COMy 2020 | Highlights from the oral abstract session

On Friday 15 May, 2020, during the 6^th World Congresses on Controversies in Multiple Myeloma (COMy) meeting, held virtually, a session entitled ‘Oral Abstracts’ took place. Within this session, five abstracts were presented. Key take-home messages from each presentation are hereby summarized by the Multiple Myeloma (MM) Hub.

JNJ-4528 for relapsed/refractory MM: phase Ib results from CARTITUDE-1

Andrzej Jakubowiak opened the session with the results of a phase Ib study, CARTITUDE-1, of the chimeric antigen receptor (CAR) T-cell therapy, JNJ-4528, in 29 patients with relapsed/refractory MM (RRMM). This population of patients was heavily pretreated, with 100% of patients being triple exposed (to a proteasome inhibitor [PI], immunomodulatory drug [IMiD®], and anti-CD38 monoclonal antibody [mAb]), and 86% triple refractory. In relation to safety, 93% of patients experienced cytokine release syndrome of any grade, which occurred (on average) 7 days post-infusion and lasted for an average of 4 days. The overall response rate (ORR) was 100%, with a very good partial response (VGPR), or better, rate of 86%. The median time to complete response or better was 1 month. At a 6-month follow-up, 27 patients were progression free and measurable (minimal) residual disease negative at 10^-4. The phase II portion of the study will proceed with a dose of 0.75 × 10⁶ CAR⁺ cells/kg and is fully enrolled.

The data presented during this session was previously presented by Deepu Madduri at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition. Read the full results of the phase Ib portion here, and watch Deepu Madduri discuss the results here.

DREAMM-2 | Primary analysis of belantamab mafodotin in patients with RRMM

Philippe Moreau subsequently presented the results of the DREAMM-2 study of belantamab mafodotin in patients with RRMM who were heavily pretreated and refractory to PIs, IMiDs, and refractory or intolerant to an anti-CD38 mAb. In this phase II study, patients received either 2.5 mg/kg (n = 95) or 3.4 mg/kg (n = 99) of belantamab mafodotin, intravenously (IV), every 3 weeks. The ORR was 31% in the 2.5 mg/kg dose cohort and 34% in the 3.4 mg/kg dose cohort. The median progression-free survival (PFS) was 2.9 months (95% CI, 2.1–3.7) in the 2.5 mg/kg dose group, and 4.9 months (95% CI, 2.3–6.2) in the 3.4 mg/kg dose group. Overall survival (OS) data were not mature for either group. In the 2.5 mg/kg group, 98% of patients experienced an adverse event (AE) of any grade, compared with 100% of patients in the 3.4 mg/kg group, leading to permanent discontinuation in 8% and 10% of patients, respectively. One patient died in each study arm: one due to sepsis (2.5 mg/kg dose cohort) and one due to hemophagocytic lymphohistiocytosis (3.4 mg/kg dose cohort). In total, four patients permanently discontinued due to keratopathy.

It has been previously announced that the primary objective of the DREAMM-2 was met, with belantamab mafodotin leading to a clinically meaningful ORR, with a consistent safety profile as reported in DREAMM-1. The full results of DREAMM-2 were published in The Lancet Oncology in February 2020; read a summary of the results on the MM Hub here.

DREAMM-5 | Belantamab mafodotin in combination with novel agents for RRMM

Ira Gupta presented the third abstract of the session, which centered around the trial design of the DREAMM-5 study (NCT04126200). This phase I/II clinical trial is investigating belantamab mafodotin in combination with novel anti-cancer agents in several sub-studies under one master protocol. The phase I dose exploration portion will enroll ten patients or less at each dose level, and an interim analysis will be performed based on the ORR to determine whether patients proceed to the phase II portion and to identify the recommended phase II dose. In the phase II cohort expansion portion, 35 patients or less will be enrolled per sub-study, and each investigatory arm will be compared with a belantamab mafodotin monotherapy control arm. Primary analysis will be conducted 6 months after the last patient receives the first dose for each sub-study.

The primary objectives of the phase I portion are to evaluate dose-limiting toxicities and AEs, and the primary objective of the phase II portion is ORR. Eligible patients have RRMM, having received three or more prior lines of therapy including a PI, IMiD, and anti-CD38 mAb. Patients receiving prior anti-B-cell maturation antigen (BCMA) or CAR T-cell therapy within 3 months of screening will be excluded. A prior autologous stem cell transplant was permitted if it was more than 100 days prior to screening and the patient had no active infection, though patients with prior allogeneic stem cell transplant were excluded.

The sub-study combinations, with a summary of rationale, are given below:

• Sub-study 1: Belantamab mafodotin plus GSK3174998 (GSK998)
  • GSK998 is a humanized wild-type IgG1, anti-OX40 agonistic mAb
  • GSK998 binds to the co-stimulatory OX40 receptor that is primarily expressed on activated CD4⁺ and CD8⁺ T cells
  • OX40 signaling leads to effector T-cell proliferation and survival, inducing a T-cell-mediated immune response against tumor cells
  • Belantamab mafodotin will potentially enhance the immune-mediated antitumor activity of GSK998 and overcome immune resistance
  • Open to accrual
• Sub-study 2: Belantamab mafodotin plus GSK3359609 (GSK609)
  • GSK609 is a humanized anti-ICOS Ig4 mAb that is an ICOS agonist
  • ICOS is mainly expressed on CD4⁺ and CD8⁺ T cells
  • ICOS is a co-stimulatory receptor, and member of the CD28-superfamily, that is involved in the function of T cells
  • GSK609 binds to ICOS and may enhance T-cell function and antitumor activity
  • Open to accrual
• Sub-study 3: Belantamab mafodotin plus nirogacestat (PF-03084014)
  • Nirogacestat inhibits gamma-secretase, increasing cell-surface levels of BCMA
  • Inhibiting gamma secretase may increase the efficacy of BCMA-targeted therapies

