Triple-class Refractory Multiple Myeloma Research Articles

A phase Ib trial of isatuximab, bendamustine, and prednisone in relapsed/refractory multiple myeloma.

Patients with triple-class refractory (TCR) multiple myeloma (MM) often need cytoreductive chemotherapy for rapid disease control. Bendamustine is an outpatient-administered, bifunctional alkylator and isatuximab is an anti-CD38 monoclonal antibody with unique cytotoxicity characteristics. We hypothesized that isatuximab-bendamustine-prednisone would be well-tolerated regimen in TCR MM, and conducted single-center, phase Ib, investigator-initiated study. Patients had TCR MM and last daratumumab exposure ≥ 6 weeks. This study was conducted as a 3 + 3 design to establish the maximally tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Isatuximab 10mg/kg IV was administered weekly (cycle 1), and every 2 weeks thereafter. Bendamustine was administered on days 1 and 2 at 3 dose levels (DL): 50, 75, and 100 mg/m2. Methylprednisolone was administered as 125mg on day 1 and prednisone 60mg days 2-4. Common definitions were used for DLTs, adverse events (CTCAE v 5.0), and disease response. Fifteen patients were treated (3 DL1, 6 DL2, 6 DL3). Median age was 71, 53% had high-risk cytogenetics, and 34% had prior BCMA-targeting therapy. One DLT was observed at DL2 (Grade 3 thrombocytopenia plus bleeding). There were no Grade 5 treatment-related AEs. The MTD was not reached. The overall response rate was 20% (3/15) including one stringent complete response. The median PFS was 2.5 months (95% CI 0.9-4.1 months). We demonstrated the safety and tolerability of isatuximab-bendamustine-prednisone. Toxicities were mild and manageable with limited intervention. The study was discontinued due to slow accrual. However, we observed responses even among highly refractory patients. This study was registered on clinicaltrials.gov as NCT04083898 on 9/6/2019.

A research center’s experience of T-cell–redirecting therapies in triple-class refractory multiple myeloma

AbstractThe efficacies of chimeric antigen receptor T cells (CAR-Ts) and bispecific monoclonal antibodies (BiAbs) for triple-class refractory (TCR) myeloma have not previously been compared, and clinical data on how to rescue patients after relapse from these immunotherapies are limited. A retrospective study of 73 TCR patients included in trials was conducted: 36 received CAR-Ts and 37 received BiAbs. CAR-Ts produced a higher overall response rate (ORR) than BiAbs (97.1% vs 56.8%, P = .002). After a median of follow-up of 18.7 months, no significant difference in progression-free survival (PFS) was observed between the CAR-T and BiAbs groups (16.6 vs 10.8 months; P = .090), whereas overall survival (OS) was significantly longer in the CAR-T than in the BiAbs group (49.2 vs 22.6 months; P = .021). BiAbs after CAR-Ts yielded a higher ORR and longer PFS2 than did nonredirecting T-cell therapies after CAR-Ts (ORR: 87.5% vs 50.0%; PFS2: 22.9 vs 12.4 months). By contrast, BiAbs after BiAbs resulted in an ORR of 33% and PFS2 of 8.4 months, which was similar to that produced by the nonredirecting T-cell therapies (ORR: 28.6%; PFS2: 8.1 months). Although this is a pooled analysis of different trials with different products and the patient profile is different for CAR-Ts and BiAbs, both were effective therapies for TCR myeloma. However, in our experience, although the PFS was similar with the 2 approaches, CAR-T therapy resulted in better OS, mainly because of the efficacy of BiAbs as rescue therapy. Our results highlight the importance of treatment sequence in real-word experience.

Belantamab mafodotin in triple-refractory multiple myeloma patients: A retro-prospective observational study in Italy.

Belantamab mafodotin is the first-in-class antibody-drug conjugates targeting B-cell maturation antigen to have demonstrated effectiveness in triple-class refractory multiple myeloma (TCR-MM) patients. We performed a retrospective study including 78 TCR patients, with at least four prior lines of therapy (LOTs), who received belantamab mafodotin within named patient program and expanded access program in Italy between 2020 and 2022. Median age was 65 years (range 42-86 years), ECOG performance status was ≥1 in 45% of patients. Overall, a clinical benefit was obtained in 36 out of 74 evaluable patients (49%), with 43%, 28%, and 13.5% achieving at least partial response, very good partial response, and complete response, respectively. After a median follow-up of 12 months (range 6-21 months), median duration of response, progression-free survival (PFS), and overall survival (OS) were 14, 5.5, and 12 months, respectively. Age >70 years, good performance status and response were associated with longer PFS and OS. Keratopathy occurred in 58% of patients (G3 2.5%), corneal symptoms in 32% (G3 1.2%) and a reduction in visual acuity in 14%. Grade 3 thrombocytopenia occurred in 9% of patients. Only 3% of patients discontinued belantamab mafodotin because of side effects. This real-life study demonstrated significant and durable responses of belantamab in TCR-MM patients with four prior LOTs, otherwise ineligible for novel immunotherapies.

