median 64 vs 70 years, p &amp;lt; .001), had higher frequency of M protein of the IgM type (21 vs 10%, p= .002), and oftentimes exhibited small/transient paraproteinemia (42 vs 2%, p&amp;lt; .001). No specific features were enriched in the MG/LGL cases when compared to the LGL cohort, except for a higher proportion of proliferations of NK-cell subtype (12 vs 4%, p= .02). Finally, to confirm the observed association, we focused on the subgroup of non-active MGs by excluding cases with initial diagnosis of MM or lymphoma. Multivariable analysis (adjusting by sex, age and MG risk) revealed a lower risk of immunoparesis (aOR: 0.4, 95%CI: 0.2 - 0.7, p= .002) in MG/LGL as opposed to MG without LGL, whereas no effect was found in progression to MM/lymphoma (aHR: 0.9, 95%CI: 0.4 - 2.1, p= .81 in a competitive-risk setting). Moreover, when opposed to its MG and LGL counterparts, MG/LGL more frequently presented with severe cytopenias (aOR vsMGs: 28.9, 95%CI: 14.0 - 59.0, p&amp;lt; .001; aOR vsLGL: 2.7, 95%CI: 1.7 - 5.6, p= .008), and with immune-mediated cytopenias (aOR vsMGs: 10.5, 95%CI: 4.9 - 22.2, p&amp;lt; .001; aOR vsLGL: 2.8, 95%CI: 1.0 - 4.8, p= .04) ( FigB). In conclusion, our study reveals that: 1) the association between MGUS and LGL is more than an age-related epidemiological coincidence; 2) distinctive nosologic features for the MG/LGL dyad; and 3) that even “non-active” MGs associated with LGL might be of hematological clinical significance through humoral or cellular immune mechanisms. These findings point towards alternative treatment strategies of cytopenias in MGUS and LGL (immunosuppression vs anti-myeloma therapies, respectively), and provide impetus for the investigation of tumor surveillance in MGUS vs common etiologic factors intertwining these clonopathies.

Taste Abnormalities Emerging during Anti-Myeloma Therapies Including GPRC5D x CD3 Bispecific Antibody Talquetamab

Background: Dysgeusia is a common, yet underexamined side-effect of anti-tumor therapy. In multiple myeloma (MM) it has received more attention recently with the introduction of talquetamab, a bispecific T-cell engaging antibody targeting GPRC5D. Although GPRC5D expression is mainly restricted to plasma cells, cornified tissues including some cells in the oral cavity also express GPRC5D. This expression could be associated with changes in taste perception in patients undergoing therapy with talquetamab. Abnormalities in taste perception can negatively affect patients' quality of life and nutritional status, and in some cases may even require treatment interruption with a potential negative impact on outcome. Our objective was to determine the quality and severity of dysgeusia and its impact on quality of life in MM patients treated with talquetamab. To take our findings into perspective, we compared these results to patients who received high-dose melphalan, a treatment which goes along with taste abnormalities frequently (positive controls) as well as with BCMA targeting bispecific antibodies for which taste abnormalities have not been reported thus far (negative controls). Methods: We used a validated diagnostic instrument, “Taste-Strips”, to objectively assess gustatory performance in all five qualities of taste (sour, sweet, bitter, salty and umami). Further, we used a validated diagnostic instrument, “Sniffin' Sticks Identification Test 16”, to identify possible changes in olfactory perception. In addition, we used a questionnaire to document subjectively perceived changes in taste perception, oropharyngeal symptoms, nutritional status, individual diet-related symptoms, therapy compliance and quality of life. Results: We enrolled 55 patients with MM in our study. Seven (13%) patients were treated with a GPRC5D bispecific. Twenty-one (38%) patients received a BCMA bispecific and 27 (49%) patients received melphalan. All patients receiving a GPRC5D bispecific responded to treatment but also reported a significantly impaired overall taste sensation. They were significantly more likely to report loss of appetite ( P&amp;lt;0.01; Fisher test), loss of bodyweight (GPRC5D bispecifics: -4.3kg (SD4.6); BCMA bispecifics: -0.3kg (SD2.0); melphalan: -2.8kg (SD2.8)) and dry mouth ( P&amp;lt;0.01; Fisher test). Futhermore, patients receiving a GPRC5D bispecific reported a severe to very severe subjectively perceived level of impairment in quality of life due to subjectively perceived changes in gustatory perception of sweet, bitter, umami, and salty flavors (in descending order; P&amp;lt;0.01; Fisher test) and dry mouth ( P&amp;lt;0.01; Fisher test) than patients receiving BCMA bispecifics or melphalan. Forty-eight% of patients on BCMA bispecifics and 59% of patients on melphalan reported some level of dysguesia, which was objectified by “Taste-strips”-testing, highlighting the overall underreported frequency of this side effect. Of note, melphalan patients reported nausea and vomiting significantly more frequently than the other groups ( P&amp;lt;0.01; Fisher test). Objective olfactory testing did not show significant differences in olfactory perception between patients who received GPRC5D bispecifics, BCMA bispecifics or melphalan. Conclusion: Our results demonstrate the importance of monitoring taste perception and quality of life changes caused by cancer therapies. The frequency of dysgeusia is underreported in MM patients receiving BCMA bispecifics and melphalan therapy. For optimal nutritional management, hospitals should consider patients' individual taste preferences.

