Multiples Myelom I
V320 KarMMa Studie: Analyse der Hochrisikopatienten mit rezidiviertem und refraktärem Multiplen Myelom behandelt mit der CAR-T-Zelltherapie Idecabtagen Vicleucel (Ide-Cel, bb2121)
Hartmut Goldschmidt, Heidelberg, D
Introduction: Outcomes remain poor in pts with high-risk RRMM receiving conventional care, including immunomodulatory agents, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs). In the pivotal phase 2 KarMMa study (NCT03361748), deep and durable responses were observed with idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in pts with triple-class exposed RRMM (Munshi NC, et al. N Engl J Med 2021;384:705-716). We examined safety and efficacy in high-risk pt subgroups from the KarMMa study (Raje NS, et al. Blood 2020;136[suppl 1]:37-38). Methods: Pts had ≥3 prior regimens (including an immunomodulatory agent, a PI, and an anti-CD38 mAb) and were refractory to their last regimen. After lymphodepletion for 3 d and then 2 d of rest, pts received target doses of 150, 300, or 450 × 106 CAR+ T cells. Subgroup analyses were performed in pts stratified by high-risk characteristics (extramedullary disease [EMD], high-risk cytogenetics [del(17p), t(4;14), t(14;16)], high tumor burden [≥50% bone marrow plasma cells], receipt of bridging therapy, disease stage III at baseline [revised International Staging System], and >1 prior regimen per year). Primary endpoint was overall response rate (ORR). ORR and complete response (CR) were assessed per International Myeloma Working Group criteria; duration of response and progression-free survival were analyzed by Kaplan-Meier methods.
Results: Among 128 ide-cel-treated pts, 39% had EMD, 35% had high-risk cytogenetics, 51% had high tumor burden, 88% received bridging therapy, 16% had stage III disease, and 47% received >1 prior regimen per year. ORR and CR rates were ≥65% and ≥20% across all subgroups examined except disease stage III (Table). Presence of EMD did not substantially affect ORR (70% with and 76% without EMD) nor did baseline tumor burden (71% with and 77% without high tumor burden).
Conclusions: Deep and durable responses were observed in most subgroups, even in those with the highest risk, including pts with more aggressive disease features (EMD, high-risk cytogenetics, high tumor burden), and those who received bridging therapy or >1 prior regimen per year.
V624 MCT1 ist ein prädiktiver Marker für Lenalidomid-Erhaltungstherapie im Multiplen Myelom
Jacob Stroh, München, D
Introduction: Lenalidomide-based maintenance therapy is the currently approved standard of care for multiple myeloma (MM) patients after high-dose melphalan and autologous stem cell transplantation (HD- Mel), which significantly prolongs progression-free (PFS) and overall survival (OS). Predictive markers of response to lenalidomide maintenance have remained elusive. We have previously shown that IMiDs exert their anti-MM activity via destabilization of MCT1 and CD147 (Eichner et al. Nature Medicine 2016).
Methods: CD138-purified myeloma cell samples of 654 patients receiving high-dose melphalan therapy and autologous stem cell transplantation and either bortezomib (n=101), thalidomide (n=98) or lenalidomide (n=455) maintenance treatment were assessed by gene expression profiling (GEP) using U133 2.0 plus DNA microarrays, 316 by RNA-sequencing (RNA-seq). Expression of CD147 and MCT1 were assessed and correlated with PFS and OS data.
In vitro, CD147 and MCT1 were lentivirally overexpressed in MM1S and U266 cells, which were subjected to lenalidomide or bortezomib treatment and proliferation analysis. Xenografted MM-tumors were followed by 18FDG-PET/MRI and analyzed by immunohistochemistry.
Results: Patients with high gene expression levels of MCT1 showed significantly reduced PFS (31.9 vs. 48.2 months in MCT1high vs. MCT1low,P=.03) and OS (75.9 months vs. not reached (NR) months in MCT1high vs. MCT1low; P=.001) in case of lenalidomide maintenance. For bortezomib-based maintenance, MCT1 expression had no significant impact on PFS (39.8 months vs. 32.6 months in MCT1high vs. MCT1low) and OS (125.8 months vs. 129.8 months in MCT1high vs. MCT1low).