Assessment of algorithms for identifying patients with triple-class refractory multiple myeloma using real-world data

Objective: Patients with triple-class refractory (TCR) multiple myeloma (MM) have limited treatment options and poor prognoses. This high unmet need has prompted the development of new therapies allowing for improved outcomes for these patients. Recently, new targeted therapies for the treatment of patients with relapsed or refractory MM have been approved based on single-arm clinical trial results. Real-world (RW) data enable a better understanding of the effectiveness of new therapies in clinical practice and provide external controls for single-arm studies. However, using RW data to identify patients with TCR MM is challenging and subject to limitations. Methods: In this retrospective cohort study of an analysis of the COTA electronic health record (EHR) database, we used four algorithms to define refractory status and created four groups of patients with TCR MM initiating post-TCR therapy. Each algorithm relied on slightly different criteria to identify TCR patients, but all were based on the International Myeloma Working Group (IMWG)-derived and/or healthcare provider (HCP)-reported progressions within the database. Results: A total of 3815 patients with newly diagnosed MM met the eligibility criteria for this study. The choice of the algorithm did not impact the characteristics of identified patients with TCR MM (Algorithm 1 [n = 404], Algorithm 2 [n = 123], Algorithm 3 [n = 404], and Algorithm 4 [n = 375]), including their demographic and disease characteristics, MM treatment history, or treatment patterns received after becoming TCR. However, identifying TCR MM using a combination of IMWG-derived and HCP-reported progressions allowed up to a 70% increase in the size of the identified group of patients compared with using only IMWG-derived progressions. Conclusion: In RW settings, progressions from both IMWG-derived data and physician reports may be used to identify patients with TCR MM.

Elranatamab efficacy in MagnetisMM-3 compared with real-world control arms in triple-class refractory multiple myeloma.

Elranatamab efficacy in the single-arm, registrational MagnetisMM-3 trial (NCT04649359) was compared with that of physician's choice of treatment (PCT) for triple-class refractory multiple myeloma. MagnestisMM-3 eligibility criteria were applied to two USA-based oncology electronic health record databases, COTA and Flatiron Health (FH), to identify cohorts for this study (NCT05932290). Applied statistical techniques accounted for cohort imbalances. MagnetisMM-3 (BCMA-naive; n=123) outcomes were compared with those from COTA (n=239) and FH (n=152). Elranatamab was associated with a significantly higher objective response rate (risk ratios, 1.88-2.25), significantly longer progression-free survival (hazard ratios [HRs], 0.37-0.57), and, across most analyses, significantly longer overall survival (HRs, 0.46-0.66) versus PCT. BCMA-naive patients who were treated with elranatamab exhibited significantly better outcomes than patients treated in real-world clinical practice.

Development and prospects of bispecific antibodies for multiple myeloma

Patients with triple-class refractory multiple myeloma once had a poor prognosis, but recently developed bispecific antibodies (bsAbs) targeting B-cell maturation antigen (BCMA), G protein-coupled receptor 5D (GPRC5D), and Fc receptor-homolog 5 (FcRH5) have shown significant clinical activity in these patients. However, responses to bsAbs are not universal, and resistance often develops during therapy. Mechanisms that mediate resistance may be tumor-intrinsic or immune-dependent. Tumor-intrinsic factors include antigen loss (biallelic or functional) due to deletion or mutation of target genes, increased soluble BCMA (for BCMA targeting bsAbs), high tumor burden, and extramedullary disease. Immune-mediated resistance highly depends on T cell fitness and the resistant immune environment. This article describes bispecific antibodies against multiple myeloma that are currently being developed.

Outcomes of Triple Class Refractory Multiple Myeloma Patients: A Single Center Retrospective Study

