Interesting Early Research in Multiple Myeloma

We prefer to focus on developments in late state research as those give us something to look forward to in terms of treatment alternatives that may become available to us in the ‘near term’. That doesn’t mean, however, that we should ignore results from early research. Novel treatments and treatment combos are already extending the lives of all of us multiple myeloma patients so we may as well start planning for the long(er) haul. Several interesting papers, relating to early stage research, have been published over the past few weeks that merit mention.

Individually wrapped mesenchymal stem cells

The most recent issue of the Proceedings of the National Academy of Sciences of the United States presented research done at the Wyss Institute at Harvard University, titled ‘Programmable microencapsulation for enhanced mesenchymal stem cell persistence and immunomodulation’. A nice summary of this work was published in the electronic journal Genetic Engineering & Biotechnology News.

The latter authors write, ‘Good things come in small packages, and therapeutic stem cells are no exception. They appear to be more effective if they are delivered individually wrapped, encapsulated in so-called microgels, rather than deposited in bulk. The main advantage of singly encapsulated stem cells is that they stay fresher, longer. That is, they are protected from immune attack and cleared more slowly from the body. Consequently, they promise to improve cell-based therapies, which often fail due to rejection by the patient’s immune system or graft-versus-host disease.’

Individual stem cells were encapsulated in a microgel. The team at the Wyss Institute feels that, as far as they know, their research program is the first to encapsulate single cells to improve cell therapies with intravenous infusion. The research, so far, has been done on several different mouse models (typical of early stage development). The crowning success was the infusion into mice with transplanted bone marrow, half of which was ‘immune compatible’ and half being ‘allogeneic’, being an ‘immune mismatch’. Results after nine days showed that mice with the encapsulated stem cells showed double the fraction of allo-cells in their bone marrow, compared to mice who had been infused with ‘bare’ stem cells. The engraftment of the encapsulated stem cells was also higher than was seen in the mice infused with ‘bare’ stem cells.

It will be some years from now when we may see the practical application of this novel technology in clinical practice but we may want to keep an eye on future developments of this innovation.

Understanding what drives the efficacy of anti CD-137 monoclonal antibodies

A recent issue of the Journal of Clinical Insight presented the results of preclinical studies of anti CD-137 mAb in myeloma mouse models. We are already familiar with several monoclonal antibody products that are actively used in treating relapsed/refractory myeloma: e.g., Darzalex (a CD-38 targeting mAB), and Empliciti (anti SLAM7 mAB). These monoclonal antibody's target proteins on the surface of myeloma cells and they exert their anticancer effect using different mechanisms. Anti-CD 137 immunotherapy requires the presence of the CD8+ T-cells and natural killer cells. Chances are that, by now, you have pretty much lost your appetite to continue reading. So, let me get right to the bottom line(s) :

• Anti CD-137 is NOT a serious candidate when used by itself in the treatment of relapsed/refractory myeloma;
• But, is a solid product when used in consolidation therapy after disease burden has been reduced either by the administration of cyclophosphamide or melphalan.

There are currently two anti-CD 137 products being tested in humans: urelumab (BMS-663513) and utomilumab (PF-05082566). The authors write :

‘Doses of acceptable toxicities had to be defined for urelumab, as this mAb had caused severe liver damage at high doses (16). By contrast, only mild toxicities were observed with utomilumab (17, 18).  … Therefore, anti-CD137 mAbs hold promise for the treatment of a broad range of malignancies, including MM, for which urelumab is now being assessed in combination with elotuzumab (NCT02252263).’

The significance of the research mentioned in the above referenced journal article is that is has not only unraveled the mechanism of action of this class of anti-myeloma compounds but has also pinned down when exactly they will have the best patient outcomes. It is this added understanding that is so critical to be known when talking about ‘precision medicine’.