What drugs are available in the induction setting? Is there an optimal induction therapy?

Starting treatment for multiple myeloma can feel overwhelming, but it's important to know that you are not alone.

Treatment is a personalized journey, often involving a combination of medications. And your care team will tailor your plan to fit the characteristics of your myeloma.

Ask your doctor about treatment options, possible side effects, and how this might affect your day to day life.

In this Health Tree University lesson, you'll learn what myeloma specialists consider to be the most effective approach to induction therapy.

Is there an optimal induction therapy for treating multiple myeloma?

we have three major classes of drugs. So I should say four, I guess there's cd38 antibodies. These are monoclonal antibodies target a protein called cd38 that's present on myeloma cells. There are two FDA approved drugs that target cd38. One is called daratumumab, the other one is called isatuximab. Then we have proteasome inhibitors. These are another class or mechanism of drug.

And there's three FDA approved proteasome inhibitors. There's bortezomib. There’s ixazomib and there's carfilzomib. And then we have immunomodulatory drugs which are yet another class of treatments. And again there are three FDA approved options there thalidomide, lenalidomide and pomalidomide. And finally we have steroids which is dexamethasone. So those are the four classes of drugs very early on.

We know we're talking about about 20 years back when you were had patients with newly diagnosed myeloma, it was an option to potentially only use two of these four classes of drugs. So for instance, lenalidomide and dexamethasone.

And daratumumab was not even available 20 years backwards 88 antibodies were not available.

Over a period of time, clinical trials were done which showed that actually giving patients three drugs.

And again, daratumumab was not part of the picture then. So a proteasome inhibitor like bortezomib or carfilzomib when the combination with lenalidomide mostly, which is the immunomodulatory drug, and dexamethasone was found to be superior or better compared to just giving patients two drugs. So around 2010 to 2014-15, in the about 10-12 years back, it became standard of care for most newly diagnosed myeloma patients to be treated with a combination three drugs.

So the obvious next question when daratumumab and isatuximab came into picture was if three is better than two, perhaps four is better than three.

And now in the last two years, we have multiple multiple large randomized clinical trials that have looked at combinations of four drugs, that is adding either daratumumab or isatuximab to the three drug combination compared to just the three drug combination.

And what has been shown in each of these large studies is that adding a CD 38 antibody to the backbone of the three drug combination improves response rates. That is, more patients respond and importantly, more patients have complete responses. It improves what is called as progression free survival. That is the time before which the disease comes back or patients have other adverse outcomes is significantly longer with the combination of four drugs compared to three drugs, the follow up is not long enough to know yet as to fully whether that also translates to overall survival, that is, patients living longer, period.

But there's at least some hints from the earliest of these studies that perhaps the overall survival will also likely be longer. With the combination of four drugs versus three.

Some of the nuances of this were the first studies in this space were done in patients were considered as transplant eligible. That is, patients were going to get a bone marrow transplant or stem cell transplant.

These patients tend to be younger, better health and fewer comorbidities. Other diseases in that setting, it was clear that four drugs were better than three drugs.

The concern as we go to older patients, let's say, or patients with some co-morbidities, or patients who we don't think are transplant candidates because they have other issues, is that maybe the addition of four drugs adds to toxicities.

And one benefit you might see is it negated by the adverse effect of adding the four drug.

And so in the last year or so, there have been at least a couple of trials that have shown that even in transplant ineligible patients, the addition of the fourth drug either isatuximab or Daratumumab, can improve these clinical outcomes without a significantly increased risk of toxicities.

What is yet unknown is that the truly frail patients, that is, patients who have multiple medical issues, the patients who are older than 80 years, who are not included in these trials, or, patients who have other medical issues, cardiac, kidney, liver issues in those patients. It's not yet clear that the benefits outweigh the risks for adding the four drug, but otherwise the broad majority of patients where I would consider maybe 80 to 90% of people who are diagnosed with multiple myeloma should be considered for a four drug combination, as opposed to three drugs.

Given the significant amount of data we now have from multiple trials suggesting that a four drug combination is superior to three drugs.

Which four drugs should be considered.

there's good data now for both adding daratumumab and isatuximab to the backbone of three drug combinations. That's based on multiple trials for both transplant eligible and transplant ineligible patients showing benefit in terms of the proteasome inhibitor. The two choices are carfilzomib and bortezomib. Most of the data we have is with bortezomib, but there's also some data at least suggesting that carfilzomib may be equivalent but with different side effect profiles.