BACKGROUND Despite recent advances in the treatment of multiple myeloma (MM), the disease remains incurable. Recent studies suggest that patients who are triple class refractory (TCR) to a proteasome inhibitor (PI), immunomodulatory agent (IMiD), and anti-CD38 monoclonal antibody (mAb) have especially poor outcomes with a median overall survival (OS) of less than 1 year. However, studies with these results have been conducted in large academic institutions. In this study, we retrospectively analyzed outcomes among MM patients with TCR MM in a single clinic specializing in the care of patients with MM. METHODS A retrospective chart review was conducted among patients with TCR MM who were treated in a single clinic specializing in the care of patients with this B-cell malignancy. From July 2003 to July 25, 2022, we determined these patients' progression-free survival (PFS), OS, cytogenetics, lines of prior therapy (LOT), and first treatment they received after they became TCR. Kaplan-Meier analysis was utilized to assess differences in PFS, OS from diagnosis, and OS from TCR status based on high-risk cytogenetics, defined as the presence of t(4;14), t(14;16), t(14;20), 1q gain, or deletion 17p, compared to those with standard-risk cytogenetics. Kaplan-Meier analysis was also used to compare PFS according to number of lines of prior LOT, time to TCR, and drug class used for the first treatment after becoming TCR. RESULTS TCR developed in 121 patients. The median time from diagnosis to development of TCR disease was 33.4 months (mo; range, 1.5-187 mo). Patients with a time to TCR status of > 33.4 months had a longer PFS (median 5.2 mo) compared with patients with a time to TCR status of < 33.4 mo (median 2.5 mo; p=0.0171). The median LOT these patients received was 7 (range, 3-26). The median LOT prior to becoming TCR was 3 (range: 2-12). The median PFS of patients from their first treatment following the development of TCR was 4.5 months; patients with < or > 3 LOT prior to becoming TCR had the same median PFS (4.5 mo). However, PFS was shorter for high-risk (median = 2.5 mo) than standard risk (median = 4.2 mo) TCR MM patients, but this did not reach statistical significance (p = 0.0633). The median OS from diagnosis of MM was 94.8 mo (range, 5.8 - 320.6 mo). Cytogenetic data was available for 65 patients (54%). Of these, 35 (54%) harbored high-risk cytogenetics. The median OS of TCR patients with high-risk cytogenetics from diagnosis was 98.2 mo and was not different from those with standard risk disease (74.2 mo; p = 0.704). Notably, the median OS of patients from the time of development of TCR was 25.5 mo (range, 1.5 - 186.8 mo); OS was shorter (median 18.7 mo) among those TCR patients with high-risk cytogenetics compared with that of standard risk (38.5 mo), but this was not significant (p = 0.1109). The first line of therapy administered following the development of TCR for the majority of patients (n= 108 [89%]) was retreatment with an IMID, PI, mAb, or a combination of agents from these drug classes. Thirteen patients (11%) were treated with a venetoclax- or alkylating agent-based combination therapy. In addition, all except 2 patients received steroids as part of their first treatment after developing TCR. The regimen with the longest PFS was the combination of a mAB and steroids (median 9.0 mo) but only 6 patients were treated with this combination. The shortest PFS was among those retreated with a PI and steroids (n = 15; median 2.4 mo). The use of an IMID with steroids was the most frequently used combination treatment (n=32) with a median PFS of 3.4 mo. CONCLUSION Despite being refractory to a PI, IMID, and mAb, TCR patients in our single-center retrospective study showed a median OS of more than 2 years (25.5 mo) from the development of TCR. This OS is the longest reported to date in this population of MM patients. Cytogenetic differences failed to predict both OS and PFS from the development of TCR. In addition, the number of prior lines of therapy did not predict PFS from their first treatment after showing TCR. The time to development of TCR, however, did predict OS as patients who took longer to become TCR had a longer median OS. The results of this study show that time to becoming TCR is a prognostic factor for this group of patients. Our study shows that OS is considerably longer for patients with TCR than has been previously reported.

An Indirect Comparison of Elranatamab's Progression-Free Survival and Overall Survival from Magnetismm-3 Versus Real-World External Control Arms in Triple-Class Refractory Multiple Myeloma

BACKGROUND Elranatamab(ELRA) is a BCMAxCD3 bispecific antibody being investigated for the treatment of relapsed/refractory multiple myeloma (MM). The phase 2 MagnetisMM-3 (MM-3; NCT04649359) trial was single-armed; the aim of this study was to contextualize the efficacy data from MM-3 with two real-world (RW) external control arms. METHODS We conducteda retrospective cohort study to indirectly compare the efficacy observed in MM-3 Cohort A (BCMA-naïve; N=123) from the March 2023 data cut (approximately 15 months of follow-up) with two US-based oncology electronic health record databases, COTA and Flatiron Health (FH), as external controls. MM-3 inclusion (eg, prior MM diagnosis, ECOG≤2, refractory to ≥1 PI, ≥1 IMiD, and ≥1 anti-CD38) and exclusion (I/E) criteria (eg, plasma cell leukemia, smoldering MM) were applied to each RW database to obtain comparable patient populations across sources. After imposing MM-3 I/E criteria, we conducted comparisons between data sources on progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier estimators or Cox proportional hazard models (“unweighted analyses”) and restricted mean survival time (RMST) analyses in instances where the proportional hazards assumption was violated. We used additional Cox proportional hazard models, Kaplan-Meier estimators, or semi-parametric models implementing inverse probability of treatment weighting (IPTW), doubly robust, and propensity score (PS) matching analyses to adjust for any remaining imbalances across cohorts on confounding variables (eg, age, comorbidities, Eastern Cooperative Oncology Group (ECOG) score, International Staging System (ISS), prior lines/refractoriness, cytogenetic risk, extramedullary disease [COTA only], lab values). RESULTS N=123 patients from MM-3 Cohort A were compared with the 239 and 152 patients identified from the COTA and FH databases, respectively. Treatment regimens in the RWD sources included various combinations of PIs (carfilzomib- and bortezomib-based regimens were each used by 43% and 15% of patients, respectively), IMiDs (lenalidomide- and pomalidomide-based regimens were used by 9% and 41% of patients, respectively), and mAbs (daratumumab- and isatuximab-based regimens were used by 32% and 1% of patients, respectively), among other agents (eg, selinexor-based regimens were used by 5% of patients). Across unweighted, IPTW, doubly robust, and PS matching analyses, ELRA was associated with significantly longer PFS than RW physicians' choice of treatment from both COTA and FH (hazard ratios [HRs] ranged from 0.37 to 0.57; see Table 1). Similarly, across unweighted, IPTW, doubly robust, and PS matching analyses, ELRA was associated with significantly longer OS than RW physicians' choice from COTA (HRs ranging from 0.46 to 0.65) and longer OS across unweighted (RMST difference at 15 months = 1.70) and PS matching analyses (HR = 0.60) than RW physicians' choice from FH. IPTW and doubly robust methods indicated only directionally longer OS for ELRA than RW physician's choice from FH (RMST difference at 15 months = 0.72 and HR = 0.66, respectively). CONCLUSIONS Among BCMA-naïve patients who resemble those enrolled in the MM-3 trial, those treated with ELRA exhibit significantly longer PFS and OS compared with real-world treatments.

