Multiples Myelom Iples Myelom III
Charlotte Sophie Uhlenbrock, Heidelberg, D
Introduction: Plasma cell infiltration (PCI) is an important factor for staging and risk stratification in patients with monoclonal plasma cell disorders but can only be obtained by invasive biopsy. Radiomics is a new method that allows for objective, in-depth tissue characterization by non-invasive imaging by calculating a large number of histogram, shape and textural features from medical images. The purpose of this work was to investigate with which accuracy radiomics models can predict PCI results from unguided biopsy at the iliac crest.
Methods: One hundred fifty-eight patients with smoldering or multiple myeloma who had undergone whole body-MRI at 1.5 Tesla as well as bone marrow (BM) biopsy were included. Data was split by date of the MRI in training set (n=116) and independent test set (n=42). BM of the right and left hip bone was segmented in coronal T1 turbo-spin-echo images. Two hundred thirty-three radiomics features were calculated for each hipbone. A random forest classifier was trained to predict PCI from radiomics features on the training set and the model was evaluated in the independent test set. Mean absolute error (MAE) in [%PCI] reports the accuracy of the PCI prediction. For comparison, a linear model correlating the mean T1-BM-signal intensity of the pelvis (normalized to muscle) to the PCI was established on the training set and applied to the test set (mean intensity model). Additionally, two radiologists rated the diffuse infiltration (DI) according to 3 levels of severity (none-to-mild vs. moderate vs. severe). The mean PCI within each severity level from the training set was determined and assigned as a prediction to patients with the same level diffuse infiltration in the test set (the radiologists' prediction).
Results: The MAE of the mean intensity model was 23.4 [%PCI]. The MAE of the radiomics model was 14.3 [%PCI]. The MAE of the radiologists' prediction of raters 1 and 2 were 16.1 [%PCI] and 16.7 [%PCI], respectively.
Conclusions: We established a radiomics model to predict PCI from T1 MR images of the pelvic BM. The radiomics model, which also analyses textural features of the BM, performs markedly better than a model based on mean T1-BM signal intensity only and similar to the prediction by two radiologists based on DI severity. Further improvement of the model is necessary, which might be obtained by enlarging the amount of training data and adding T2 and diffusion-weighted imaging based radiomics features in the model.
V251 Im Gegensatz zur Behandlung mit Checkpoint-Inhibitoren verlängert der genetische KO von PD-L1 auf Myelomzellen das Überleben in einem murinen Myelommodell
Nathalie Heider-Hönatsch, Bonn, D
Check point inhibition (CPI) has shown dramatic improvements in overall survival in many malignant diseases. However, in multiple myeloma (MM) the results were disappointing resulting in an early termination of clinical trials.
Methods: We analyzed the efficiency and immunological mechanisms of antibodies targeting PD-1/PD- L1, CD47 or TIGIT using KaLwRij mice that develop MM upon injection of 5T33 myeloma cells. Treatment of mice started d19 post inoculation. Bone marrow and spleen cells were analyzed by flow cytometry for the phenotype of immune cells.
Results: Treatment with mAbs blocking PD-1 or PD-L1 had no effect on survival. Analyses of immune cell subpopulations revealed no differences between the groups. The pan-HDAC inhibitor panobinostat inhibited the development of MM in treated mice. Surprisingly, the combined application of anti-PD-1 with panobinostat reduced the anti-myeloma effect of the compound. By analyzing the phenotype of immune cells, we found in the panobinostat treated group a significant decrease of CD8+ T cells expressing CD1d and CXCR4 in the spleen. Similarly, CD4+ T cells showed a decrease of CD1d expression in this group. The combination of PD-1 blocking antibodies with anti-CD47 or anti- TIGIT could not improve the efficiency of CPI. We next generated a PD-L1 KO of 5T33 cell line using the CRISPR Cas9 technology. We found no differences in the expression of MHC class I and II, co-stimulatory or adhesion molecules, proliferation and migration between the knock out and mock cells. Interestingly, mice inoculated with the 5T33 PD-L1 KO cells showed a significant longer survival compared with the 5T33 mock, indicating that direct blocking of PD-L1 on malignant cells rather than in the tumor microenvironment might have an impact on the clinical efficiency. In the bone marrow of the 5T33 PD-L1 KO treated mice, both CD4+ and CD8+ T cells showed an increase in PD-1 and PD-L1 expression. Additionally, analyses of the spleen cells demonstrated a significant increase of TIGIT on CD4+ and CD8+ T cells and of CD40L expression on CD4+ T cells.
