ASH 2019 – Multiple Myeloma congress summary

Haematology experts from around the globe gathered to share the latest clinical research advances at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition, which took place in Orlando, Florida. Spanning five days, the conference featured scientific abstract presentations on malignant and non-malignant blood diseases, from revolutionary advances in gene therapy to practice changing discoveries in immunotherapy. See below for our top picks from the multiple myeloma (MM) research presented at ASH this year.

ASH 2019 summary

Abstracts summary*

EARLY-PHASE STUDY SHOWS THAT CC-93269, A B-CELL MATURATION ANTIGEN (BCMA) T-CELL ENGAGER, HAS PROMISING EFFICACY IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM)1
CC-93269 is a bispecific antibody that binds to BCMA-expressing myeloma cells and to CD3-expressing T cells, thereby activating T cells and initiating release of pro-inflammatory cytokines and cytolytic enzymes, resulting in myeloma cell death. This ongoing Phase I study in patients with RRMM (≥3 prior regimens; N=19), aimed to assess the tolerability and optimal dose of CC-93269. Grade 3–4 treatment-related adverse events (AEs) were reported in 15/19 patients (79%). In patients receiving the ≥6 mg dose of CC-93269, 10/12 (83%) obtained a partial response (PR) or better. Although lacking a control arm, these exciting preliminary tolerability and efficacy results support further investigation of this agent in patients with heavily pre-treated MM.

CARTITUDE-1 SHOWS EARLY, DEEP RESPONSES IN THE TREATMENT OF RRMM2
CARTITUDE-1 is Phase Ib/II study evaluating the efficacy and safety of JNJ-4528, an investigational BCMA-directed chimeric antigen receptor T-cell (CAR-T) therapy in patients with RRMM (≥3 prior regimens; N=25). At data cut-off, reduction in tumour burden was observed in all patients and the overall response rate (ORR) was 91%. The most frequently reported AEs were cytokine release syndrome (CRS; 88% [22/25 patients]), neutropenia (80% [20/25 patients]), anaemia (76% [19/25 patients]) and thrombocytopenia (72% [18/25 patients]). These results suggest high anti-myeloma activity of JNJ-4528 in this setting.

THE ALCYONE TRIAL SHOWS AN OVERALL SURVIVAL (OS) BENEFIT OF DARATUMUMAB IN TRANSPLANT-INELIGIBLE NEWLY DIAGNOSED MM (NDMM)3
This long-term follow-up (>36 months) from the ALCYONE Phase III trial (N=706) examined OS in patients treated with daratumumab, bortezomib, melphalan and prednisone (DVMP) vs. bortezomib, melphalan and prednisone (VMP) in patients with NDMM ineligible for transplant. The estimated 36-month OS rate was 78% with DVMP vs. 68% with VMP, with a significant benefit for OS observed for DVMP vs. VMP alone (hazard ratio [HR]=0.60, 95% confidence interval [CI]: 0.46–0.80; p=0.0003). With a median follow-up of 40 months, median progression-free survival (PFS) was 36.4 months with DVMP vs. 19.3 months with VMP (HR=0.42, 95% CI: 0.34–0.51; p<0.0001).

GEM-CESAR SHOWS ENCOURAGING RESULTS IN PATIENTS WITH HIGH-RISK SMOULDERING MM4
Previous reports have shown that patients with high-risk smouldering MM benefit from early treatment with lenalidomide-based regimens. This Phase II, single-arm trial (N=90) had the goal of a cure, which was defined as sustained minimal residual disease (MRD) negativity at 5 years after high-dose autologous stem cell transplant (ASCT). Patients were treated with carfilzomib, lenalidomide and dexamethasone (KRd) as induction therapy prior to ASCT and, after a median follow-up of 32 months, 56% of those who completed induction achieved MRD negativity and an impressive 93% of patients were alive and progression-free at 30 months.

EARLY RESULTS FROM A FIRST-IN-HUMAN STUDY USING CRISPR/CAS9 IN PATIENTS WITH ADVANCED MM SHOW THAT THE PROCEDURE IS WELL TOLERATED5
In this Phase I trial, researchers edited the genes of T cells in three patients (two patients with MM and one with sarcoma) using the CRISPR/Cas9 technology, removing immune receptors and programmed cell death protein 1 (PD-1; a molecule involved in immune suppression). Analysis of blood samples demonstrated that the CRISPR/Cas9-edited T cells expanded, survived and targeted tumour cells in all three patients. The treatment was well tolerated with no signs of neurotoxicity or CRS.

THE PHASE III CANDOR TRIAL HIGHLIGHTS THE SURVIVAL BENEFITS OF ADDING DARATUMUMAB TO CARFILZOMIB AND DEXAMETHASONE IN THE TREATMENT OF RRMM6
This late-breaking abstract showcased the results of CANDOR, a Phase III trial comparing carfilzomib, dexamethasone and daratumumab (KdD) vs. carfilzomib and dexamethasone (Kd) in patients with RRMM (1–3 lines of therapy; N=466). The authors reported a 37% reduction in the risk of progression or death with KdD vs. Kd (HR=0.63, 95% CI: 0.46–0.85; p=0.0014). This PFS benefit was maintained across subgroups, including lenalidomide-exposed and lenalidomide-refractory patients. Additionally, patients treated with KdD vs. Kd achieved deeper responses; MRD-negative complete response (CR) rate at 12 months was 13% for KdD vs. 1% for Kd (p<0.0001). Grade ≥3 AEs occurred in 82% (KdD) and 74% (Kd) of patients. KdD could represent an efficacious novel regimen for the treatment of patients with RRMM.