Treatment Patterns and Outcomes in Patients with Multiple Myeloma Who Received Ixazomib and in Patients with Triple-Class Refractory Multiple Myeloma: A Retrospective, Observational, Real-World Historical Database Analysis Study from China

Background: Multiple myeloma (MM) is a fatal, malignant disease of plasma cells characterized by an abnormal proliferation of monoclonal antibodies. China is estimated to have 22,450 newly diagnosed (ND) cases of MM and 17,360 related deaths in 2022. Emerging novel therapies have significantly improved survival in MM, and treatment guidelines have been updated to reflect these advances. Ninlaro® (ixazomib) is the first oral proteasome inhibitor (PI) approved by the US FDA in 2015 and by China's National Medical Products Administration in 2018 (conditionally) for MM patients receiving ≥1 prior therapy owing to its convincing efficacy and well-tolerated safety profile as seen in the landmark Phase III TOURMALINE-MM1 trial and the China Continuation Study. Novel drugs such as PIs, immunomodulatory drugs (IMDs), and anti-CD-38 monoclonal antibodies are the core component of MM treatment and have improved patient outcomes considerably. However, many patients remain refractory to these drugs (triple-class refractory, TCR) and have poor clinical outcomes. There is a lack of real-world evidence characterizing treatment patterns and outcomes of MM patients receiving ixazomib and TCR-MM patients, in China. The objective of this study is to bridge this data gap by providing vital information on the treatment patterns and outcomes, and healthcare resource utilization in Chinese MM patients receiving ixazomib and TCR-MM patients in real-world clinical practice. Study Design and Methods: This study is an ongoing, single-centre, non-interventional, retrospective database analysis study of MM patients identified from the Chinese National Longitudinal Cohort of Haematologic Diseases (NICHE)-MM registry, a historical and ongoing longitudinal data registry of the Institute of Haematology and Blood Diseases Hospital (IHBDH), and representing the top-tier MM care in China. The patients will be divided into two groups. Patients (aged ≥18 years) with a confirmed MM diagnosis receiving all ixazomib-based regimen as 2nd-line and above therapy (RR-MM), or as a 1st-line therapy (ND-MM) will form group one and TCR-MM patients' refractory to at least one IMiD (lenalidomide, pomalidomide or thalidomide), one PI (bortezomib, ixazomib, or carfilzomib) and one anti-CD-38 monoclonal antibody (daratumumab and isatuximab) will form group two. TCR-MM patients receiving ixazomib will be part of both groups. Patients enrolled in clinical trials will be excluded. The data for analysis will be collected from the ixazomib launch date in China (April 12, 2018) and/or the index date of the first patient enrolled in ixazomib Named Patient Program to September 2023 (tentative). Since 2000 till January 2023, the NICHE-MM registry has enrolled 3,329 MM patients of whom 156 patients have received ixazomib. This is the preliminary sample count and the final sample size will be calculated during data cleaning and analysis phases. The primary objective of this study will be to determine 1) treatment patterns and responses by lines of treatments and 2) time-to-event outcomes. The treatment patterns will include treatment name, dosage, type (induction, consolidation, or maintenance), number of cycles, duration and severe adverse event causing hospitalization. The treatment responses will include complete response (CR), stringent CR, partial response (PR), very good PR, minimal response, stable disease, and progressive disease as defined by the International Myeloma Working Group. The overall response rate of the last line of treatment for both study groups will be calculated as composite endpoint. Time-to-event outcomes will include progression-free survival, overall survival, duration of therapy, and time to next line of treatment in ND/RR-MM and TCR-MM patient groups. Secondary objectives will include assessment of patients' demographic, disease and clinical characteristics. Depending on data availability, the exploratory objective will be to determine the healthcare resource utilization and costs incurred by patients in both groups. Subgroup analysis between ND-MM vs. RR-MM or RR-MM patients receiving ixazomib in 2nd-line setting vs. TCR-MM patients receiving ixazomib in >3rd-line setting is also planned. Descriptive statistics will be used for the analyses. Our findings will also help clinicians in making strategic decision about more apt positioning of ixazomib in the treatment algorithm of MM.