Functional validation experiments showed that MCT1 overexpression in human MM cell lines significantly reduced efficacy of lenalidomide, while no change was observed upon bortezomib treatment, both in vitro and in an in vivo MM xenograft model.
Conclusion: Taken together, we establish MCT1-expression as a predictive marker for response to Ienalidomide-based maintenance treatment. Both PFS and OS were significantly reduced in patients with high gene expression levels of MCT1. In vitro and in vivo, MCT1 overexpression reduced sensitivity to lenalidomide unlike bortezomib treatment.
V411 Update der Interimanalyse der GMMG-CONCEPT Studie: Isatuximab, Carfilzomib, Lenalidomid und Dexamethason (Isa-KRd) in der Erstlinientherapie des Hochrisiko Multiplen Myeloms
Lisa Leypoldt, Hamburg, D
Background: While treatment and survival outcomes have significantly improved in Multiple Myeloma (MM), this does not equally translate into high risk (HR) MM patients (pts). With a median overall survival (OS) of < 2 years for ultra-high-risk pts, an unmet need for new therapeutic strategies remains. Recent data indicate that deep remissions, including minimal residual disease (MRD) negativity may translate into prolonged survival. The GMMG-CONCEPT trial (NCT03104842) investigates the quadruplet regimen of isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in HR newly diagnosed (ND) MM pts. First results of the interim analysis (IA) showed an overall response rate (ORR) of 100% during induction. Here, we report an update for progression-free survival (PFS) of the IA population. Methods: 153 pts with HR NDMM were included into the trial, an extension cohort is planned in 2021. HR MM was defined by ISS II/III stage disease in combination with del17p or t(4;14) or t(14;16) or > 3 copies of 1q21. Transplant-eligible pts undergo high-dose therapy after induction (Arm A) while transplant-ineligible (TI) pts receive 2 additional Isa-KRd cycles (Arm B). All pts receive consolidation and Isa-KR maintenance. MRD negativity after consolidation is the primary endpoint. Here, we report PFS data of the IA population.
Results: The IA population consisted of 50 pts (46 Arm A, 4 Arm B). Del17p was the most common HR CA in 52%, followed by t(4;14) in 38%, t(14;16) in 12% and > 3 copies 1q21 in 42%. 26% of pts showed 2 HR CA and 4% 3 HR CA, 20% of pts increased LDH. Overall response rate (ORR) defined as best response achieved during induction was 100% with 90% of pts achieving a very good partial response or better. MRD negative remissions were seen in 20/33 evaluated pts during induction. Median follow-up of this updated IA was 24.9 months. For the overall population analysed, 12- and 24-month PFS (95%-confidence level) was 79.6% (68.3%; 90.9%) and 75.5% (63.5%; 87.6%). PFS-rates at 12 and 24 months were 80.0% (68.3%; 91.7%) and 75.6% (63.0%; 88.1%) for Arm A. For the 4 TI pts in Arm B, a 12-month-PFS of 75.0% (32.6%; 100%) was seen. No new safety signals occurred.
Conclusions: This updated IA of the first 50 pts in the CONCEPT trial reports an encouraging PFS rate of 79.6% and 75.5% after 12 and 24 months in solely HR NDMM pts. The data underline the high potency of Isa-KRd quadruplet treatment especially in HR disease. Further results will be reported.
V179 Schwere Infektionen und frühe Todesfälle während der Induktionstherapie mit neuen Substanzen beim neudiagnostizierten, transplantationsfähigen Multiplen Myelom
Elias K. Mai, Heidelberg, D
Introduction: At initial diagnosis of multiple myeloma (MM), about 25% of patients develop severe infections and up to 10% decease during induction therapy (IT) due to immunosuppression from MM and effects of antineoplastic therapy. The present analysis aims at characterization and identification of predictive factors for severe infections (SI) and deaths during IT.
Methods: Between 07/2005 and 01/2018, 1333 patients from three subsequent multicenter phase III trials, HD4, MM5 and HD6 from the German-speaking Myeloma Multicenter Group (GMMG), received a novel agent-based IT with either bortezomib (BTZ) / doxorubicine / dexamethasone (DEX; PAD: n=192, HD4; PAd: n=296, MM5), BTZ / cyclophosphamide / DEX (VCD: n=300, MM5), BTZ / lenalidomide / DEX (VRD: n=272, HD6) or elotuzumab / VRD (ELO-VRD: n=273, HD6). SI were defined as any infection ≥ grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE). Uni- and multivariate logistic regression models were used to assess predictive factors accounting for trial effects.
