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Purpose The phase III COLUMBA study evaluated daratumumab (DARA) intravenous (IV) and subcutaneous (SC) in patients with relapsed or refractory multiple myeloma. Here, we report patient-reported satisfaction with therapy (SWT) in COLUMBA. Methods DARA IV or DARA SC was administered weekly (cycles 1–2), every 2 weeks (cycles 3–6), and every 4 weeks (cycles 7 +). Patients completed a modified version of the Cancer Therapy Satisfaction Questionnaire (CTSQ) at weekly (cycles 1–2) and monthly (cycles 3 +) intervals and at the end of treatment. Results for each item and the SWT domain score were summarized using descriptive statistics. The distribution of responses for individual items was calculated for each assessment. The proportion of patients for whom SWT domain score change from first assessment met or exceeded the minimally important difference (MID) of 5.9 points was calculated at each assessment time point. Results Two-hundred fifty-nine patients were randomized to DARA IV and 263 to DARA SC. Mean scores for SWT domain questions were high and largely positive during treatment. Responses indicating positive perceptions of therapy were given by a numerically greater proportion of patients in the DARA SC group than the DARA IV group for most questions. Changes from the first assessment in SWT domain scores met or exceeded the MID for an average of ~ 40% of patients. Conclusion In COLUMBA, modified CTSQ results suggest patients in the DARA SC group were more satisfied with their cancer therapy than those in the DARA IV group. Trial registration ClinicalTrials.gov identifier NCT03277105. Registered September 8, 2107.

IntroductionPatients 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/MethodsPatients 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 10 mg/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 125 mg on day 1 and prednisone 60 mg days 2–4. Common definitions were used for DLTs, adverse events (CTCAE v 5.0), and disease response.ResultsFifteen 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).ConclusionWe 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.Clinical trial registrationThis study was registered on clinicaltrials.gov as NCT04083898 on 9/6/2019.

Multiple myeloma (MM) almost invariably progresses through novel therapies. Patients with quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and penta-refractory MM (additional refractoriness to daratumumab) have few treatment options. Two chemotherapy regimens, bendamustine/prednisone (BP) and dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP), are often used in quad- and penta-refractory MM, but there are limited data on outcomes in this heavily pre-treated population. We conducted a single-center retrospective study to identify all patients who received DCEP and/or BP for quad- or penta-refractory MM. Disease response and refractoriness were defined by International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and duration of response (DOR). We identified 27 patients who received BP for quad- or penta-refractory MM. The median number of prior lines of therapy was 6. The ORR for BP was 26%. The median PFS for BP was 1.4 months (95% CI 1.1–1.6) and median OS was 8.7 months (95% CI 2.3–15.0). Patients treated with cyclophosphamide had less response to BP. Thirty-one patients received DCEP for quad-refractory or penta-refractory MM. The median number of prior treatment regimens was 8. The ORR to DCEP was 35%. The median PFS was 2.7 months (95% CI 1.5–3.8) and median OS was 6.2 months (95% CI 4.4–7.8). DCEP and BP retain efficacy in quad- and penta-refractory MM. Our analysis supports prospective study of these regimens, possibly in combination or in comparison with other agents in this area of unmet need.

Relapsed/refractory multiple myeloma (RRMM) and extramedullary multiple myeloma (EMM) present significant challenges for patients with multiple myeloma (MM) after their disease progresses.Despite notable advancements in treatments like autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor (CAR)-T-cell therapy, most patients with RRMM and EMM face a short survival period. Currently, there are no effective treatments available. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the treatment options for MM. Reduced-intensity conditioning (RIC) regimens have largely replaced myeloablative conditioning (MAC) regimens. RIC is now preferred because it significantly lowers transplant-related mortality, which has dropped to 10-20%. However, RIC regimens are linked to higher relapse rates compared to MAC. To enhance the efficacy of allo-HSCT, it is essential to identify a safer and more effective conditioning regimen. We report a case of EMM involving the breast, supraclavicular region, mediastinum, and pleural effusion, among other sites. The patient did not respond to several treatments, including a proteasome inhibitor (PI) like bortezomib, immunomodulatory drugs (IMiDs) such as lenalidomide, and a monoclonal antibody targeting CD38, like daratumumab. Consequently, we recommended haploidentical hematopoietic stem cell transplantation as a salvage treatment. After undergoing allo-HSCT with a conditioning regimen that mainly included selinexor and helical tomotherapy, the patient achieved a complete remission(CR) and enjoyed long-term disease-free survival for 11 months. Along with existing literature, this case provides encouraging insights for future research on RRMM and EMM, and we anticipate more reports on allo-HSCT cases in the future.

