Pembrolizumab

At the 2015 Annual Meeting of the American Society of Hematology (ASH) there was a lot of excitement about one drug (already FDA-approved with the brand name Keytruda® for melanoma and non-small cell lung cancer) that is a new type of monoclonal antibody against a “checkpoint inhibitor” called PD-1. Checkpoint inhibitors are parts of our immune system that read messages on cell surfaces. These messages let them know whether a cell is healthy, unhealthy, or foreign to the body. If the cell is unhealthy or foreign, the checkpoint inhibitor will call out the immune system’s troops – T cells – to mount an attack on the unwanted cells. Cancer cells protect themselves from this attack by creating cell surface proteins that say “I’m a healthy cell – don’t destroy me!” Pembrolizumab – often referred to as “pembro” – overrides the checkpoint inhibitor, enabling T cells to mount a strong attack on the cancer cells. Like other monoclonal antibodies in the new category of “immuno-oncology” drugs, pembrolizumab may work better against myeloma cells when combined with an immunomodulatory drug (IMiD) such as Revlimid® or Pomalyst®. Used with these IMiDs, pembro has shown early results that are quite promising. There are now seven trials with pembrolizumab that are actively recruiting myeloma patients, and another three that will soon be open to accrual. Pembro is being tested in combination with drugs other than IMiDs – experimental agents in their own right – and across disease settings in myeloma, including for smoldering disease and post-stem cell transplant therapy.

Clinical trials:

Phase I pembro+Rd 
Phase III pembro+Rd versus Rd 
Phase III pembro+Pom/dex versus Pom/dex 
Phase I/II pembro+Pom/dex
Phase I pembro as a single agent in hematologic malignancies
Phase II pembro+Revlimid post-stem cell transplant
Phase I/II pembro+ACP-196 in hematologic malignancies
Phase I pembro+dinaciclib in hematologic malignancies
Not yet recruiting as of April 15, 2016:
Pembro for smoldering myeloma
Phase II pembro in myeloma patients with residual disease

Selinexor

Selinexor causes tumor suppressor proteins (also known as anti-oncogenes) to remain in the nuclei of myeloma cells, shutting down cancer cells’ ability to export proteins that are harmful to them. 

Oncogenes turn cancer cells on; anti-oncogenes shut oncogenes down. When anti-oncogenes cannot be exported from cancer cells, they are able to cause cell death.
Selinexor is a completely new type of drug, and is currently being tested in five new clinical trials. In the STORM trial, selinexor is combined with dexamethasone for patients who are “quad refractory” to Velcade, Revlimid, Kyprolis, and Pomalyst. Selinexor is also being tested in other trials with each of these “backbone” drugs individually to see if it is effective for patients who are less heavily pretreated. There are currently five trials with selinexor in myeloma that are ongoing and actively accruing.

Clinical trials:

Phase II selinexor+dex for patients who are quad-refractory
Phase I/II selinexor in combination with backbone treatments
Phase I selinexor+Kyprolis+dex
Phase II selinexor+Kyprolis+dex vs placebo+Kyprolis+dex: 
Phase I/II selinexor+Doxil (pegylated liposomal doxorubicin)

CAR-T cells

The third – and possibly most exciting – category of clinical trials being conducted in 2016 involves what are called CAR (chimeric antigen receptor) -T cells. These are T cells that have been removed from the body, engineered to attack the myeloma, and given back to the patient.

These T cells then target specific antigens on the surface of the myeloma. Results have been achieved in myeloma with T cells engineered to target the CD19 cell surface antigen – anti-CD19 – and were published in The New England Journal of Medicine (September 2015). A late-breaking ASH abstract from the annual meeting last December presented data on the use of CAR-T cells targeting the B cell maturation antigen (BCMA). Those results were also very promising, despite severe toxicities.

Clinical trials:

Phase I T cells targeting the B cell maturation antigen
Phase I/II CD138-modified T cells
Phase I CAR-T cells targeting NKG2D-Ligands
Phase I CAR-T cells targeting CD19 for lymphoid malignancies

 

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