Updates on Melflufen (Pepaxto) in Multiple Myeloma
Updates on melflufen show that it may kill Velcade-resistant cells and reduce bone-related issues, according to two new studies.
The Myeloma Crowd by HealthTree has recently published several articles relating to the recently approved anti-myeloma drug Pepaxto (melflufen or melphalan flufenamide, developed by the Swedish company Oncopeptides), a first-in-class peptide-drug conjugate. To learn more about this drug you may wish to refer to this prior article. Apart from three clinical updates that were presented at the most recent ASCO forum, there are two very recent publications in peer reviewed journals that are also interesting to be aware of.
Melflufen Kills Velcade-Resistant Cells
The journal Hemasphere published a study that indicates that melflufen eradicates Velcade (bortezomib) resistant myeloma cells and their tumor initiating precursors. The key points of this study are:
- ‘Bortezomib (Velcade) is one of the common backbones in the treatment of newly diagnosed MM (NDMM) patients. Nevertheless, patients with MM ultimately develop resistance to bortezomib and relapse. Nowadays, almost all relapsed/refractory patients become bortezomib-resistant and require novel agents for further treatment.’
- Prior research has shown that higher expression of the RNPEP gene is a risk factor for myeloma patients and is associated with a shorter progression free survival. This elevated RNPEP gene expression is also observed in plasma cell precursors, residing in a B-lymphoid cell compartment, where the tumor initiating ‘stem’ cells are found.
- ‘Myeloma precursor cells can give rise to [different cell types] generating the bulk of myeloma tumor in a patient’s bone marrow, and are proposed to be one of the reasons of incurability of MM.’ [emphasis added]
This study showed that drugs that most of us are familiar with, specifically dexamethasone, Revlimid, Velcade and cyclophosphamide, have only a limited effect on eradicating these early myeloma progenitor cells.
More advanced drugs such as Kyprolis, iberdomide (a new drug in the Bristol-Myers pipeline), CC-29480 (a Bristol-Myers CelMOD agent currently in clinical trials, and the fairly recently approved drug Xpovio (Karyopharm’s selenixor), ARE active in suppressing the growth of clones from precursor cells, but not with 100% efficiency.
Melphalan (another drug that those of us who have had auto stem cell transplants, are familiar with) IS 100 % active, but only at very high doses. Melflufen has shown the same effect (100 % efficiency) at concentrations 100-fold lower [than melphalan]. [emphasis added]
Oncopeptides (the company that developed melflufen and that recently secured full FDA approval) has recently reported several studies where triplets that included melflufen had positive outcomes. For example: ‘The daratumumab/melflufen/dexamethasone arm of the ANCHOR study have shown overall response rate of 76% and clinical benefit rate of 79%.’
Melfufen May Reduce Bone-Related Problems
The journal Bone Reports published a study that indicates that melflufen may have beneficial effects of reducing myeloma bone related problems. The key points of this study are:
- “Myeloma bone disease is a major complication in multiple myeloma affecting quality of life and survival.”
- “Myeloma bone disease is characterized by increased activity of osteoclasts, bone resorbing cells. The multiple myeloma microenvironment promotes a process of production of osteoclasts from their precursor cells (monocytes). This is called osteoclastogenesis’.
- The effects of two anti-myeloma drugs, melphalan flufenamide (melflufen) and melphalan, on the activity and proliferation of osteoclasts and their progenitors, monocytes, were assessed in this study.
- Melflufen was ten-fold more active than melphalan in inhibiting proliferation of osteoclast progenitors, [and] … was also superior to melphalan in inhibition of osteoclastogenesis and bone resorption.
These results demonstrate that melflufen may exert beneficial effects in patients with multiple myeloma such as reducing bone resorption and immunosuppressive milieu by inhibiting osteoclastogenesis. [emphasis added]
Both of the above referenced papers are not the easiest to read or digest but I will still encourage you to try as they are full of interesting ‘stuff’ to learn and know about with respect to our disease and I commend Oncopeptides for digging deep into the mechanisms of action of melflufen. The better understanding of the compound will provide for better, targeted use in the future.