GRIFFIN STUDY UPDATE: DEPTH OF RESPONSE TO DARATUMUMAB, LENALIDOMIDE, BORTEZOMIB AND DEXAMETHASONE IMPROVES OVER TIME IN PATIENTS WITH NDMM7
The Phase II GRIFFIN trial examined daratumumab, lenalidomide, bortezomib and dexamethasone (DRVd) vs. lenalidomide, bortezomib and dexamethasone (RVd) in transplant-eligible patients with NDMM (N=207). The study met its primary endpoint: stringent CR rate by the end of consolidation in the DRVd arm was 42.4% vs. 32.0% in the RVd arm (odds ratio=1.57, 95% CI: 0.87–2.82; two-sided p=0.1359). Furthermore, responses deepened over time: the stringent CR rate in the DRVd vs. RVd arm was 12% and 7%, respectively, by the end of induction and increased to 21% vs. 14% after ASCT. With a median follow-up of 13.5 months, these rates had reached 50% and 37%. The trial is ongoing with patients continuing maintenance therapy.

DREAMM-3: ONGOING PHASE III TRIAL EXAMINING FIRST-IN-CLASS AGENT BELANTAMAB MAFODOTIN IN PATIENTS WITH RRMM8
Belantamab mafodotin is a novel BCMA monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Once bound to BCMA on the surface of myeloma cells, it is rapidly internalised and the cytotoxic moiety (cys-mcMMAF) is released, enhancing cellular cytotoxicity and initiating immunogenic cell death. The ongoing Phase III DREAMM-3 study is evaluating the efficacy and safety of belantamab mafodotin compared with a standard of care regimen (pomalidomide and dexamethasone) in patients with RRMM (≥2 lines of therapy). The primary endpoint is PFS, with OS as a key secondary endpoint.

PHASE III TRIAL WITH VENETOCLAX, BORTEZOMIB AND DEXAMETHASONE IDENTIFIES A NEW BIOMARKER FOR RRMM9
Venetoclax, a highly selective B-cell lymphoma 2 protein (BCL-2) inhibitor, was examined in combination with bortezomib and dexamethasone (VenVd) vs. bortezomib and dexamethasone (Vd) in patients with RRMM (1–3 prior therapies [N=291]) in the Phase III BELLINI trial. Results showed an improvement of PFS with VenVd vs. Vd, particularly in patients harbouring a t(11;14) translocation (HR=0.10, 95% CI: 0.02–0.46; p=0.003) and with high levels of BCL-2 (HR=0.26, 95% CI: 0.13–0.51; p<0.001). In the t(11;14) subgroup, VenVd induced a 95% ORR (vs. 47% with Vd), including a very good PR (VGPR) in 75% of patients (vs. 27% with Vd), a CR of 55% (vs. 7% with Vd) and MRD negativity in 25% (vs. 0% with Vd). The ORR in patients with high BCL-2 was 88% with VenVd (vs. 75% with Vd), including a VGPR of 76% (vs. 31% with Vd), a CR of 41% (vs. 0% with Vd) and MRD negativity in 18% (vs. 0% with Vd).

MM-REACTIVE T CELLS ARE CD27-NEGATIVE AND COULD BE A PROGNOSTIC MARKER IN NDMM10
Given the rapidly evolving landscape of immune-based therapies, examination of the T-cell microenvironment found in MM patients could help to develop more tailored treatments. This study aimed to characterise the MM immune microenvironment at the single-cell level in order to identify clinically relevant subsets for effective immune monitoring. The researchers found, for the first time, that potential MM-reactive T-cells are CD27-negative and that their abundance in the immune microenvironment of NDMM patients is prognostic and may be related to prior treatment (e.g. immunomodulatory drugs and stem cell transplant).

 

* This selection of abstracts is intended to be representative of MM abstracts presented at ASH 2019. For a full list of ASH 2019 abstracts, please consult https://ash.confex.com/ash/2019/webprogram/start.html

References

1. Costa LJ et al. Abstract 143. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper122895.html (accessed December 2019).
2. Madduri D et al. Abstract 577. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper121731.html (accessed December 2019).
3. Mateos M-V et al. Abstract 859. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper123401.html (accessed December 2019).
4. Mateos M-V et al. Abstract 781. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper125204.html (accessed December 2019).
5. Stadtmauer EA et al. Abstract 49. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper122374.html (accessed December 2019).
6. Usmani SZ et al. Abstract LBA-6. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper132629.html (accessed December 2019).
7. Voorhees PM et al. Abstract 691. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper123465.html (accessed December 2019).
8. Weisel K et al. Abstract 1900. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper129893.html (accessed December 2019).
9. Harrison S et al. Abstract 142. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper126094.html (accessed December 2019).
10. Botta C et al. Abstract 506. Presented at the 61st American Society of Hematology (ASH) 2019 Annual Meeting & Exposition. Available at: https://ash.confex.com/ash/2019/webprogram/Paper123974.html (accessed December 2019).

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