ASH 2019 Day 3 – Venclexta & Immunotherapies Session

DAY 3 – Evening Session 2 

We’ve come full-circle: the last myeloma session of the day follows the same theme as the first day—with presentations on new drugs: Venclexta (venetoclax) and immunotherapies!

Tonight’s session featured additional data focused on Venclexta which targets a protein called Bcl-2 found in myeloma cells. As we noted in our earlier blog post, Venclexta works by interfering with a myeloma cell’s ability to grow and survive. Initial studies of Venclexta combined with dexamethasone showed encouraging activity in patients who harbored the chromosomal translocation 11;14—t(11;14). And when Velcade was added to this combination and studied in all myeloma patients in phase 1 trials it was shown to have a tolerable safety profile.

Dr. Jonathan Kaufman from Emory University presented results from a trial of Venclexta combined with dexamethasone (Vd) in patients with relapsed/refractory myeloma who have the t(11;14) chromosomal abnormality (ABSTRACT 926 https://ash.confex.com/ash/2019/webprogram/Paper125871.html). The study was carried out in two phases: phase 1—dose escalation and phase 2—expansion. Twenty patients were enrolled in phase 1 and 31 in phase 2.

  • Phase 1, 60% of patients responded and duration of response was 12 months
  • Phase 2, 48% of patients responded and duration of response could not yet be determined

This combination is being investigated in the ongoing phase 3 trial (CANOVA) in t(11;14) relapsed/refractory myeloma patients.

We now transition to our final presentations of the day in which we focus on the immunotherapies.

First is a presentation on the updated results from an ongoing phase 1 trial of the CAR T-cell therapy construct called bb21217. This construct is engineered to bind to the B-cell maturation antigen (BCMA) on myeloma cells and is similar to bb2121, which is currently being evaluated in a phase 3 trial and was recently published in the New England Journal of Medicine this year. Dr. Jesus Berdeja from the Sarah Cannon Center for Blood Cancers provided the update on 38 relapsed/refractory patients treated with bb21217 to assess the duration and efficacy of this therapy (ABSTRACT 927 https://ash.confex.com/ash/2019/webprogram/Paper126660.html).

  • Many of these patients had previously received Darzalex and many of the other common myeloma drugs.
  • Eighty-three percent of patients responded to bb1217 (and MRD negativity achieved in assessable patients).
  • Many patients developed cytokine release syndrome (CRS) which was manageable.
  • Five patients developed neurotoxicity such as dizziness or encephalopathy—the encephalopathy resolved.
  • The investigators showed long-term persistence of bb21217 CAR T cells in long-term responders.

The CAR T-cell construct called JNJ-4528 (that also targets BCMA on myeloma cells) was the subject of the next presentation. JNJ-4528 is engineered to latch onto BCMA on two different areas of the protein designed to make this CAR T-cell therapy hold on to myeloma cells tighter. In an earlier session today, the results were presented of a clinical trial of relapsed/refractory patients treated for the first time with JNJ-4528—called the CARTITUDE trial. In our current session, investigators from Mount Sinai looked at how the JNJ-4528 CAR T-cells behaved in patients treated on the CARTITUDE trial and found: (ABSTRACT 928 https://ash.confex.com/ash/2019/webprogram/Paper127309.html)

  • JNJ-4528 expanded in blood between days 10–14 post-infusion
  • Peak expansion did not correlate with response
  • Expansion correlated with increases in serum cytokines levels

Investigators from Wuhan, China presented their results of a phase 1 trial of a new CAR T-cell construct—called BM38—that was engineered to bind not only to BCMA but also another protein called CD38, which is the same target on myeloma cells that the monoclonal antibody Darzalex binds to. By binding to 2 different myeloma targets, this is called bispecific CAR T-cell therapy.

  • On this trial, 16 patients with relapsed/refractory myeloma were treated (ABSTRACT 930 https://ash.confex.com/ash/2019/webprogram/Paper130340.html).
  • The investigators showed that BM38 bispecific CAR T-cell therapy results in high response rates (88% of patients responded to treatment and even elimination of extramedullary disease) and a long duration of complete responses (the longest response lasted over 51 weeks).
  • No neurotoxicity was observed and cytokine release syndrome was manageable.

Further development of bispecific CAR T-cell therapy continues.