Less neuropathy, which we see with bortezomib, perhaps more cardiac toxicities with carfilzomib. So different side effect profiles. Similar efficacy. So it's a reasonable option to try both bortezmob or carfilzomib as the partner for proteasome inhibitor. And in terms of immunomodulator drugs, almost all of the data is with lenalidomide and dexamethasone of course is the steroid that's used in all of these studies.

So different permutations and combinations, the choices would be which proteasome inhibitor to use carfilzomib or bortezomib. Again most of the data is with bortezomib. But depending on side effect profiles, doctors and patients may choose one or the other. With the Cd38 antibodies there’s isatuxmiab and Daratumumab. Again, there's no head to head comparisons between the two.

Both are quite effective. Both have somewhat similar safety or side effect profiles. But isatuximab is still given as an IV infusion, daratumumab is given as a subcutaneous injection, it’s a little faster.

So there may be some logistical considerations to picking one versus the other. But there's unfortunately no head to head comparisons between two different four drug combinations, for instance.

So some of this will boil down to feasibility logistics side effect profiles, patient preference, physician preference, etc.. But I think in general, a four drug combination for patients who are younger or older but in good health would be preferred over a three drug combination with newly diagnosed myeloma

What is the optimal dose of dexamethasone? Can it be decreased over time?

Before we had all these drugs we talked about dexamethasone was really one of the most effective myeloma treatments. That was not saying much because it was not highly, highly effective. So back in about 25 years back, if you had patients with multiple myeloma, the standard dose of Dex was 160mg a week. That's, four times the dose that is now given at least four times the dose that is now given.

So and many of you may know this, but about 20 years back, a patient who had multiple myeloma prompted his doctors to run a clinical trial because dexamethasone at those very high doses, 160mg is actually very difficult to tolerate.

And so a patient actually asked his doctor, could we test a lower dose of dexamethasone? So Doctor Vincent Rajkumar ran this study with ECOG, a large national cooperative group, where they tried 160mg of dexamethasone versus 40mg of dexamethasone with lenalidomide.

So both patient groups of patients got the same dose of lenalidomide. The only difference was high dose dexamethasone, which was 160mg or low dose dexamethasone which is 40mg.

And what they saw, what the outcomes were no different patients who got 40mg did as well as 160mg, but with much fewer side effects. And therefore it has now become the standard to do 40mg.

That was this study was done in the early 2000, 2008, 2009. Since then, obviously we've had many more treatment options when the obvious question now is do we even need 40mg? So can we do with less? Because of how many different new drugs have been available? There's not a lot of prospective randomized clinical data, but many of us feel comfortable saying that you probably don't need 40mg for a very long period of time.

After 1 or 2 cycles, he could probably lower the dose to 20 or 10.

There's at least some trials now coming out of France, for instance, where you could even potentially stop the dexamethasone altogether after the first couple of cycles or so.

So at our practice here, for younger patients, we start with 40mg. For somewhat older patients we would start with 20mg would have a very low threshold to start lowering the doses of dexamethasone because we don't think the efficacy of dexamethasone, particularly in these four drug combinations, is necessarily very high.

There's certainly both short term and long term toxicities to steroids. So with that being the case, dialing down doses of steroids to 40 to 20 to ten to even lower doses, depending on side effects, is something that we and others are doing quite routinely now for patients with newly diagnosed myeloma.

If an individual is not planning to have an autologous stem cell transplant, is there a switch to a maintenance like phase where the four drug induction combination is decreased?

Is it based on maximum response or a specific number of cycles?

I would say for most people the point of maximum response is usually about 6 to 8 cycles, which is also usually the number of cycles I would plan on doing. So I would say typically for most patients, if they're not proceeding with transplant, we would do maybe six or anywhere from 4 to 8 cycles, let's say.

And that would partly depend on side effects. It also depends on how the patients are tolerating their treatments. And as you said, what is the depth of response for people who have a very early deep response? We may be able to stop sooner. For patients whose numbers are continuing to go down, we may continue on beyond, six or four, 6 or 8 cycles.

But rarely do we go beyond eight cycles. I would say, for that initial induction.