What is the Role of P53 in Deciding a Treatment Approach for Relapsed MM?

At the 2019 Lymphoma & Myeloma Congress, Shaji Kumar, MD, Mayo Clinic, Rochester, Minnesota, discussed the role of the P53 gene in deciding the best treatment approach for patients with relapsed multiple myeloma (MM).

Transcript

My name is Shaji Kumar. I'm a consultant in hematology at Mayo Clinic in Rochester, Minnesota.

Multiple myeloma is a very heterogeneous disease with very different outcomes between patients, which is mostly defined by the presence of various cytogenetic abnormalities.

Over the past decade, initially because of uniform use of FISH, or fluorescence in situ hybridization, we got a better sense of the genetic abnormalities in myeloma and realized that nearly all patients have some or other genomic abnormality in the myeloma cell.

In the past few years, we have used next-generation sequencing approach and other more advanced genomic technologies, which have allowed us to get a better understanding of not only the genome but also the epigenome in myeloma.

The understanding that the majority of patients with myeloma and, for that matter, even those with smoldering myeloma or monoclonal gammopathy of undetermined significance already have some genomic abnormalities in the form of mutations, tells us how this disease evolves over time and how it manages to become refractory and resistant to the various therapies that we use for myeloma.

There are few recurring mutations that we always see in the plasma cells in the spectrum of myeloma disorders, the most common of which includes mutations of the RAS, NRAS and KRAS.

P53 is a gene that has fascinated oncology researchers for a long, long time. The human body is a marvelous machine with a variety of different checks and balances, and the P53 gene plays a pivotal role in making sure the cells that are damaged in the human body are eliminated appropriately and they don't grow aberrantly.

For instance, which we don't fully understand, in all cancers we can see mutations involving the P53 gene that can significantly alter the clinical outcome. Myeloma is no different. In myeloma we see not only mutations, but more commonly we actually see deletions involving chromosome 17, the short arm of which carries the P53 gene.

In about 7-11% of patients with newly diagnosed myeloma, we can see either complete loss of chromosome 17 or loss of the 17P, which is the short arm, leading to loss of one of the locus of the TP53 gene. In some patients, both the chromosomes 17Ps can be lost, which can lead to loss of both the copies of the gene.

More commonly, what we see is that the remaining TP53 gene on the 17P is mutated in patients who already have a deletion of one of the 17P short arms. What does it mean from a clinical standpoint?

What we have seen is that patients who either have the loss of the TP53 gene or mutations involving the TP53 gene have a clinical course that is more aggressive. They do tend to respond to the treatments we use, but the treatment responses usually last very short periods of time, and they become refractory to the treatments very soon.

These patients have median overall survival of less than 3 years compared to 8-10 years for the remaining patients with myeloma who don't have high-risk cytogenetic abnormalities. Me and others have studied this phenomenon both at the time of diagnosis and also have tried to understand why patients develop these mutations and deletions.

It seems that patients who have high-risk genomic abnormalities are the ones who are more likely to develop these abnormalities later on in the course of the disease, suggesting that there's an unstable genome at the heart of developing these TP53 gene-related abnormalities.

What we have also seen is that the mutations are almost always seen in patients in whom the myeloma cell have already lost one of the copies of the gene through a deletion or monosomy 17.

The mutation on top of the deletion leads to a complete loss of the TP53 checks and balance that the myeloma cell has leading to increased proliferation and expansion of the tumor clone, which then is resistant to the available therapies.

How do we manage patients with the P53 deletion or mutation? In the clinic today, mutation panels are not common, so most of us only can identify the presence of a 17P deletion or monosomy 17, which can be a surrogate marker or at least identify the patients who are more likely to be carrying the mutation as well.

Studies have shown that the real prognostic effect of the TP53 loss is actually when patients have a mutation on top of a deletion. Patients who have these abnormalities need to be dealt with differently than how we treat patients with standard risk myeloma.

The way we can tailor therapy for these patients is by either using specific groups of drugs or specific combinations or specific approaches like transplant and tandem transplants. In terms of the specific drugs, what we have seen is the proteasome inhibitors appear to provide a benefit for patients with the 17P or TP53 abnormalities.

What we have seen is patients who get bortezomib-based therapy, as part of the initial therapy or often in the context of stem cell transplant, and then maintenance with bortezomib appears to decrease the poor effect of the P53 abnormalities in these patients.

Similarly, what we have seen is if you use combinations of multiple drugs, this patient seems to do better. Studies from single institutions have shown that if you use a maintenance therapy that consists of bortezomib, lenalidomide, and dexamethasone, after an autologous stem-cell transplant, this patient seems to have better outcome than what we have historically observed for these patients.

More recently we have started looking at different approaches. One is to try and target minimal residual disease negativity by changing therapy in some of these high-risk patients.

What we have seen is that patients with 17P abnormalities had the best outcome when they get to be MRD-negative, whether it is achieved through multi-drug combinations or by use of approaches like tandem autologous stem-cell transplant.

At the same time, we are also trying to explore the possibility of interfering in the biology of this abnormality. In patients who have lost one of the copies of the TP53 gene, we and others have hypothesized that we can use drugs that are called the MDM2 antagonist which can enhance the activity of the remaining TP53 gene and, hopefully, can overcome the effect of the loss.

This is being explored in clinical trials right now. We don't know if it's going to work. We also don't know if it's going to work if the patients have a mutation in the TP53 gene on the remaining allele.

There's clearly much more that needs to be learned, but the increasing ability to look at individual cells and also look at not only genomics, but also epigenomics, metabolomics, and proteomics in these myeloma cells will allow us to figure out the best way to treat patients with abnormalities of the TP53 gene whether it's a loss of the gene or a mutation in the gene.