The importance of NF-kB pathway in myeloma

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Published: 3 Dec 2018
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Dr Nizar Bahlis - University of Calgary, Calgary, Canada

Dr Nizar Bahlis speaks to ecancer at ASH 2018 about the results of the TOURMALINE-MM1 study and the use of proteasome inhibitors.

He explains that the study compares lenalidomide‑dexamethasone with a combination of lenalidomide‑dexamethasone and ixazomib in relapsed/refractory multiple myeloma patients with the combination arm superior in showing improving progression free survival.

Dr Bahlis acknowledges the importance of the NF-κB pathway and that patients with an activated non-canonical NF-κB pathway saw the best benefit from the ixazomib and lenalidomide‑dexamethasone combination.

He also discusses the use proteasome inhibitors (PIs) as a treatment for multiple myeloma patients and the benefit of PI maintenance.

This programme has been supported by an unrestricted educational grant from Takeda.

The TOURMALINE-MM1 study was a randomised phase III trial comparing Revlimid/dexamethasone, which at that time was the standard treatment for relapsed multiple myeloma patients. The active arm or the testing arm was the same regimen in combination with ixazomib which was the first oral proteasome inhibitor. So comparing again ixazomib/Revlimid/dexamethasone with Revlimid/dexamethasone, looking at improvement in progression free survival and obviously response rate as well as overall survival.

What is the importance of the NF-κB pathway?

The NF-κB pathway has been known to be an important pathway in all malignancies. In particular in multiple myeloma studies have demonstrated for several years the NF-κB pathway can be activated whether the canonical pathway or the non-canonical pathway. This gained a particular traction with the advent, or the availability, of proteasome inhibitors because one of the ways you regulate the NF-κB pathway is through regulating the stability of a protein called IκB which the inhibition proteasome allows it to be stable and then inhibit the NF-κB pathway.

Also in a particular subset of myeloma, especially high risk myeloma with translocation (4;14), it’s known to have high NF-κB activity.  Again, NF-κB is a transcription factor family so it drives the gene expression and multiple oncogene expression and it’s important to inhibit that pathway.

What was the patient population that was studied?

Basically relapsed multiple myeloma with 1-3 prior lines of therapy were offered this regimen. Again, the typical standard relapsed myeloma population after first line therapy.

What were the primary results from the TOURMALINE-MM1 study?

The TOURMALINE-MM1 study was already published and presented a couple of years ago now. It clearly showed improvement in progression free survival in favour of the ixazomib/Revlimid/dexamethasone arm. The benefit was seen across all subgroups. Importantly, what was seen in that study that high risk myeloma patients, patients with deletion 17, translocation (4;14), translocation (14;16), did have the same outcome as patients with standard risk myeloma. This result still intrigues everybody and this has also been proven in multiple sub-analyses, that high risk myeloma did equally benefit as standard risk myeloma from this combination.

What did the results show in patients with tumours harbouring a constitutively activated non-canonical NF-κB pathway?
That’s very interesting because at this meeting the Takeda Group, in collaboration with many physicians on this study, did go back to look at what subset of patients did benefit the most from adding ixazomib to Revlimid/dexamethasone. Luckily on this study they did collect bone marrow samples on these patients and they performed whole transcriptome analysis with RNA-Seq as well as exome sequencing. So they had the ability to go back and interrogate the transcriptome of these tumour cells to see what subset did benefit the most.

They found basically patients who have activation of the non-canonical NF-κB pathway did reap the most benefit and significantly benefitted from adding ixazomib to Revlimid/dexamethasone. More importantly, these patients did very poorly, as we expect them to do, when they have an active NF-κB pathway from using Revlimid and dexamethasone alone.

So in particular in this study, at the presentation at this ASH meeting, they examined NF-κB activation using variable tools. The first one was looking at the gene called TRAF3. TRAF3 is mutated in myeloma patients, especially in patients with translocation (4;14) and they found those patients that have low TRAF3 expression or levels did benefit the most from adding ixazomib to Revlimid/dexamethasone or performed poorly with Revlimid/dexamethasone alone. The other subset of patients that also have a mutation in a gene called Nyk. Nyk also regulates the NF-κB pathway and those who have an activating mutation in Nyk also benefitted from using ixazomib, or adding ixazomib to Revlimid/dexamethasone.