Update Analysis of Central Nervous System Multiple Myeloma Prognosis and Survival: A Real-World Multi-Institutional Study of the Greek Myeloma Study Group

Central Nervous System Multiple Myeloma (CNS-MM) is a rare but aggressive complication of MM, and its treatment remains an unmet clinical need. Herein we present a real-world national analysis of incidence, characteristics, prognostic factors and outcome of a large cohort of patients with CNS-MM. We evaluated 53 patients with CNS-MM (M/F: 23/30; median age: 59, range: 20-96 years; IgG: 27, IgA: 10, light-chain: 11, non-secretory: 4, IgD: 1; ISS1: 22, ISS2: 13, ISS3: 18; RISS1: 15, RISS2: 22, RISS3: 16) out of 4352 MM patients (1.2%), who were treated within the Greek Myeloma Study Group centers from 2000 to 2022 (23% of patients were diagnosed after 2016). A control group of MM patients matched for age, gender, and stage (ISS/RISS) who were treated during the same period was used for comparisons. Presence of soft tissue plasmacytomas (STP) and/or plasma cell leukemia (PCL; circulating plasma cells, cPCs: ≥5%) was determined and analyzed as extramedullary involvement (EMI). Median time to CNS-MM from MM diagnosis was 28 months (range 0-149 months); 6/53 (11.3%) patients experienced CNS-MM at initial MM diagnosis. Clinical manifestations of CNS-MM included visual disturbances/diplopia: 32%, paresis/paraplegia: 22%, lethargy/confusion: 37%, headache: 22%, cranial nerve palsy: 13% and dysarthria: 11%. PCL was present in 16/53 (30%) CNS-MM patients, while 29/53 (54.7%) CNS-MM patients had bone and/or STP vs. 13/53 matched controls (p=0.001); EMI was found in 24/53 (45%) patients with CNS-MM vs. 4/53 (7%) in controls (p&amp;lt;0.001). 35/53 (66%) CNS-MM patients had leptomeningeal infiltration (LMI) and 34% had intraparenchymal lesions. Median number of cells in the cerebrospinal fluid (CSF) was 60/μL (range 10-2550) and almost all of them (80%, range: 20-100%) were clonal plasma cells. Out of 53 CNS-MM patients, 14 (26.4%) had only CNS involvement without marrow infiltration by PCs; 51% had ≥1 high-risk molecular features (i.e., del17p, t4:14, t14:16, 1q+), and this was marginally higher vs. controls (36%; p=0.15). CD56 negative marrow PCs did not differ between groups (33% vs. 37%). A binary logistic regression analysis demonstrated that EMI was the strongest prognostic factor for the development of CNS-MM (p=0.01; HzR: 5.7). Median number of lines of treatment before the development of CNS-MM was 2 (range 0-9). First line anti-myeloma treatment in patients who developed CNS-MM included conventional chemotherapy (CT) or thalidomide-based regimens in 19 patients, bortezomib-based triplets in 27 and daratumumab-based regimens (DBR) in 7; this did not differ from controls. Overall response rate (ORR) in first-line therapy was similar between CNS-MM and controls (85% for both groups; CR 41% vs. 36%, respectively). After a median follow-up of 150 months post-MM diagnosis (95% CI: 107-192), 46 CNS-MM patients (87%) deceased (MM progression: 34, infection/sepsis: 10, cerebral hemorrhage: 2). Median overall survival (OS) of CNS-MM patients vs. matched controls from initial MM diagnosis was 43 months (95% CI: 31-54) vs 60 months (95% CI: 34-86) (p=0.002; Figure). Regarding CNS-MM therapy, 17 patients received IMiD-based regimens and 26 received PI-based regimens, 6 received CT and 4 received DBR. Patients with CNS-MM and marrow infiltration by PCs displayed an ORR of 31% only; CNS symptoms improved in 74% of all patients. Median OS of CNS-MM patients from the time of CNS involvement was 4 months (95% CI: 2.6-5.3), and it was longer in 12 patients treated after 2016 [18 months (95% CI: 7-29) vs. 2 months (95% CI: 1-3)]. Cerebrospinal fluid (CSF) infusions were performed in 28 patients (53%); 9 patients (19%) underwent radiotherapy. A multivariate analysis showed that EMI, either at diagnosis or during MM course, was the strongest negative predictor for post CNS-MM OS (p=0.008; HR: 3.4 95% CI: 1.4-8.0). Moreover, LMI was a negative predictor (p=0.02; HR: 2.7, 95% CI: 1.2-6.3) for OS, whereas treatment after 2016 had a positive impact (p=0.02; HR: 0.28, 95% CI: 0.12-0.8); CSF infusions did not affect OS. In conclusion, our analysis representing one of the largest real-world series of CNS MM patients after 2016, showed that, OS of CNS-MM remains poor however, there is a positive impact of treatment after 2016, reflecting the efficacy of modern anti-myeloma therapy; EMI strongly predicts for CNS-MM and induces a 3-fold increase in the probability of post CNS-MM death indicating a potential need for CNS prophylaxis in these patients.

