Multiples of Multiple Myeloma

Last post I made a bad joke about matcha and myeloma, so I figured that I would continue this week. However I don't have any good puns right now, but once I have some tea'd up, I'll let you know. See what I did there? Just call me Shakespeare 2.0. Speaking of 2.0, the patient is a 60 something woman with relapsed multiple myeloma (rMM) after a stem cell transplant (SCT). 

So now everyone knows what MM is from my last blog post but what about when it comes back? It is a sad truth that many, if not all, cancers that relapse are more aggressive and resistant to therapy. For a widely dispersed malignancy such as MM, this is no different. So most patients have their SCT then go on an immunomodulatory drug like lenalidomide. Now what? Another SCT can be an option for some of these patients, following a similar model of the first, if the relapse is more than 12 months out. If less than 12 months, typically get varieties of chemotherapy that they have not used in the last round. 

After that, salvage therapy or possible allogenic SCT are on the table. For salvage therapy, three or four drug regimens are the most effective and commonly used. The patient in the opening was on doxorubicin, cisplatin, etoposide, cyclophosphamide, and probably others outside of the brief time I was on her care team. For most of the recommended regimens, there is a monoclonal antibody, steroid, proteasome inhibitor, more traditional chemo drug, and/or, immunomodulatory drug. Chimeric antigen receptor T-cell therapy is the final bullet in the gun after those options have been exhausted. 

Speaking of exhausted, I just learned about T-cell exhaustion and senescence and how the effect ongoing immune responses to cancers. Specifically hematological malignancies, since they naturally effect blood and cells related to the production or maturation of blood cells, can cause this effect to accelerate. Ok John, what is the effect? 

Exhaustion is just what it sounds like, and honestly senescence is very similar. So in the resources there is a great article breaking down the differences between the two. In simplified terms that I can understand, both have to do with the continued activity and replication of the T-cells in response to disease. This was first reported in chronic viral infections but is seen in other conditions as well. For exhaustion, continued stimulation leads to decreased proliferation, in senescence it is the excessive replication plus DNA damage that leads to the decreased proliferation. Both also have different mechanisms and genes that go wrong, those which would normally prevent this from happening, which means each may have different targets for therapies. 

Regardless of the path taken, it leads to a more ineffective immune system which means less activity against said cancer or infection. In other words, reduced cytotoxicity. However, they also increase reactive oxygen species which can lead to more cellular damage and inflammation causing a negative feedback loop. So I’m short, ain’t no good. Want some icing on the cake? This also leads to decreased overall immune function that’s to the jacked up T-cells. Fun. 

Overall, that being said, now I (and maybe you) learned something. I now have more ideas for posts, like the role of immune therapy to target the dysfunctional cells. I know that is the point but what else does it do? How do these beat up cells get turned back on? Anyways, that’s for another time. I really do find this interesting and seeing it in actual patients is sad and motivating at the same time. Sad of course given the human cost, but motivating in that as time progresses, people smarter than I will give us the tools to fight better against these diseases. 

Love y’all, bye. 

References 

Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment by Zhao et al., in Cancer and Molecular Immunology 2019

Image of MM cells from Pathology Outlines

Multiple Myeloma section from Medscape

Multiple Myeloma Relapse Following Autologous Stem Cell Transplant Presenting With Diffuse Pulmonary Nodules by Sumrall et al., in the Ochsner Journal 2013

Relapse after Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma: Survival Outcomes and Factors Influencing Them by Chhabra et al., in the journal Biology of Blood and Marrow Transplantation 2022

T cell exhaustion in multiple myeloma relapse after autotransplant: Optimal timing of immunotherapy by Chung et al., in Cancer Immunology Research 2015