ASCO and EHA 2019 – Multiple Myeloma congress summary

The American Society of Clinical Oncology (ASCO) and the European Hematology Association (EHA) 2019 congresses, which took place this year in Chicago and Amsterdam, respectively, offered exciting educational and scientific programmes. Both congresses are renowned for facilitating interaction between healthcare professionals and academics in Europe and worldwide. They are innovative platforms for scientific exchange and sharing information on novel clinical research and, this year, there was a breadth of posters and oral presentations on multiple myeloma (MM). In this joint congress summary, we have selected some key abstracts to offer a glimpse into MM clinical trials and results presented at both ASCO and EHA this year.

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Abstract summary

Key:     █ ASCO and EHA       █ ASCO only       █ EHA only

ISATUXIMAB SHOWS POSITIVE RESULTS IN PHASE III TRIAL IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM) PATIENTS1
Isatuximab is a monoclonal anti-CD38 antibody capable of triggering programmed tumour cell death and provoking immunomodulatory effects. This Phase III, randomised, open-label, multicentre study comparing isatuximab, pomalidomide, and low-dose dexamethasone (IsaPd) versus pomalidomide and dexamethasone (Pd) in patients with RRMM (N=307) showed that IsaPd prolonged progression-free survival (PFS) and improved overall response rates (ORRs) versus Pd. At a median follow-up of 11.6 months, median PFS by independent review committee was 11.5 months for IsaPd versus 6.5 months for Pd (hazard ratio [HR]: 0.596 [95% confidence interval [CI]: 0.44–0.81]; p=0.001). ORR was 60.4% for IsaPd versus 35.3% for Pd (p<0.0001). Grade ≥3 adverse events (AEs) were observed in 86.8% of patients treated with IsaPd versus 70.5% of patients treated with Pd. The most frequent treatment-emergent AEs (all Grades) in the IsaPd arm were upper respiratory tract infections (28.3%), diarrhoea (25.7%) and bronchitis (23.7%). In the Pd arm, the most frequent treatment-emergent AEs were fatigue (21.5%), diarrhoea (19.5%) and asthenia (18.1%).

CASSIOPEIA PART 1 RESULTS SHOW SIGNIFICANT CLINICAL BENEFIT WITH QUADRUPLET REGIMEN IN NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM)2
This Phase III, randomised study in transplant-eligible patients with NDMM (N=1,085) compared daratumumab in combination with bortezomib, thalidomide and dexamethasone (D-VTd) with bortezomib, thalidomide and dexamethasone (VTd) alone. The quadruplet regimen induced a significantly higher stringent complete response (sCR) rate compared with triplet therapy omitting daratumumab, with 28.9% of patients in the D-VTd arm achieving sCR compared with 20.3% in the VTd arm (odds ratio: 1.60 [95% CI: 1.21–2.12]; p=0.0010). The most common (≥10%) Grade 3–4 treatment-emergent AEs (D-VTd/VTd) were neutropenia (27.6%/14.7%), lymphopenia (17.0%/9.7%), stomatitis (12.7%/16.4%) and thrombocytopenia (11.0%/7.4%).

FORTE TRIAL RESULTS: KRD-ASCT-KRD AND KRD12 INDUCE ROBUST RESPONSES IN NDMM3
This study, conducted by Francesca Gay and colleagues, randomised patients with transplant-eligible NDMM (≤65 years of age, N=474) to receive either induction therapy with carfilzomib, cyclophosphamide and dexamethasone (KCd) followed by autologous stem cell transplantation (ASCT) and consolidation with KCd (Arm A), induction therapy with carfilzomib, lenalidomide and dexamethasone (KRd) followed by autologous stem cell transplant (ASCT) and consolidation with KRd (Arm B), or to 12 cycles of KRd (Arm C). The aim of the analysis presented this year was to compare Arm B with Arm C in patients with standard-risk or high-risk MM. In both arms, rates of very good partial response (VGPR), complete response (CR), sCR and minimal residual disease negativity were comparable between Arm B and Arm C; however, a significantly lower number of patients in Arm B versus Arm C experienced early relapse (12 patients [8%] vs 26 patients [17%], respectively; p=0.015). This difference was mainly related to a significantly lower rate of early relapse in patients with a revised International Staging System stage of 2–3 in Arm B versus Arm C (11 patients [12%] vs 22 patients [23%], respectively; p=0.05). These results suggest that ASCT flanked by KRd induction and consolidation therapy may be superior to 12 cycles of KRd without ASCT. The treatment regimens had an acceptable safety profile, as previously presented at ASCO 2017.4