Clinical Outcomes of Subsequent Therapies in Patients with Relapsed/Refractory Multiple Myeloma Following Talquetamab Treatment: Analyses from the Phase 1/2 MonumenTAL-1 Study

Introduction: Talquetamab (tal) is an off-the-shelf, T-cell redirecting bispecific antibody (BsAb) targeting G protein-coupled receptor family C group 5 member D. Results from the phase 1/2 MonumenTAL-1 (NCT03399799/NCT04634552) trial showed overall response rates (ORRs) of &amp;gt;71%, which were durable, and a manageable safety profile with the recommended phase 2 doses (RP2Ds) of subcutaneous (SC) tal, 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), in patients (pts) with relapsed/refractory multiple myeloma. Data with tal also demonstrated preservation of B cells throughout treatment, contributing to relatively few severe infections. To date, there is a paucity of data describing pt outcomes after T-cell redirection therapies. Here, we report outcomes for pts who received subsequent antimyeloma therapies (SATs) after discontinuing tal in MonumenTAL-1, including pts who went on to receive subsequent T-cell redirection therapies. Methods: Pts eligible for MonumenTAL-1 were intolerant to or progressed on established therapies (phase 1) or had ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor (PI), ≥1 immunomodulatory drug (IMiD), and ≥1 anti-CD38 monoclonal antibody (mAb) (phase 2). Pts received step-up doses and the QW or Q2W RP2Ds of SC tal until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. Following tal discontinuation, SAT, start/end date of SAT, best response to SAT, and date of PD on SAT were recorded, if available. Data are pooled for the QW and Q2W RP2D cohorts. Response to SAT is based on investigator-reported assessment. Efficacy is presented for first SAT received post tal discontinuation. Results: As of 17 Jan, 2023, 288 pts with no prior exposure to T-cell redirection therapies received tal at the RP2Ds (0.4 mg/kg QW [n=143] or 0.8 mg/kg Q2W [n=145]). Median prior LOT was 5. In the QW and Q2W cohorts, respectively, 74.1% and 69.0% were triple-class refractory, 29.4% and 23.4% were penta-drug refractory, and 15.4% and 11.0% had prior belantamab mafodotin exposure. Overall, 135 pts received ≥1 SAT post tal discontinuation: chemotherapy-based regimens (n=60 [44.4%]), a PI-, IMiD-, or other anti-neoplastic-containing regimen (n=40 [29.6%]), anti-CD38 mAb-containing regimens (n=36 [26.7%]), BsAbs (mostly monotherapy, n=23 [17.1%]: n=18 [13.3%] anti-B-cell maturation antigen [BCMA]; n=5 [3.7%] anti-Fc receptor-like protein 5 [FcRH5]), chimeric antigen receptor T-cell (CAR-T) therapy (n=20 [14.8%]; of whom n=18 [13.3%] were reported as receiving anti-BCMA-targeting CAR-T therapy), or anti-BCMA antibody-drug conjugates (n=13 [9.6%]). Time from tal discontinuation to the start of first SAT was generally similar across all drug classes (median, 1.1 months [range, 0.1-7.4]), including T-cell redirection therapies and bridging therapy in pts receiving CAR-T therapy: 1.5 months (range, 0.1-7.4) with CAR-T, 1.7 months (range, 1.0-3.5) with anti-BCMA BsAbs, and 1.0 month (range, 1.0-2.3) with anti-FcRH5 BsAbs. Best responses for each treatment class are shown in the Table. Pts had deep responses to CAR-T therapy as the first SAT post tal discontinuation with an ORR of 66.7% (8/12) (Table). ORR was 33.3% (2/6) in pts treated with anti-BCMA BsAbs as the first SAT post tal and 66.6% (2/3) with subsequent anti-FcRH5 BsAb therapy. Conclusions: Pts from MonumenTAL-1 who discontinued tal were effectively treated with several classes of therapy. Subsequent treatment with T-cell redirection therapies appears feasible, with 25.0% of pts achieving a complete response or better with CAR-T therapy post tal. Further investigation in larger pt populations is warranted to better understand the sequencing of T-cell redirecting therapies after tal to optimize outcomes.