Background The autologous anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up. Methods Participants received an average dose of 0.5 × 10 6 cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated. Results Seventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes. Conclusions These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma. Trial registration LEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.

Relapsed/refractory multiple myeloma (RRMM) with extramedullary disease (EMD) represents a challenging condition, with limited treatment options and poor prognosis. We conducted a phase 1 clinical trial to evaluate the safety and effectiveness of a novel bispecific chimeric antigen receptor (CAR) T-cell therapy targeting two antigens, B-cell maturation antigen and G protein-coupled receptor class C group 5 member D (BCMA/GPRC5D), in this high-risk population. A total of 12 patients were enrolled, of whom 3 were excluded due to disease progression or death before CAR T-cell infusion, despite meeting the inclusion criteria, leaving 9 for analysis. The median follow-up was 6.08 months (Interquartile Range [IQR]: 0.9–16.5). All patients received BCMA/GPRC5D bispecific CAR T-cell therapy after bridging therapy with localized radiotherapy or Elranatamab. Efficacy assessments revealed that 100% of patients achieved partial response (PR) or better, with 44.4% achieving complete response (CR). Common adverse events included hematological toxicities such as anemia, leukopenia, and thrombocytopenia. Cytokine release syndrome (CRS) occurred in 66.7% of patients, all of which were grade 1–2, and no neurotoxicity (ICANS) was observed. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 60% and 63%, respectively. Median OS and PFS were not reached. Collectively, these findings highlight a potential therapeutic strategy involving BCMA/GPRC5D dual-targeted CAR T-cell therapy for patients with aggressive forms of multiple myeloma, particularly those with extramedullary disease, and support the need for further exploration and validation in larger, multi-center clinical studies.

Background B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR T-cell) therapy has exhibited remarkable efficacy in refractory or relapsed multiple myeloma (R/R MM), but recurrence and rapid progression of disease are still observed within a short time after treatment. Long-term pomalidomide therapy, which potentiates T-cell functionality, might enhance the efficacy of BCMA CAR T-cell therapy. Methods We performed a single-center retrospective clinical study. Patients with relapsed or refractory multiple myeloma who received BCMA CAR T-cell infusion were enrolled in our study, and were followed by long-term pomalidomide treatment (4 mg/day) or not one month after infusion. The response and adverse events were assessed after infusion. The effect of pomalidomide on BCMA CAR T-cells was assessed in vitro. Results The objective response rate (ORR) of BCMA-CART was 100%. Three months following CAR T-cell infusion, of the 8 patients receiving pomalidomide, except for 2 patients who stopped maintenance therapy and were lost to follow-up, all patients (6/6) achieved VGPR (very good partial response) or CR (complete response), while only 5 patients (5/8) who did not receive pomalidomide treatment achieved VGPR or better. At a median follow-up of 27 months, for the 8 patients who did not receive pomalidomide administration, the median TTP (time to progression) was 5.85 (1–14) months, while the OS (overall survival) was 10.7 (1.2–16) months. Of the 8 patients who received pomalidomide therapy after CAR T-cell infusion, the median TTP was 13 (7–13) months, while the OS was not reached. Moreover, neither long-term hematological toxicity nor drug-induced liver damage was observed during the follow-up period. Mechanistically, pomalidomide promotes antimyeloma efficacy of BCMA CAR T-cells by inhibiting cell apoptosis and enhancing cytoxicity. Conclusions Our results confirmed that BCMA CAR T-cell therapy combined with long-term pomalidomide had a low recurrence rate and manageable therapy-related side effects, providing a promising option for treating R/R MM. Graphical Abstract