Selinexor Combined Bortezomib, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma with Extramedullary Disease(EMD) or High-Risk Cytogenetics

BACKGROUND: High-risk(HR) cytogenetics are significantly enriched in MM with EMD , and studies consistently showed EMD and HR cytogenetics were associated with poor outcome. To date, there is no established approach for treatment of newly diagnosed multiple myeloma (NDMM) with EMD. Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that selectively binds and inactivates XPO1, which leads to accumulation of tumor suppressor proteins in the nucleus and re-activation of cell cycle regulators such as p53, FOXO, IkB. Meanwhile, by forcing the nuclear retention of the eIF4E protein, Selinexor reduces the cytoplasmic ribosomal translation of oncoproteins, including c-Myc, Bcl-2 and Bcl-6. In the STORM study(NCT02343042), 122 patients(pts) with penta-exposed, triple-class refractory multiple myeloma were enrolled to receive Selinexor combined with low-dose dexamethasone. 27 patients were diagnosed with EMD at baseline. The median age of patients was 64 years, the median prior therapies were 7, and 8 pts had high risk cytogenetics. Follow-up evaluation of plasma cell tumor was performed in 16 cases, and complete disappearance or shrinkage of extramedullary lesions was observed in 9 cases. It indicates that Selinexor has clinical activity in the treatment of plasma cell tumor or EMD. The treatment of MM with EMD or HR cytogenetics still faces great challenges, because there is no uniform guideline and consensus to recommend standard protocols, and prospective clinical studies are urgently needed to explore new treatment strategies. METHODS: Eligible pts were aged≥18 years of NDMM with EMD or HR cytogenetics, and an Eastern Cooperative Oncology Group(ECOG) performance status of 0-2. For induction/consolidation(21-day cycles), pts received 8 cycles of SVRd (Selinexor 60 mg PO weekly, Bortezomib 1.3 mg/m2 SC days1, 4, 8, 11, Lenalidomide 25 mg PO days 1-14, and Dexamethasone 40 mg PO weekly. In maintenance (28-day cycles), pts received SR (Selinexor+ Lenalidomide) at least 2 years until disease progression, death or withdrawal. The primary endpoint was overall response rates (ORR) by end of induction. The secondary endpoints are complete response (CR), duration of response (DOR), progression free survival (PFS), overall survival (OS) and toxicity. This trial is registered with Chinese Clinical Trial Registry, number ChiCTR2200062860. RESULTS: 8 pts with previously untreated NDMM were included from August 2022 to July 2023 in 3 hospitals. Median age was 62 (range 55-81). R-ISS stage 3 was present in 2 (25%) pts(Table 1). Based on inclusion criteria, 7 pts had EMD and 1 patient had HR cytogenetic, including 17p deletion (n=2, 25%), 1q21 gain(n=2, 25%). According to IMWG criteria, the ORR of 8 pts with NDMM was 100%, including 2 stringent complete response(sCR), 3 CR, 2 very good partial response (VGPR) and 1 partial response (PR). 1 patient evaluated with sCR at the end of the induction period was evaluated with MRD negativity after autologous stem cell transplantation (ASCT). Median time to first response in patients with a partial response or better was 1 months (1-2). This result established that SVRd regimen has a prospective response for MM with EMD or HR cytogenetic. The most common grade 3-4 treatment-emergent adverse events (occurring in ≥10% of pts) were thrombocytopenia. The most common treatment-related adverse events were grade 1 or 2, including nausea (25%), fatigue (25%), and anorexia (25%). Overall, the severe toxicities are manageable. CONCLUSIONS: SVRd as induction prior ASCT is safe and allows deep responses in NDMM patients with EMD or HR cytogenetic profile. It is worthy of further study based on the preliminary efficacy results. Longer-term results still require more pts have been enrolled and further follow-up.

Real-World Clinical Outcomes in Patients With Multiple Myeloma Administered With Elotuzumab-Based Treatment.

Objective Elotuzumab is used to treat relapsed and/or refractory multiple myeloma (MM). However, the optimal patient selection and sequencing in MM therapy are less clear. Therefore, this retrospective cohort study assessed the clinical outcomes of patients with MM who underwent elotuzumab-based therapy. Methods We reviewed the medical records of 85 patients with relapsed/refractory MM who received elotuzumab for the first time. Participants were divided into progressive disease (PD group) and those without PD (non-PD group) at elotuzumab treatment initiation, and each group was analyzed separately. Survival rates were calculated using Kaplan-Meier curves and compared using log-rank tests. Results The median follow-up period was 33.6 (range: 0.5-72.0) months. The median progression-free survival (PFS) and overall survival (OS) of PD and non-PD groups at elotuzumab therapy initiation were 5.3 months and not reached (NR), respectively (P < 0.0001), and 26.8 months and NR, respectively. Patients with triple-class refractory disease in both groups had worse PFS and OS. Twenty-one patients in the non-PD group received elotuzumab as post-hematopoietic stem cell transplantation, whose PFS and OS were NR(95% CI, 21.4 months-NR) and NR (95% CI, NR-NR), respectively. Conclusions Elotuzumab exhibited limited therapeutic efficacy in patients with triple-class refractory MM but better treatment outcomes in situations with adequate disease control and post-transplant treatment.