Lastly, there is a score known as the NF-κB score which takes into account the level of ten genes involved in activating the NF-κB pathway. This score has been validated by previous work from Jonathan Keats and Leif Bergsagel. Using this NF-κB score index they also very nicely showed that those who have the high NF-κB index, again reflecting activity of the NF-κB pathway, did benefit from adding ixazomib to Revlimid/dexamethasone.

So, yes, very exciting results to show that a particular subgroup of myeloma known to have poor outcomes did benefit from adding ixazomib to Revlimid/dexamethasone.

Following this study, how do you perceive proteasome inhibitors (PIs) being used to treat multiple myeloma patients?

Proteasome inhibitors biologically made the most sense to use in multiple myeloma. As we know right now, the way proteasome inhibitors work by taking advantage of the stress within the myeloma cells, within what we call the ER or the endoplasmic reticulum of the myeloma cells. Myeloma cells by nature make a lot of protein and they rely highly on the ability of the proteasome to recycle these proteins and minimise the stress on the endoplasmic reticulum. What proteasome inhibitors do by blocking that back-up machinery that recycles proteins, they increase the stress in the myeloma endoplasmic reticulum and that results in cell death.

So clearly biologically proteasome inhibitors make complete sense to be used in this disease and, as expected, various clinical trials demonstrated their efficacy in treating myeloma patients. So they clearly are one of the backbones to treat myeloma patients.

What is the position of PIs in the multiple myeloma treatment pathway?

Proteasome inhibitors are basically now used across the board with myeloma. They’re clearly now used in the front-line regimen, whether it’s the VRD or the XRD. They’re used in the relapsed setting and at this meeting we heard about the TOURMALINE-MM3 trial, also demonstrating a role for ixazomib as a maintenance regimen. So proteasome inhibitors are, again, one of the pillars along with immunomodulators used across all the disease stages in myeloma, whether up front, relapsed and even maintenance right now as well.

What is the benefit of PI maintenance?

As we said earlier, the phase III TOURMALINE-MM3 trial presented at this meeting that examined the role of proteasome inhibitors as a maintenance regimen in myeloma. Until today we had some small studies or some suggestions from subgroup analyses of other trials such as the HOVON trial suggesting that proteasome inhibitors in maintenance have a role to play, especially in patients with high risk disease. The current study with the TOURMALINE-MM3 did demonstrate in a large, randomised phase III trial that, yes indeed, using PI maintenance does improve the outcome compared to no maintenance regimen. The implication for that, moving on, that we have now a randomised trial supporting the evidence for PI as maintenance and likely we’re going to see future use likely in combination with IMiDs in maintenance, especially in high risk myeloma.

Why do we need long-term disease control, especially in patients with non-canonical NF-κB activation?

Long-term disease control is extremely important in myeloma. As of today, we cannot claim that we have cured anybody with multiple myeloma in the pure sense of the term cure. But we clearly know those who achieve long, durable responses have the best outcome, whether it’s sustained MRD or sustained complete remission or even what we used to refer to as putting the patient back into an MGUS state with a plateau phase. So durability of response in myeloma is extremely important, especially for those who have high risk disease because what we have seen until today with the high risk disease, it tends to respond initially very quickly but the disease does relapse very, very rapidly. So, having the means or the tools to allow us to maintain the deep response we achieve after initial induction therapy is extremely important, it has a prognostic implication for survival of the patient.

How do we identify patients who are suitable for this treatment?

Overall ixazomib can be used across all myeloma subgroups but the particular result presented at this meeting regarding the NF-κB activation, if one is to focus on this subset, can be done through variable assay. This study the analysis was done from RNA-Seq data, again sequencing the transcriptome of myeloma cells but I can envision in the future it can be done easily on a small panel, whether done through NanoString technology or, again, through a designed targeted panel sequence where you measure the copy number or the level of this transcriptome and use this assay as a screening method. So it can be easily applied in the clinics in the future.