EARLY THERAPY WITH LENALIDOMIDE PROVES PROMISING IN ASYMPTOMATIC HIGH-RISK SMOULDERING MM5
The E3A06 trial is a randomised, Phase II/III study comparing the efficacy and safety of lenalidomide versus observation in patients with asymptomatic high-risk smouldering MM to determine the reduction in risk and PFS associated with the development of symptomatic disease (N=44 [Phase II] and N=182 [Phase III]). The PFS rates favoured the lenalidomide arm: 1-, 2- and 3-year PFS rates were 98%, 93% and 91% for lenalidomide, respectively, and 89%, 76% and 66% for the observation arm, respectively (HR: 0.28; p=0.0005). Among the patients treated with lenalidomide, Grade 3–4 non-haematological AEs occurred in 28% of patients in Phase III, with fatigue being the most common AE (N=5). The results suggest that early intervention with a prevention strategy, such as lenalidomide, could reduce the risk of developing symptomatic MM in patients with high-risk smouldering MM.

BELLINI TRIAL: VENETOCLAX (VEN) COMBINED WITH BORTEZOMIB AND DEXAMETHASONE (BD) SIGNIFICANTLY IMPROVED PFS IN PATIENTS WITH RRMM VS PLACEBO-BD, BUT INCREASED THE RISK OF DEATH6
The BELLINI trial was a Phase III study that investigated the efficacy and safety of Ven and Bd versus placebo and Bd (placebo-Bd) in patients with RRMM (N=291). In patients with Ven and Bd, the median PFS was 22.4 months versus 11.5 months in the placebo-Bd arm (HR: 0.630 [95% CI: 0.443–0.897]; p=0.01) with a median follow-up of 18.7 months. Among the 14 treatment-emergent deaths (those occurring on therapy or ≤30 days from the last dose), 13 were in the Ven and Bd arm and one was in the placebo-Bd arm. In the safety population (N=289), the most common treatment-emergent AEs (Ven and Bd/placebo-Bd) were diarrhoea (58%/48%), nausea (36%/22%), constipation (34%/31%) and fatigue (31%/32%). In a subgroup analysis, t(11;14) patients demonstrated improvements in PFS with Ven and Bd vs placebo-Bd, and a positive trend in overall survival with Ven and Bd was observed, suggesting that a biomarker-driven approach could be appropriate with this regimen.

MELFLUFEN IN COMBINATION WITH DEXAMETHASONE SHOWS PROMISING ACTIVITY IN THE HORIZON TRIAL7
The Phase II HORIZON trial investigated the efficacy and tolerability of melflufen, a peptide-conjugated alkylator, and dexamethasone in RRMM patients who had received ≥2 prior lines of therapy and who were refractory to pomalidomide and/or daratumumab (N=95). The updated results from the trial showed an ORR of 30%; 1 patient achieved sCR, 11% VGPR and 18% PR. Treatment-related Grade 3–4 AEs were reported in 68 patients (72%), and the most common (occurring in >20% of the population) were neutropenia (55%), thrombocytopenia (52%) and anaemia (26%). There were no reports of treatment-related deaths. The Phase III OCEAN trial is currently comparing the melflufen and dexamethasone regimen with pomalidomide and dexamethasone in RRMM patients.8


References

1. Richardson PG et al. Abstract 8004. Presented at the American Society of Clinical Oncology Meeting 2019.

2. Moreau P et al. Abstract 8003. Presented at the American Society of Clinical Oncology Meeting 2019.

3. Gay F et al. Abstract 8002. Presented at the American Society of Clinical Oncology Meeting 2019.

4. Gay F et al. Abstract 8003. Presented at the American Society of Clinical Oncology Meeting 2017.

5. Lonial S et al. Abstract 8001. Presented at the American Society of Clinical Oncology Meeting 2019.

6. Kumar S et al. Abstract LB2601. Presented at the European Hematology Association Conference 2019.

7. Richardson PG et al. Abstract S1605. Presented at the European Hematology Association Conference 2019.

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