Iberdomide Maintenance after Autologous Stem-Cell Transplantation in Newly Diagnosed MM: First Results of the Phase 2 EMN26 Study

Background. Iberdomide is a novel oral cereblon E3 ligase modulator (CELMoD TM) with enhanced direct antitumor effects and immune stimulatory effects, compared to lenalidomide or pomalidomide. In the ongoing phase 1/2 CC-220-MM-001 study, iberdomide plus dexamethasone had a favorable safety profile and demonstrated clinically meaningful activity in triple-class refractory multiple myeloma (MM) patients, including those refractory to lenalidomide and pomalidomide (IMiDs ®). Based on these data, we aimed to evaluate the safety and clinical activity of 3 different doses of iberdomide as a novel maintenance treatment post-transplant in newly diagnosed MM patients. Here we report results from the first interim analysis for patients who have been treated with at least 6 treatment cycles, or discontinued treatment earlier. Methods. The EMN26 study is a multicohort, phase 2 study conducted in 4 European countries. Patients aged 18 years or older with MM, who had achieved at least a partial response (PR) after induction therapy containing a proteasome inhibitor (PI) plus IMiD followed by single or double autologous stem-cell transplantation (ASCT) +/- consolidation, were enrolled into one of 3 different cohorts (iberdomide 0.75, 1.0, or 1.3 mg on days 1-21 of each 28-day cycle; treatment continued until progression or unacceptable toxicity; 40 patients in each cohort). The primary outcome is improvement in response, and secondary outcomes include safety and progression-free survival (PFS). Response was evaluated at screening and after every cycle (bone marrow analysis was done at screening, at 6 and 12 months after treatment initiation, and to confirm (s)CR). This trial is ongoing and is registered with ClinicalTrials.gov (NCT04564703). Results. At data cut-off (May 31, 2023) 31 patients were enrolled in the 0.75 mg cohort, and 40 patients each in the 1.0 and 1.3 mg cohorts (total of 111). A total of 69 patients had received ≥6 cycles of iberdomide treatment or discontinued earlier (n=34 in 1.0 mg cohort; n=35 in 1.3 mg cohort; n=0 in 0.75 mg cohort [this cohort was added later]). Median age of these 69 patients was 59 years, and 57% were male. At diagnosis, 37% of patients presented with International Staging System (ISS) stage 1 disease, 35% with ISS stage 2, and 28% with stage 3. High-risk disease (del(17p), t(4;14), and/or t(14;16)) was present in 14% of patients. All patients received a PI/IMiD-containing induction regimen which also included daratumumab in 41% of patients. Double ASCT was administered to 19% and post-ASCT consolidation to 7%. Best response at the time of enrollment in the study was PR in 15%, very good (VG)PR in 59%, complete response (CR) in 12%, stringent (s)CR in 15% [≥CR: 26%] in the 1.0 mg cohort, and PR in 3%, VGPR in 69%, CR in 11%, sCR in 17% [≥CR: 29%] in the 1.3 mg cohort. After 6 treatment cycles, there was comparable deepening of response in both cohorts (1.0 mg cohort: PR 6%, VGPR 44%, CR 3%, sCR 47% [≥CR: 50%]; 1.3 mg cohort: PR 3%, VGPR 37%, CR 9%, sCR 51% [≥CR: 60%]). Improvement of response was reported in 48% (90% CI 32-65%) of patients treated with 1.0 mg iberdomide and 45% (90% CI 29-62%) in the 1.3 mg iberdomide cohort ( Figure), which are significantly higher than the null hypothesis of ≤20% response improvement within 6 months. The most common grade 3 or worse adverse events (AEs) during cycles 1-6 were neutropenia (21% in 1.0 mg cohort and 46% in 1.3 mg cohort), infections (3% and 14%), fatigue/asthenia (12% and 14%). There were no events of ≥grade 3 thrombocytopenia, anemia, diarrhea, VTE, or neuropathy. Dose reductions were used to manage AEs in 18% of patients in the 1.0 mg cohort and 31% in the 1.3 mg cohort. Treatment discontinuation occurred in 3 patients in 1.0 mg cohort (1 due to AE, 2 PD), and 4 patients in 1.3 mg cohort (2 due to AE, 1 PD, and 1 death [unknown cause]). PFS at 6 months was 97% and 94% in the 1.0 and 1.3 mg cohorts. With longer follow-up, results from the 0.75 mg cohort and MRD conversion data will be presented at the meeting. Conclusions. Iberdomide represents a novel effective post-ASCT maintenance strategy with a favorable safety profile and superior response improvement at 6 months than what has been observed with lenalidomide maintenance (26% at 6 months in the EMN02 study). Additional follow-up is needed to define the recommended maintenance dose that will be used in the randomized phase 3 EXCALIBER maintenance study, which will evaluate iberdomide vs. lenalidomide maintenance post-ASCT.