• Sub-study 4: Belantamab mafodotin plus D
• More sub-studies may be subsequently added

Isatuximab (isa) plus carfilzomib (K) for RRMM | Final analysis of phase Ib study

Tom Martin moved on to present the penultimate abstract of this session, detailing the results of a phase Ib study investigating isa in combination with K in patients with RRMM. The primary objective was to determine the maximum tolerated dose (MTD) of isa with standard K dosing. Secondary objectives included assessment of preliminary activity and confirmation of safety. The trial was conducted in two phases — dose escalation and dose expansion:

• Dose escalation:
  • Induction therapy: Cycles 1–8, 28-day cycles:
    • K (IV):
      • 20 mg/m² on Days 1 and 2
      • 27 mg/m² on Days 8, 9, 15, and 16
      • Dose adjustments permitted: 27 mg/m² to 20 mg/m² to 15 mg/m²
    • Isa (IV): Three dose levels with 3–6 patients at each dose level:
      • Dose level 1: Isa, 10 mg/kg every other week (QOW)
      • Dose level 2: Isa, 10 mg/kg weekly (QW) for 4 weeks then QOW
      • Dose level 3: Isa, 20 mg/kg QW × 4 then QOW
      • No dose adjustments were permitted
    • Dexamethasone (dex): Mandatory in Cycle 1, to be decreased/discontinued after Cycle 1
      • 20 mg IV or orally on Days 1, 8, 15, and 22
      • 4 mg orally on Days 2, 9, and 16
  • Optional maintenance from the ninth cycle was given until disease progression (PD)
    • Isa on Day 1 and 15
    • K on Days 1, 2, 15, and 16
• Dose expansion: 18–21 patients (24 in total at MTD) with more K-sensitive patients than K-refractory patients
  • Induction with K and dex (as in the dose escalation portion), with isa at the MTD
  • Maintenance as described above

Patients with RRMM following two or more prior lines of therapy and patients who were previously exposed or refractory to K were permitted to enroll. Exclusion criteria included cardiovascular disease and prior anti-CD38 therapy. In total, 33 patients were enrolled: 15 in dose escalation and 18 in dose expansion. Approximately 30% of patients were 65 years old or older, 70% were refractory to bortezomib, and 27% were K-refractory.

At a median follow-up of 28-months, 29 patients had PD, 11 patients had died (all due to PD), and four patients remain on therapy. The median number of cycles administered was ten.

Safety:

• No deaths or discontinuations occurred due to toxicity
• No dose reductions were required due to cumulative hematologic toxicity
• Most common non-hematologic AE: Infusion-associated reactions
  • 3% of patients experienced a Grade 3 event
  • 51% were isa-related
  • 3% were K-related
• The most common Grade 3 non-hematologic AE was hypertension
• Infections were common, observed in ~90% of patients, most of which were not determined to be related to treatment

Efficacy: Best responses are summarized in Table 1. The median PFS is 10.1 months (95% CI, 6.47–16.4), and median OS has not been reached. The probability of OS at 30 months was 63.3% (95% CI, 47.6–84.1).

Table 1. Responses to isatuximab plus carfilzomib

The doublet of isa + K led to an ORR of 70%, which was maintained in subgroups, including those with K-refractory disease and high-risk cytogenetics. The regimen was well tolerated, with no significant cardiovascular toxicity.

The results of this trial have led to the phase III IKEMA study, which is comparing isa + K to K alone in patients with RRMM following one to three prior lines of therapy. Early results from the IKEMA trial (NCT03275285) have recently been released and are summarized here.

Outcomes of patients treated with ixazomib, lenalidomide, and dexamethasone (IRd) in routine clinical practice compared with the TOURMALINE-MM1 trial

Xavier Leleu concluded the session with a presentation focusing on the real-world outcomes of patients with relapsed MM treated with IRd compared with those reported in patients treated in the TOURMALINE-MM1 study. To compare outcomes, Xavier Leleu and colleagues conducted an expanded pooled analysis of the Czech RMG and INSIGHT MM registries, including elderly patients, patients with advanced disease, and patients with comorbidities (N = 217).

IRd was found to be effective in routine clinical practice when compared with the efficacy reported in the TOURMALINE-MM1 study (real-world vs TOURMALINE-MM1):

• ORR: 74% vs 78%
• Median PFS: 21.6 vs 20.6 months

Additionally, patients receiving IRd in earlier lines of relapse appeared to have improved outcomes compared with those receiving IRd in later lines of therapy. In relation to safety, no new safety signals were identified, the rate of dose reductions due to AEs was low (10% for ixazomib and 21% for lenalidomide) and discontinuations due to AEs were similar for ixazomib (32%) and lenalidomide (31%).

Based on this analysis, the real-world experience of IRd appears to be comparable to the clinical trial setting.

Further Resources

The full oral abstracts session is currently available via this link [Correct as of May 19, 2020].