What treatments are available for first relapse with lenalidomide refractory disease?

What treatments are available for first relapse with revlimid or lenalidomide refractory disease?

So revlimid or lenalidomide is the, generic name is an immunomodulatory drug. And it is part of a class of, drugs that we use very commonly in myeloma. It's convenient because it's oral. And it works by activating the immune system. It's brothers and sisters are pomalidomide and thalidomide. So they are also in the same class. Some patients who are resistant to lenalidomide, may not be resistant to pomalidomide or thalidomide. And so there is an option to switch out to a, similar, type of drug. However, my general recommendations are to change to the different class of drug if the, current class is not working. So it's a hard question to answer without knowing the patient's history, but if the patient hasn't received a proteasome inhibitor or hasn't received a monoclonal antibody against CD38, I might recommend then switching to one of those different classes of therapy, because it's less likely that the tumor has had resistance to that class.

So, for example, I might give pomalidomide, daratumumab, dexamethasone in a patient who is resistant to lenalidomide. Or I might give daratumumab, carfilzomib, dexamethasone to to that patient. There's also some exciting new therapies that have recently been approved, after the first relapse. And one of those is CAR-T cell therapy. So this can now be given earlier on in the, in the disease course, which I think is particularly important since, the CAR-T cell therapy depends on functional T cells to work well. these are T cells that have not been exposed to multiple lines of therapy and are probably healthier and more capable of doing a better job.

Of course, patients could also consider an autologous stem cell transplant. It's a more aggressive approach, but it certainly is an option. there is new data that's recently emerging that is starting to indicate but a second autologous stem cell transplant may not be very beneficial in the current era of modern therapy. So at this point in time, I'm not sure that giving a second transplant is really the right choice for everyone. I think it's very important that a patient have a long discussion with their doctor and transplant expert. If it's to discuss if a second transplant would really be beneficial.

Are there any targeted therapies that may be considered at first relapse?

We would evaluate their FISH testing to see if they have translocation 11;14 if so, we might consider Venetoclax, which is a drug that does particularly well. And that subtype of myeloma Note that Venetoclax is not currently approved by FDA for treating myeloma.

Is CAR T-cell therapy in the second line the best option for everyone?

doing a CAR-T for second line is probably not best for everyone. CAR-T cell therapy is complex, expensive, and a bit time consuming. It can take several weeks to generate the Car T-cell therapy, which sometimes patients don't have, and we need to make quick decisions. It's also not available at all cancer centers. So, it's important that a patient who's in that first relapse seek a second opinion at an academic institution where they have lots of available, clinical trials as well as, options for CAR-T cell therapy in addition to their primary oncologist when making a decision about the next line of therapy.

I think there our standard here in the US, or at least for sure our standard here at MSK, right, is to, treat patients, after their initial therapy with, maintenance, lenalidomide. So upon and so maintenance, lenalidomide is a lower dose of lenalidomide than we might use an induction typically in our case, it's ten milligrams, administered daily, 25mg being the typical, full dose, of lenalidomide. So when patients progress, at, maintenance, you know, one can consider them, lenalidomide, refractory. And in that situation, agents, using pomalidomide, a cousin of lenalidomide, in combination with, one of the anti CD38 antibodies, either Daratumumab or isatuximab. Those those can be used or alternatively, proteasome inhibition, with carfilzomib can be used also in combination with one of the anti CD38 antibodies.

So currently those are probably the two combination mechanism of action that we routinely will use in some instances depending on the qualities of the relapse. There are other, monoclonal antibodies. So one can use Anti-SLAM7F antibody elotuzumab in combination with full dose lenalidomide. And sometimes one can see, response to that as well.