Patient-Reported Outcomes Among Patients with Triple-Class Refractory Multiple Myeloma in Real-World Clinical Practice: A Prospective, Multi-Site Observational Study

BACKGROUND Several studies have highlighted the poor outcomes observed among patients with relapsed/refractory multiple myeloma (MM), particularly those with triple-class refractory (TCR; refractory to at least one PI, one IMiD, and one anti-CD38 mAb) disease. The aim of this study was to describe the longitudinal changes in quality of life (QOL) and other patient-reported outcomes (PROs) among TCR MM patients in real-world clinical practice who initiate a new line-of-therapy. METHODS A prospective, multi-site observational study of patients with TCR MM was conducted through the Mayo Clinic system. Patients initiating a new post-TCR therapy (defined as the index date) were followed for a 12-month observation period during which PRO surveys were administered for the first 6 months. For patients initiating a CAR-T therapy, a survey assessment was conducted at apheresis, lymphodepletion chemotherapy, and every month after T-cell infusion until Month 6. All other patients received a survey assessment before index and then every month thereafter until Month 6. PRO measures included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30; including the Global Health Score [GHS]), the EORTC Multiple Myeloma Questionnaire (QLQ-MY20; including the Disease Symptoms [DS] domain score), the EORTC QLQ for Chemotherapy-Induced Peripheral Neuropathy (CIPN20), the EuroQoL-5 Dimensions (EQ-5D), the Patient Global Impression of Severity (PGIS), and the Patient Global Impression of Change (PGIC). Patient surveys were supplemented with retrospective chart reviews conducted 3 months and 12 months following the index date to obtain clinical information. Descriptive data were reported at each timepoint separately for patients who received CAR-T and non-CAR-T index therapies. The study is ongoing and this abstract reflects all patient visit data as of April 2023. RESULTS N=55 patients (60% male, 96% White, mean age 66 years) were included in this interim analysis. The median time interval between becoming TCR and the index date was 3.9 months (interquartile range [IQR]: 1.7, 15.5). Most patients had an ECOG score of 0 or 1 (53% and 38%, respectively) and were R-ISS I or II (36% and 54%, respectively); 53% of patients had high-risk cytogenetics and 20% had extramedullary disease. The median (IQR) number of prior treatment lines was 4 (4.0, 5.5). N=24 patients initiated a CAR-T therapy as their index therapy (equally split between ide-cel and cilta-cel); the remaining N=31 patients predominantly initiated a treatment regimen containing an IMiD (52%), a PI (55%), an anti-CD38 antibody (13%), or an alkylating agent (36%). Among CAR-T patients, QOL and disease-related symptoms worsened from baseline through Month 2-3 (eg, mean GHS was 65.9 at apheresis, 64.9 at lymphodepletion, and 53.3 at Month 2 [higher scores indicate better QOL]; mean DS domain score from the QLQ-MY20 was 24.1 at apheresis, 23.4 at lymphodepletion, and 33.7 at Month 2 [higher scores indicate more symptoms]; see Table 1). These decrements were followed by improvement back to baseline levels and, in some cases, improvement above baseline levels (eg, GHS was 67.9 and 65.0 at Months 4 and 5, respectively; DS was 18.3 and 17.8 at Months 4 and 5), though few patients had sufficient follow up to analyze QOL at later timepoints. Based on the PGIC, 77.8% of patients reported being “a little better” or “much better” as early as Month 1, though this number declined over time. Among non-CAR-T patients, QOL largely plateaued (GHS was 62.2 at baseline and 58.3 at Month 6), though disease symptoms improved over time (DS was 28.6 at baseline and 24.5 at Month 6; pain was 42.3 at baseline and 29.2 at Month 6). Based on the PGIC, 34.7% of patients reported being “a little better” or “much better” at Month 1, which improved to 50% by Month 6. CONCLUSIONS In this interim analysis of an ongoing prospective observational study, QOL and symptom measures generally worsened over the first few months for CAR-T patients in the real-world though improved to baseline levels and beyond at later time points. Patients did, however, directly report improvement in their disease state as early as Month 1 based on the PGIC. Non-CART patients generally showed a QOL plateau with some modest improvement in disease symptoms which was also reflected in their self-reported assessment of disease state improvement based on the PGIC.

