Small Molecules Making a Resurgence in the Treatment of Multiple Myeloma

Cesar Rodriguez Valdes, MD

Cesar Rodriguez Valdes, MD

Small molecules are not new to oncologists who treat patients with myeloma, as they have existed in the space since the 1960s. However, new classes of small molecules are emerging and offering better responses and quality of life in patients with myeloma.

Now that studies have established many of the newer small molecules, like selinexor (Xpovio) and melflufen, the next step will be to combine them with other therapies for optimal outcomes. Small molecules alone are not likely to bring patients into complete remission, says Cesar Rodriguez Valdes, MD. However, when paired with either immunotherapy, vaccines, or chimeric antigen receptor (CAR) T-cell therapy, oncologists may see durable responses in their patients.

In an interview withTargeted Oncologyfollowing a presentation at the Charlotte Plasma Cell Disorder Congress, Valdes, assistant professor of hematology and oncology and director of the Myeloma Program, Wake Forest School of Medicine, explained how small molecules fit into the myeloma treatment and notes the ongoing research that shows promise for the next class of small molecules in the future.

TARGETED ONCOLOGY: Can you provide an overview of your presentation?

Valdes: My talk focuses on where we're headed with small molecules. I covered all the things that are in the research pipeline. I discussed some of the established classes of treatment like protease inhibitors, alkylators, immune modulators, and histone deacetylase (HDAC) inhibitors that are in the pipeline.

[I also touched on] new classes, specifically nuclear export inhibitor, which is a new class of drugs that has been approved for myeloma. Then, I talked about heat shock protein, tyrosine kinase inhibitors (TKIs), and where we're heading in terms of exploring other small molecules in myeloma. 

TARGETED ONCOLOGY: With new small molecules emerging, how do they fit into the paradigm for myeloma?

Valdes: Small molecules are a treatment for myeloma that has existed since the [the 1960s] with melphalan (Evomela), which is considered the first small molecule that was used for myeloma, to the most recent one, selinexor (Xpovio), which was approved just last month.  

All the treatments that are being used in myeloma, the majority of them that are not immunotherapy are considered small molecules.

We've had a great evolution in the last 20 years in terms of what we have available for treatment. [Since 20 years ago when we had just a few options of treatment, a whole new class and new generations of drugs have appeared that we can use]. They are more effective and have translated into a better quality of life and overall survival for patients with myeloma.

Going forward, we're still exploring these classes of therapies and trying to find new molecules that we can use that will be more effective at controlling the disease while reducing the [adverse effects associated with] these treatments. Hopefully, this will give us a better aim for controlling or curing the disease.

We do know that a small molecule is not going to be the one thing that will do the trick. But, combing the small molecule therapies with immunotherapies, vaccines, or CAR T-cell therapy is probably going to be the best way of going forward in how we treat myeloma. It's going to be a team effort. It's not going to be one type of therapy that will work. I think we're going to have to get creative and combine what we know with what's coming—like immunotherapies, vaccines, and all these novel therapies—and find a nice balance between them so that we can keep people in remission.

TARGETED ONCOLOGY: Which small molecules are the most significant in the treatment landscape for myeloma patients?

Valdes: I focused a lot on the small molecules that we've had the most research on and one of them would be melflufen. It is surprisingly an alkylator, similar to melphalan. It would seem like this is obsolete at this point, but it's wanting to do a comeback. [I also spoke about] new derivatives of alkylators and combing them with either HDAC inhibitors or just a different variant of melphalan itself. I also talked about TKIs and the emergence of the use of Ibrutinib (Imbruvica), for example, in clinical trials and how that factors in with myeloma. 

There is data right now from Paul Richardson, MD, on using ibrutinib as a single-agent and that has shown promising results which have led to the combination of ibrutinib with other established agents like lenalidomide (Revlimid) and dexamethasone or with pertuzumab (Perjeta) and dexamethasone. Those are studies that are ongoing and, unfortunately, we don't have data yet. Hopefully, we will have some preliminary data in the next year so that we determine if this is something we should focus on more seriously. 

I also talked about BCL-2 inhibitors and how venetoclax (Venclexta) was this promising drug that has now been put on hold temporarily. [It is now trying to do this] resurgence and I discussed how we can fit this in the landscape of management. 

I talked about the future of heat shock proteins and Bruton tyrosine kinase (BTK) inhibitors to see in what direction that is heading and if there is a niche for this type of therapy in myeloma.

TARGETED ONCOLOGY: What role do you think BTK inhibitors play in this paradigm?

Valdes: We know that BTK inhibitors have played a role in solid tumors. There is a role in myeloma in term of inhibiting some of the BTKs that are specific for myeloma. That is the one area that shows promise for the future.

These molecules that we're studying right now are not for the general myeloma populations. It is for [subgroups] of patients that might have certain mutations, alterations, or characteristics that would make them more sensitive or prone to [respond to] this therapy. It's generally going to be something that we're going to be seeing more of in the next year and hopefully, that will define what [subgroup of patients can benefit from this form of targeted therapy].

TARGETED ONCOLOGY: What research exists on the new classes of small molecules?

Valdes: There's been an interesting perspective now that we have the ability to understand the biology of myeloma better and we can do genome sequencing. We've been able to identify certain mutations or targets that we can use for managing myeloma. Some of the drugs and small molecules that have been used in solid tumors and that physicians are very experienced with but have never been explored in myeloma, we are now starting to explore them. We're trying to understand if there is a role for these therapies in myeloma.

[There have been some failure and some successes, but trial and error are all a part of research]. In the next year or 2, we'll be seeing a lot about new classes of drugs that are going to be presented in upcoming meetings and [we’ll see how they'll be relevant to myeloma].

TARGETED ONCOLOGY: What combinations are currently being explored with small molecules?

Valdes:Currently, there are studies that are combining small molecules with other therapies. These studies either have new agents combined with established agents, normally combining them with another protease inhibitor or with an immune modulator and a steroid. But there are also ongoing studies combing small molecules with vaccines, especially in the smoldering myeloma setting. There's also the interest of trying to combine CAR T-cell therapy with some small molecules as maintenance therapy or something to boost the effectiveness of the treatment so we can have durable, lasting effects. [This will prevent us from] dealing with the problem that we're having with immunotherapy right now where amount of response [is limited] to a year or over a year and then we are starting to see some failures in the therapies. 

So, hopefully by combining the new therapies and immunotherapies with small molecules we can achieve synergy and keep all of the remissions or the responses lasting longer.

TARGETED ONCOLOGY: What would you like community oncologists to take away from your presentation on small molecules?

Valdes: Small molecules are not an obsolete thing. There are a lot of drugs that in the pipeline, many of which I didn't have time to discuss during my presentation. Many options are going to come out and hopefully be FDA approved in the coming years. [These drugs] will allow patients to have more therapy, hopefully with less toxicity and better responses. These are going to be therapies that can be used as bridges to immunotherapy or in combination with immunotherapy.