Results: SI occurred in HD4-PAD: 27.1%, MM5-PAd: 10.8%, MM5-VCD: 9.3%, HD6-VRD: 7.3% and HD6-ELO-VRD: 9.9% of patients (overall rate of severe infections of 11.9%). Death from any cause occurred overall in 1.8% (n=24) of patients during IT with 62.5% (n=15) of deaths being infection- related. Multivariate analyses identified three major factors, besides trial effects, to predict an increasing risk for SI during IT: age >60 years (odds ratio, OR=1.81,p< 0.001), International Staging System (ISS) stage III (OR=1.79,p< 0.016) and low platelets (< 150/nl; OR=2.07,p< 0.001) at initial diagnosis. An additive score based on these three factors (one risk factor=one point) was built and included n=559, n=559 and n=203 patients with a score of 0, 1 and ≥2 points, respectively. A higher score gradually predicted an increasing risk for both, SI and early death during IT: 0 points: 7.9% / 0.9%, 1 point: 11.8% / 1.8% and ≥2 points: 22.2% / 4.4%.
Conclusions: Our present analysis highlights the persisting association between SI and early death in newly diagnosed MM. Our proposed easy-to-use scoring system allows identification of a subgroup of patients at high risk for SI and early death during IT in clinical routine. This enables close monitoring of patients at risk and might guide preventive anti-infective strategies in clinical routine and future prospective trials. Validation of the score is being planned.
V364 Immunprofil und MRD Level nach Induktionstherapie bei Patienten mit Multiplem Myelom, die eine Hochdosistherapie erhalten können
Anke Schilhabel, Kiel, D
Introduction: The phase 3 DSMM XIV trial tested the efficiency of Lenalidomid, Bortezomib and Dexamethasone (VRD) vs. Lenalidomid, Adriamycin and Dexamethasone (RAD) as induction therapy in newly-diagnosed, transplant-eligible multiple myeloma (NDMM). The impact of immune cells on the response in this group of patients is understudied. We analyzed the immune data of patients within the DSMM XIV trial.
Methods: Flowcytometric data of 253 patients treated in the DSMM XIV trial measuring MRD with a second-generation flow approach have been reanalyzed to identify immune cell subsets: NK cells were defined as CD45++/CD138-/CD19-/CD56+, T-cells as CD45++/CD138-/CD19-/CD56- and mature B-cells as CD45++/CD138-/CD19+/CD27+. Immune cell counts were correlated to MM MRD status and clinical response according to IMGW criteria. Unsupervised clustering was based on age, MRD, and ratios of various additional immune cell populations determined by flow cytometry.
Results: Three principal components, cellularity, plasma cell infiltration, and age were identified post induction treatment. Using the principal components of the post induction analysis, clusters were generated using the data of the screening time point, and included 26/247 (10.5%), 98/247 (39.7%), and 123/247 (49.8%) patients, respectively. Patients in cluster 1 had a median age of 55.3 years, cluster 2 had a median age of 48.4 years and cluster 3 a median age of 59.5 years. 225 patients remained in the data set to evaluate the clinical response in the clusters. Cluster 2 showed the highest rate of MRD positive samples (79.5%; 70/88), whereas MRD negativity was achieved in 26.1% (6/23) and 30.9% (34/110) of patients in cluster 1 and 3, respectively. Intriguingly, cluster 3 patients showed the best clinical response with 61.8% patients reaching a clinical response of VGPR or better, compared to 56.2% and 46.6% in cluster 1 and 2. When reanalyzing the immune profile for those clusters, we found that patients in cluster 3 had significantly more T-cells and a trend towards more NK-cells at screening compared to cluster 1. However, there was no significant difference in the distribution between treatment with RAD or VRD.
Conclusions: Cluster analysis revealed that patients with higher T- and NK-cell count are more likely to show a better response to induction treatment. Analyzing side populations during standard MRD assessment by flow cytometry offers additional parameters that help to predict therapy response.