ASH 2019 Day 1 – New Therapies & XPOVIO Session

DAY 1 – Morning Session 2

In the mid-morning session today, we heard about many new therapies being studied in myeloma including: a monoclonal antibody, update on Venclexta (venetoclax), a T cell engager antibody, and a drug-conjugate that delivers toxic radiation specifically to myeloma cells! Also, we learned more about the newly approved drug—XPOVIO—as part of a triplet combination therapy.

The first presentation of the morning came from MMRC member Dr. Amrita Krishnan at the City of Hope Medical Center where she presented preliminary results from a phase 1 study of the monoclonal antibody called TAK-079 (ABSTRACT 140 https://ash.confex.com/ash/2019/webprogram/Paper128007.html).

  • TAK-079 binds to the protein CD38 on the surface of myeloma cells and was designed to selectively bind more to myeloma cells than to red blood cells (which also have the CD38 protein on their surface). This is the same target that Darzalex (daratumumab) uses as well as another investigational antibody called isatuximab.
  • A unique feature of TAK-079 is that it is administered as a subcutaneous injection that takes a minute or less to inject, as opposed to a long injection.
  • TAK-079 was studied at increasing doses in 34 patients with relapsed/refractory myeloma—many of these patients no longer responded to proteasome inhibitors or immunomodulatory drugs and 23% of patients had been previously exposed to an anti-CD38 monoclonal antibody. 56% of patients responded to TAK-079 at the 300 mg dose and no patient experience an infusion reaction.
  • The excitement for TAK-079 is the potential for home-based self-administration. We look forward to hearing more about this agent.

XPOVIO was approved in July in combination with dexamethasone for the treatment of patients who have relapsed or refractory multiple myeloma, have received at least four prior antimyeloma treatment regimens, and are refractory to at least two proteasome inhibitors (such as Velcade, Kyprolis, and Ninlaro), at least two immunomodulatory drugs (such as Revlimid and Pomalyst), and an anti-CD38 monoclonal antibody (Darzalex). XPOVIO is the first in a new drug class called selective inhibitors of nuclear export (SINE).  At this meeting, the results of a phase 1 trial of XPOVIO in combination with Pomalyst and dexamethasone (SPd) in patients with relapsed/refractory myeloma was presented (ABSTRACT 141 https://ash.confex.com/ash/2019/webprogram/Paper122907.html).  SPd was studied in 48 relapsed patients who had previously received proteasome inhibitors (like Velcade or Kyprolis) and the immunomodulatory drug Revlimid. Treatment with SPd resulted in responses in:

  • 56% of patients that had not received any Pomalyst as their previous treatments
  • 31% of patients that were refractory to Pomalyst or Revlimid

Side effects were manageable with ≤2% severe nausea, vomiting, diarrhea, weight loss, and decreased appetite.  The all oral drug combination of SPd is active in patients that no longer respond to Revlimid or who have not previously received Pomalyst. Results from trials investigating additional combinations—such as XPOVIO-Velcade-dexamethasone—are awaited.

The next drug discussed today was Venclexta which targets a protein called Bcl-2 found in myeloma cells. 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. However, a large, phase 3 trial (the BELLINI trial) testing Venclexta in combination with Velcade and dexamethasone for patients with relapsed/refractory myeloma resulted in more patient deaths than the control arm of that trial (Velcade-dexamethasone). This morning, the BELLINI trial investigators reported on the use biomarkers (such as expression of t[11;14] and expression of the Venclexta target, Bcl-2) to select myeloma patients who would specifically benefit from treatment with venetoclax-Velcade-dexamethasone (ABSTRACT 142 https://ash.confex.com/ash/2019/webprogram/Paper126094.html).  The investigators showed that patients with relapsed/refractory myeloma harboring either t(11;14) or myeloma cells expressing high levels of Bcl-2 benefited the most from Venclexta -Velcade-dexamethasone. Many in the myeloma community say that Venclexta has a role in myeloma specifically as a precision medicine option for patients with t(11;14) or Bcl-2 overexpression.

Next up is our first look at a new bispecific T-cell engager antibody (sometimes referred to as a BiTE) called CC-93269. BiTEs are a type of myeloma immunotherapy. BiTEs consist of two antibody fragments that have been fused together: one antibody fragment binds to a protein found on myeloma cells, and the other antibody fragment binds to—and thus activates—a protein found on the surface of an immune cells called T cells. By targeting both myeloma cells and T cells, BiTEs help the T cells kill the myeloma cells. CC-93269 is engineered to bind to B-cell maturation antigen (BCMA) on myeloma cells with one arm and to CD3—a protein on the surface of all T cells—with another arm. Dr. Luciano Costa from the University of Alabama at Birmingham reported findings of a phase 1 trial of this new therapy (ABSTRACT 143 https://ash.confex.com/ash/2019/webprogram/Paper122895.html).

  • Thirty patients with relapsed/refractory myeloma who had previously received up to 6 therapies (including stem cell transplant, and many of the common myeloma drugs; 89% of patients were refractory to Darzalex) were treated with CC-93269.
  • Side effects of treatment with CC-93269 included low white blood cells, low red blood cells, and infections.

About 77% of patients experienced cytokine release syndrome (CRS)—usually mild and occurred most frequently in the first or second dose of treatment. 89% of patients who received a dose of CC-93269 at 10 milligrams responded to treatment and 44% of those patients achieved minimal residual disease negativity. This study continues to enroll patients.