Conclusion: We found that PD-1 blockade might negatively affect the therapeutic efficacy of HDAC inhibitors. Genetic down regulation of PD-L1 on myeloma cells enables a significant improvement of the survival.
V278 Immunkontrolle und Regression des Multiplen Myeloms durch kurzzeitige Depletion von regulatorischen T Zellen
Julia Hartweg, Würzburg, D
Multiple myeloma (MM) remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow (BM) microenvironment harbors treatment-resistant MM cells, which eventually lead to disease relapse in patients. In the BM, CD4+FoxP3+ regulatory T cells (Tregs) are highly abundant amongst CD4+ T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in MM dissemination to BM compartments and disease progression.
First, we analyzed BM aspirates of 55 MM patients. Treg frequencies in MRD positive patients significantly exceeded those of MRD negative patients (12.6% vs. 9.9%, respectively, P=0.038) while the ratio of conventional T cells to Tregs was reduced (34.2 vs. 26.5, respectively, P=0.061).
Next, we employed two genetically independent immunocompetent murine MM models (MOPC‐315 and Vk*Myc). Analyzing the spatial immune architecture of MM with microscopy uncovered increased BM Tregs in vicinity to malignant MM cells. Multiparameter flow cytometry revealed an activated ICAM‐1+ICOS+CD69+ Treg phenotype. To selectively deplete Tregs in vivo we used mice expressing the diphtheria toxin (DT) receptor under the FoxP3 promoter (BALB/c.DEREG or B6a.FoxP3.Luci.DTR mice). In vivo Treg depletion before tumor cell injection completely prevented MM engraftment in both tumor models. Importantly, short‐term in vivo depletion of Tregs in mice with established MM evoked a potent, complete and long-lasting remission of MM (P=0.0001). Notably, remissions occurred independently from the quick recurrence of Treg-number avoiding undesired autoimmunity. Treg depletion evoked a direct activation of effector T cells and in vivo depletion experiments identified CD8 T cells and NK cells as mediators of the anti-tumor response. Moreover, MM re‐challenge of mice in remission with the initial tumor load revealed a sustained immune protection indicating an effective anti-MM memory formation. Conclusively, this preclinical in vivo study suggest Tregs as an attractive target for the treatment of MM.
V324 Einfluß verrschiedener Induktionstherapien vor autologer Stammzelltransplantation bei 540 Myelompatienten: eine retrospektive real-world Studie
Song-Yau Wang, Leipzig, D
Introduction: High-dose therapy followed by autologous stem cell transplantation (ASCT) is the standard first line treatment for younger patients (pts) (< 70 years) with multiple myeloma (MM). However, due to restrictive inclusion and exclusion criteria, more than half of MM pts were excluded from randomized phase 2/3 studies with ASCT. To overcome this and to better reflect clinical practice, we conducted a retrospective study to determine the efficacy and tolerability for all myeloma pts transplanted at the university hospital of Leipzig without trial-specific selection criteria.
Methods: This analysis included all consecutive pts with newly diagnosed MM who received first line induction therapy followed by high-dose therapy and ASCT between 1996 and 2019.