Modakafusp Alfa Demonstrates Type I Interferon-Mediated Innate and Adaptive Immune Enhancement in a Phase 1/2 Study in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Modakafusp alfa (moda), a novel immunocytokine, is an innate immunity enhancer comprising two attenuated interferon (IFN) α2b molecules fused to an anti-CD38 IgG4 monoclonal antibody backbone, driving preferential IFNα signalling in CD38-expressing innate and adaptive immune cells as well as myeloma cells. Here, we present pharmacodynamic (PD) data from the first-in-human Phase 1/2 study of moda as a monotherapy in patients with RRMM (iinnovate-1; NCT03215030). A total of 37 patients treated with moda at 1.5 or 3 mg/kg every 4 weeks were included in the analysis. Peripheral blood (PB) and bone marrow (BM) samples were collected during screening or pre-dose on cycle 1 day 1 (C1D1) and at multiple timepoints after treatment. BM and PB samples were evaluated by cytometry time of flight (CyTOF) and bulk RNA sequencing (RNAseq) to assess pharmacodynamic changes in immune cell populations, cell activation, and gene expression. Administration of moda led to enhanced innate immune cell activation and cytotoxic function as demonstrated by increased proportions of CD69+ and granzyme B+ in peripheral NK cells analyzed by CyTOF. This was accompanied by a decrease in the proportion of TIGIT+ NK cells, indicating reduced inhibitory signaling. Furthermore, enhanced proliferation (%Ki67+) of NK cells was observed in both BM and PB. Moda also impacted myeloid cell populations in BM and PB. Dendritic cells (DCs) and monocytes in PB showed increased surface expression of the co-stimulatory molecule CD86, suggesting a potential for enhanced antigen presentation and co-stimulation ability. Increased proliferation (%Ki67) of DCs and monocytes was detected in both PB and BM, accompanied by a decrease in numbers of peripheral DCs which may indicate recruitment or homing to secondary lymphoid organs. Additionally, RNAseq analysis revealed that treatment with moda led to upregulation of CD68 expression in both PB and BM, indicating a proinflammatory M1 macrophage type response. Finally, CyTOF analysis also indicated that moda significantly impacted adaptive immunity. We observed enhanced activation (%CD69, %PD1 and %CD40L) and cytotoxic function (%granzyme B) of peripheral CD8 T cells, and increased CD8 T cell proliferation (%Ki67 CD8) in both PB and BM samples. Enhanced activation of peripheral CD4 T cells (%CD69, %CD40L) was also detected. Consistent with activation of the adaptive immune system, there was a reduction in naïve CD8 T cells accompanied by an increase in CD8 T effector memory cells in PB. Analysis of exhaustion markers (TIGIT, PD-1) in cycle 1 (C1D8, C1D15, and C2D1 predose) showed that moda did not induce CD8 T cell exhaustion in either PB or BM, and there was no change in FoxP3+ Treg cells. Moda-induced innate and adaptive immune cell phenotypic changes were evaluated for correlation with clinical response at timepoints with sufficient number of evaluable samples. While none of the associations were statistically significant after correcting for multiplicity testing (using the false discovery rate method), we observed trends warranting further investigation. There was a greater increase of CD40L+ NK cells and PD1+ CD8 cells in responders vs. non-responders at C1D2. Additionally, at C1D15 responders showed a lower increase in proliferation (%Ki67+) of classical monocytes, NK cells, and myeloid DCs in PBas compared to non-responders. A similar trend was also observed in the BM classical monocytes. Even though the peak of Ki67 expression was observed at C1D8, diminished increases of proliferating cells at C1D15 in responders was a surprising observation that needs further consideration. The PD biomarker data from this first-in-human clinical trial demonstrated that treatment with moda enhances both innate and adaptive immune cell activation in PB and BM. Importantly, moda-mediated immune activation did not result in T cell exhaustion during cycle 1, as evaluated in both PB and BM. We have observed interesting trends of immune phenotypic changes that may correlate with response. Follow-up analyses of the correlation of biomarkers with clinical response are in progress and will be presented. Further clinical trials are underway (iinnovate-2, NCT05556616; iinnovate-3, NCT05590377) to evaluate moda's novel immune activating mechanism in combination with standard of care anti-myeloma therapies.