Day 2 at Myeloma 2018 brought sessions on drug resistance and immunotherapy.
- Dr. Mike Chapman of the University of Cambridge reported on use of CoMMpass Study data to identify a seven gene signature to predict Velcade and Revlimid sensitivity, as well as sensitivity to Velcade/Revlimid/dex. The goal of his study is to develop a simple genomic sequencing test for patients that could bring results within 3 days and that doctors could then use to help determine the best therapy for patients.
- Dr. Brian Van Ness of the University of Minnesota reported on discovery of a gene expression signature to that predicts sensitivity to proteasome inhibitors (ie, Velcade, Kyprolis and Ninlaro). This signature, which can be seen when sequencing just a single myeloma cell, might soon be used to determine which newly diagnosed patients are the best candidates for proteasome inhibitor therapy
- Dr. Marc Raab of University of Heidelburg Germany reported on gene expression signatures for drug sensitivity and resistance in relapsed refractory myeloma (RRMM) patients, that are clearly different from those seen in newly diagnosed patients and involves different gene pathways. Several recurrent targetable alterations in RRMM, such as CD20,Mcl-1, and HGF (hepatocyte growth factor) overexpression, are in early phase clinical trials and are showing some activity against myeloma.
BCMA CAR-T (Clinical)
- Dr. James Kochendorfer of NIH gave an update on his group’s BCMA CAR-T trial. 16 patients were enrolled at a dose of 9 million cells. 13 of these patients showed objective response. 4 of the 16 patients had duration of response over 1 year. 2 patients had grade 4 cytokine release syndrome (CRS), 4 had grade 3 CRS, and the rest had grade 2 or below. NIH has also recently opened a trial of a BCMA CAR-T that contains the heavy chain region only which may be longer lived in patients and produce more durable responses.
- Dr. Adam Cohen of UPenn gave an update on their study, where data has been collected and evaluated on 25 patients who received different amounts of CAR-T with or without Cytoxan. In this study the overall response rate was 48% (12 of 25 patients responded) and median duration of response was 4 months. In the 11 patients who received the highest dose of cells (up to 500 million) plus Cytoxan, the response rate was 63%.
- Dr. Yi Lin of Mayo Clinic gave an overview of industry sponsored BCMA CAR-T trials.
- bb2121 Bluebird/Celgene trial (39 evaluable patients with a 77% overall response rate; PFS was 11.8 months at active doses and 17.7 months for patients who achieved MRD negativity)
- Legend trial (40 evaluable patients, 92.5% overall response rate;, 3 of 4 patients who are have greater than 2 year response are still in remission).
- Both studies showed low/manageable toxicity
- Both are in Phase 2clinical trials
- Bb2121 KarMMa PhII trial now accruing in US
- JNJ-68284528 Ph Ib/II now accruing in US
- Other companies with BCMA trials ongoing: Poseida, Autolus, Kite/Gilead, Cartesian, June/Celgene, Unum. All except Juno/Celgene are currently in PhI.
- Some factors which can predict success of BCMA CAR-T therapy in patients include
- High risk cytogenetics
- Disease burden at time of treatment
- BCMA expression levels
- CAR-T cell dose
SLAM F7 CAR-T (Preclinical)
- Dr. Krina Patel of MD Anderson Cancer Center presented her work on an off-the-shelf CAR-T therapy that targets SLAM F7, another cell surface target on myeloma cells. These cells are manufactured in the lab from healthy donor cells and do not have to be collected from the myeloma patient and expanded, making them available sooner to patients who need therapy right away. However, similar to an allogenic stem cell transplant, this does increase the risk of graft vs host disease where the patients’ body may reject the CAR-T therapy. A PhI/II trial is planned.
- Dr. Michael Heducek of University of Wurzburg Germany reported on a more conventional approach with SLAM F7 CAR-T, where cells are collected from the patient and engineered to attack myeloma cells and then reinfused to the patient, similar to what is being done in the BCMA CAR-T trials. Currently, in mouse models this therapy is showing deeper response than what is seen with BCMA CAR-T. A European PhI/II trial is planned.
BiTEs in myeloma
Dr. Herman Einsele of University of Wurzburg Germany reported on development of bi-specific antibodies against myeloma. These antibodies bind to both T cells and myeloma cells; when the T cell is brought into close proximity of the myeloma cell it will attack and kill it. This type of therapy is already approved for relapsed refractory B-ALL.
o PhI study underway in Europe with a small group of RRMM patients with Amgen’s BCMA-BiTE, AMG 420
o Patients received the antibody by continuous IV infusion over 4 weeks with 2 weeks off for up to 5 cycles
o Treatment produces low levels of CRS especially in patients with low tumor burden at the time of treatment and lower level of neurotoxicity than CAR-T therapy
o In the 5 evaluable patients, all received a sCR with responses in 4 of these patients ongoing greater than 10 months
Day 2 was brought to a close with a discussion of the future of CAR-T therapy in myeloma. All agreed the results are exciting and very promising, but more work and more clinical trials are needed to improve depth and duration of responses in patients. The next meeting, Myeloma 2020 will be held in April 2020 in Madrid Spain. The MMRF will be there!
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