Results: 540 pts were enrolled in the study. The median age at diagnosis was 59 (range 29-75) years. In the first period up to 2005, induction therapy consisted mainly of conventional chemotherapies, e.g. vincristine/adriamycin/dexamethasone (VAD) (n=95). In the following years, the triple-combinations based on bortezomib coupled with anthracycline/dexamethasone (n=29), cyclophposphamide/dexamethasone (n=70) or bendamustine/prednisolone (n=169) became the most popular treatment options. After completion of induction therapy, the ORR in pts treated with VAD was only 66% with a ≥VGPR rate of 14% and ≥CR rate of 2%. The implementation of various bortezomib- containing therapy regimens significantly improved the ORR to 77-86% (p< 0.005), with a ≥VGPR rate between 29-41% (p< 0.001) and a ≥CR rate between 3-11% (p=0.07). 522 pts (96.7%) responded after the first ASCT with 75 sCR (13.8%), 40 CR (7.4%), 87 nCR (16.1%), 169 VGPR (31.3%) and 151 PR (28.0%). The ORR was no different following initial treatment with VAD (96%) or with bortezomib- containing therapies (97%). TRM was 0.6% (n=3). With the median follow-up of 45 months of the surviving pts, median PFS was 39 and median OS 79 months. Comparing the group of pts treated before 2006 with those treated after 2015, the use of the novel drugs improved the 48-months PFS from 33 to 47% and the 48-months OS from 61 to 85%.
Conclusions: The introduction post 2005 of modern three-drug induction regimens including bortezomib has improved the prognosis in younger MM pts undergoing first line ASCT. Our real world data in unselected pts also stress the substantial value of ASCT during the first line treatment of younger MM pts.
V203 Iberdomid (IBER) in Kombination mit Dexamethason (DEX) und Daratumumab (DARA), Bortezomib (BORT) oder Carfilzomib (CFZ) bei Patienten mit rezidiviertem/refraktärem multiplen Myelom (RRMM)
Katja Weisel, Hamburg, D
Introduction: Here we report results from CC-220-MM-001 (NCT02773030), an ongoing phase 1/2 study evaluating maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and efficacy of IBER+DARA+DEX (IberDd), IBER+BORT+DEX (IberVd), and IBER+CFZ+DEX (IberKd) in patients with RRMM.
Methods: Eligible patients received ≥2 prior regimens in the IberDd and IberKd cohorts, and ≥1 prior regimen in the IberVd cohort, containing lenalidomide or pomalidomide, and a proteasome inhibitor. All patients had progressed ≤60 days of last therapy. Escalating oral doses of IBER were given on Day (D)1‒21 of each 28-D cycle in the IberDd cohort and in the IberKd cohort with weekly CFZ, and on D1‒14 of each 21-D cycle in the IberVd cohort.
Results: As of Dec/14/2020, 34 patients had received IberDd, 24 IberVd, and 7 IberKd. Exposure to prior regimens was heterogeneous (Table); all patients were refractory to their last prior regimen. IBER doses ranged from 1.0 to 1.6mg. Median follow-up was 3.9 (0.1‒20.7), 5.5 (1.2‒18.0), and 5.1 (3.5‒15.7) months, 15 (44%), 9 (38%), and 3 (43%) patients continue on treatment, and median cycles received were 4 (1‒21), 7.5 (1‒24), and 5 (3‒16) with IberDd, IberVd, and IberKd, respectively.
Hematologic grade 3‒4 treatment-emergent adverse events of interest included neutropenia (63%), anemia (28%), and leukopenia (28%) with IberDd; neutropenia (29%) and thrombocytopenia (25%) with IberVd; and lymphopenia (57%) and neutropenia (43%) with IberKd. Neutropenia was managed with G- CSF.
The overall response rate was 41% with IberDd, 58% with IberVd, and 57% with IberKd. Median time to response was 4.1 (4.0‒12.0), 3.6 (3.0‒13.1), and 4.1 (4.1‒8.1) weeks, in the IberDd, IberVd, and IberKd cohorts, respectively. Median duration of response is 63.3 weeks in the IberVd cohort (not reached in the other cohorts). RP2D was determined at 1.6mg in the IberDd cohort; dose evaluation continues in the other cohorts.
Conclusions: In heavily pretreated patients with RRMM, IberDd, IberVd, and IberKd showed a manageable safety profile and promising efficacy, even among DARA- and BORT-refractory patients. This abstract was previously submitted to EHA 2021.