Background Patients with triple class exposed (TCE), relapsed and refractory (RR) multiple myeloma (MM) have limited treatment options and poor prognosis. Elranatamab, a bispecific BCMA-targeted antibody, is an investigational treatment for RRMM with demonstrated efficacy and safety in MagnetisMM-3, a single-arm, multi-centre, phase-2 study. This study aimed to characterise outcomes for real world TCE RRMM patients and to estimate the treatment effect of elranatamab compared to treatments available in routine clinical care for TCE RRMM in the NHS. Methods A retrospective, observational, external control arm (ECA) study combining participants from a single arm, multi-centre phase 2 study, MagnetisMM-3, receiving elranatamab to compare patient characteristics and median survival using a comparator cohort of TCE RRMM patients treated with real world regimens in five UK centres between 2015 and 2023. Both naive and adjusted treatment effect estimates for progression free survival (PFS) and overall survival (OS) were obtained using inverse probability of treatment weighted (IPTW) Cox proportional hazards models and differences in restricted mean survival time (dRMST). Quantitative bias analysis was used to assess the robustness of effect estimates to unmeasured confounding. Results From a total of 5,535 patients identified with a diagnosis of MM, 81 were identified as eligible for inclusion in the ECA. A total of 13 different regimens were recorded as being initiated from the real world RRMM at index date, the most common regimen was pomalidomide + dexamethasone (48.15%). Clinical outcomes in the ECA were poor (median PFS 3.71 months [95% confidence interval (CI) 2.73–4.73], median OS 11.00 months [8.02–18.10]). In unadjusted analyses the elranatamab cohort had significant improvements in PFS (dRMST 6.95 months [4.08–9.61]) and OS (Hazard Ratio (HR) 0.66 [0.45–0.96]). Adjusted analyses showed similar effects for PFS (dRMST 6.45 [3.05–9.45]) but were equivocal for OS (HR 0.75 [0.46–1.26]). Conclusion This study provides recent real world evidence of poor outcomes in TCE RRMM in the UK. PFS was longer among patients who received elranatamab compared with treatments for TCE RRMM in routine UK clinical practice.

To synthesize the evidence on the efficacy and safety of teclistamab in treating relapsed/refractory multiple myeloma (RRMM). A systematic search for records published from inception until June 2024 was conducted on PubMed, Web of Science, EMBASE, and Google Scholar databases. Five studies with 661 RRMM patients were included in the analysis. The pooled results showed that teclistamab led to an overall response rate (ORR) of 62.8% (95% Confidence Interval (CI): 58.6–66.8), a ≥ very good partial response or better (VGPR) of 52.1% (95% CI: 46.8–57.3), and a ≥ complete response or better (CR) of 29.5% (95% CI: 21.9–38.4). When the ORR was assessed in different subgroups, we found that patients with extramedullary disease (EMD) had considerably lower ORR than those without EMD (45% vs. 71%, p < 0.0001). The ORR was significantly lower in patients with prior (B-cell maturation antigen) BCMA-directed therapy (OR: 2.24, p = 0.002) and those with stage III disease (OR: 3.69, p = 0.0001). However, the subgroup analyses showed no considerable difference in the ORR between patients with high or standard-risk cytogenetics (OR: 1.05 p = 0.82) and those with penta-drug or triple-class-refractory disease (OR: 0.97 p = 0.89). Regarding the safety of teclistamab, the pooled results showed that the incidence of grade ≥ 3 adverse events was high (90.7%). However, grade ≥ 3 cytokine release syndrome (CRS) and neurotoxic events were low (1.5% and 2.2%, respectively). RRMM patients treated with teclistamab display good response rates.

Although the treatment of relapsed/refractory multiple myeloma has improved dramatically over the past decade, the disease remains incurable; therefore, additional therapies are needed. Novel combination therapies incorporating monoclonal antibodies have shown significant promise. Here we describe the design of a Phase III study (NCT03275285, IKEMA), which is evaluating isatuximab plus carfilzomib and low-dose dexamethasone, versus carfilzomib/dexamethasone in relapsed/refractory multiple myeloma. The primary end point is progression-free survival. Responses are being determined by an independent review committee using 2016 International Myeloma Working Group criteria, and safety will be assessed throughout. The first patient was recruited in November 2017, and the last patient was recruited in March 2019; 302 patients have been randomized, and the study is ongoing. Clinical trial registration: NCT03275285