MO50-4 Efficacy and safety of commercially approved BCMA-targeting CAR-T therapy in triple-class refractory multiple myeloma

MO50-4 Efficacy and safety of commercially approved BCMA-targeting CAR-T therapy in triple-class refractory multiple myeloma

P-304 Triple class refractory multiple myeloma: eficacy of the new immunotherapies and new unmet medical need

P-304 Triple class refractory multiple myeloma: eficacy of the new immunotherapies and new unmet medical need

P-264 A phase 1b study of isatuximab and bendamustine for triple-class refractory multiple myeloma

P-264 A phase 1b study of isatuximab and bendamustine for triple-class refractory multiple myeloma

P-268 An innovative interactive case-based online education tool significantly increases knowledge and competence of clinicians managing triple-class refractory multiple myeloma

P-268 An innovative interactive case-based online education tool significantly increases knowledge and competence of clinicians managing triple-class refractory multiple myeloma

T-cell redirecting bispecific and trispecific antibodies in multiple myeloma beyond BCMA.

B-cell maturation antigen (BCMA)-directed T-cell immunotherapies, such as chimeric antigen receptor T-cells (CAR T-cells) and bispecific antibodies (BsAbs) have markedly improved the survival of triple-class refractory multiple myeloma (MM). However, the majority of patients still develops disease progression, underlining the need for new agents for these patients. Novel T-cell redirecting BsAbs targeting alternative tumor-associated antigens have shown great promise in heavily pretreated MM, including patients previously exposed to BCMA-directed therapies. This includes the G-protein-coupled receptor class 5 member D (GPRC5D)-targeting BsAbs talquetamab and forimtamig, as well as the Fc receptor-homolog 5 (FcRH5)-targeting BsAb cevostamab. Toxicity associated with these BsAbs includes cytokine-release syndrome, cytopenias, and infections. In addition, GPRC5D-targeting BsAbs are associated with specific 'on target/off tumor' toxicities including rash, nail disorders, and dysgeusia. Trispecifc antibodies targeting two different MM-associated antigens to prevent antigen escape are in early clinical development, as well as trispecific antibodies (TsAbs) that provide an additional co-stimulatory signal to T-cells to prevent their exhaustion. Various T-cell redirecting BsAbs are in advanced stages of clinical development with promising activity and a manageable toxicity profile. Ongoing studies are evaluating combination strategies, fixed-duration treatment, and use of BsAbs in earlier lines of therapy. TsAbs hold great promise for the future.

Real-World Effectiveness and Safety of Belantamab Mafodotin Monotherapy in Triple-Class Refractory Multiple Myeloma.

B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM). The aim of this study was to assess the effectiveness and tolerability of monotherapy with the conjugated anti-BCMA monoclonal antibody belantamab mafodotin in triple-class refractory patients with MM in real-world practice. Patients refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 monoclonal antibody received belantamab mafodotin at 2.5 mg/kg intravenously every 3 weeks. Overall, 27 patients with a median age of 65 years (range 41-81) were included. Of these, 52% were male and the median number of prior lines of treatment was 5 (4-10). The overall response rate (partial response or better) was 52%, whereas the disease control rate (stable disease or better) was 70%. The median progression-free survival (PFS) was 2 months (95%CI: 0-7), whereas the median PFS among the responders was 12 months (95%CI: 6-18). Regarding the toxicity profile, the most common toxicity was eye toxicity, in 44% of the patients. Keratopathy grade 2-3 was reported in 33.3% of the patients. In conclusion, belantamab mafodotin showed a safety and efficacy profile consistent with the results of the registrational study. Importantly, heavily pretreated patients who responded to treatment derived a substantial survival benefit.

Real-world treatment patterns of triple-class refractory (TCR) multiple myeloma (MM) across the United States (US), Canada, and western Europe: A retrospective chart study.

e18826 Background: Many patients with MM relapse or become refractory to various therapeutic approaches and typically cycle through many lines of treatment. The present study sought to understand how patients with TCR MM (ie, refractory to ≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 therapy) are managed across various countries. Methods: A non-interventional, retrospective chart review study was conducted across the US, Canada (CA), the UK, France (FR), Germany (DE), Italy (IT), and Spain (ES). Oncologists/hematologists were recruited to abstract medical chart information into an electronic case report form from eligible MM patients (eg, refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody treatment, ECOG≤2, and initiated their first therapy after their TCR status [ie, their index therapy] between 1/1/2018 and 12/31/2020 to ensure at least 1 year of follow-up). Abstractions were performed from January through April 2022. Demographics, clinical characteristics, and treatment patterns were descriptively analyzed and reported here. Results: N = 314 patients with TCR MM were included (56.7% male; median age = 70). Clinical characteristics were similar to other TCR MM studies (eg, 26.1% had an ECOG score of 2, 25.8% had high cytogenetic risk (ie, t(4:14), t(14:16), and/or del(17p), and 10.2% had extramedullary disease). Patients received a median of 3 treatment lines prior to their index therapy, with 70 unique treatment regimens reported as part of their index therapy line (Table 1). The most common regimens (&gt; 10%) were Pd and Kd. Conclusions: This global chart review across the US, Canada, and Western Europe highlights the consistent lack of a standard of care for the management of MM among patients who are refractory to the three main classes of therapies. [Table: see text]