New investigational therapies in the pipeline that address multiple myeloma include both small-molecule and immunotherapeutic approaches — and in some cases, a combination of the two.
Drugs that increase the visibility of tumors to the immune system, used in combination with additional medications that bolster the immune system, will be the future focus in the management of multiple myeloma, according to a study published in Trends in Cancer.1 These combination therapies are predicted to produce dramatic results in patients, bringing patients closer to achieving a functional cure — possibly extending median lifespan in patients with multiple myeloma by at least 10 years, said researchers.
Older therapies harness various mechanisms of action, with some working directly on plasma cells and others focused on fine-tuning the tumor microenvironment until it becomes an unwelcome place for tumors to reside.
The antitumor effects of therapies released on the market for multiple myeloma from 2006 to 2012 increased median survival for patients from less than 4 years to nearly 7 years, wrote the investigators. These figures do not capture improvements in survival resulting from treatment with the monoclonal antibody (mAb)-based drugs elotuzumab and daratumumab, both of which were approved by the US Food and Drug Administration (FDA) in 2016.
In sum, the researchers identified 15 distinct targets that are being investigated in MM at various stages of clinical development across nearly 80 trials. They did not include in their overview a breakdown of the trials in MM exploiting approaches such as dendritic cell or peptide vaccines, TCR-engineered cells, or natural killer (NK)-based therapies.
The targets the authors highlighted across ongoing multiple myeloma trials include HDAC, BET, HMT, DNMT, CD38, SLAMF7, B-cell maturation antigen (BCMA), CD56, CD138, CD74, PD-1, eEIF1A2, Bcl-2, Mcl-1, and XPO-1.
BCMA is being investigated the most; 12 different trials are looking at this target, but none of these trials are in late stages. Although BCMA targeting in multiple myeloma is being investigated across all 4 types of the aforementioned classes of immunotherapies, the products that appear to be most promising are the CAR-T constructs, wrote the researchers. A CAR-T trial from Nanjing Legend demonstrated a 100% response rate in early phases and another from Bluebird Bio conferred a 94% overall response rate. These products “may form the basis of a cure for myeloma, at least in some patients,” the authors wrote.
A bulk of the new therapies being studied either incorporate a target in protein homeostasis — some of which are brand-new targets, and others that have already been targeted successfully by other medications, providing the basis for their FDA approval in those indications — or focus on epigenetics in myeloma (specifically, oncogenic transcription and translation of key proteins), wrote the study authors.
Specific strategies for disruption of protein homeostasis include the use of deubiquitylase inhibitors and Mcl-1 inhibitors, among other approaches.
One of the proposed methods to halt transcription in myeloma cells involves the inhibition of histone deacetylases (HDACs). There are numerous HDAC inhibitors already under investigation for myeloma in various drug combinations, and one anti-HDAC drug, panobinostat, is already approved for this indication — however panobinostat has not been highly utilized because of its toxicity when used in combination with bortezomib and dexamethasone. The authors counted 7 distinct molecules in the HDAC class that are currently being studied in clinical trials for multiple myeloma, vorinostat is the further along in the pipeline, now in phase 3 trials.
Immunomodulators (mostly checkpoint blockade agents) and the targeting of various tumor-specific cell-surface antigens are also major areas of focus for future treatments in multiple myeloma. There are 4 major classes of “antigen-specific immunotherapies under investigation in myeloma: mAbs, antibody–drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor-engineered T cells (CAR-Ts).”
The exploration of various targets will be especially important for the creation of alternative treatment strategies in patients who become refractory to a drug as a result of antigen escape, the researchers noted. They added that small-molecule products that “increase antigen expression at the cell surface are likely to show clinical utility,” especially in the framework of reversing therapy resistance, making baseline-resistant patients sensitive, or through their co-administration with an immunotherapy.
The agents in phase 3 stages across all targets in multiple myeloma (ie, the targets covered in the study) are vorinostat (targeting HDAC; ClinicalTrials.org Identifier: NCT00773747), panobinostat (targeting HDAC; ClinicalTrials.org Identifier: NCT01023308), daratumumab (targeting CD38; ClinicalTrials.org Identifiers: NCT02136134 and NCT02076009), elotuzumab (targeting SLAMF7; ClinicalTrials.org Identifier: NCT01239797), pembrolizumab (targeting PD-1; ClinicalTrials.org Identifiers: NCT02576977 and NCT02579863), plitidepsin (targeting eEIF1A2; ClinicalTrials.org Identifier: NCT01102426), venetoclax (targeting Bcl-2; ClinicalTrials.org Identifiers: NCT01239797 and NCT02755597), and selinexor (targeting XPO-1; ClinicalTrials.org Identifier: NCT03110562).
- Choudhry P, Galligan D, Wiita AP. Seeking convergence and cure with new myeloma therapies. Trends Cancer. 2018;4(8):P567-P582. doi: 10.1016/j.trecan.2018.05.005