Oral Oncolytic Treatment Options for Multiple Myeloma

Peter Salgo, MD: OK, so what are we talking about now? What are the oral oncolytics? How do you use them in the sense of first-line, relapse, refractory drugs? Maintenance therapy. Give me some names and let’s go through them.

Noa Biran, MD: So the most clear-cut and the most widely used category and class of drugs are the immunomodulatory drugs, the IMiDs [immunomodulatory drugs], and those include an older drug called thalidomide, which was the drug given.

Peter Salgo, MD: Can we stop right there—thalidomide.

Noa Biran, MD: Thalidomide.

Peter Salgo, MD: I can hear people’s heads exploding, of a certain age. Because back in the 1960s that was a drug of ill repute.

Noa Biran, MD: This was a drug that was accidentally found to work for multiple myeloma, and it was. It was a drug used for women who had nausea with pregnancy, and as we all know, the baby came out with severe, severe deformities.

Peter Salgo, MD: It was teratogenic.

Noa Biran, MD: And limb deformities. Limb deformity that was extremely teratogenic. So that drug was the first IMiD used for multiple myeloma. Later on lenalidomide was approved, or Revlimid, and then we have a more potent version of lenalidomide, pomalidomide, which is the third IMiD and the newest IMiD that was used. Another category of drugs is a new oral proteasome, proteasome inhibitor, which is descendant of bortezomib, or Velcade, which is the injection. So that one is Ninlaro, or ixazomib, and we also have an oral histone deacetylase inhibitor called panobinostat, or Feridex.

Peter Salgo, MD: OK. Now I heard at least 1 “myb” in there. So some of these oral agents are actually biologics. Right?

Noa Biran, MD: Yeah. Exactly, they all almost.

Peter Salgo, MD: Wow. Oral acting biologics.

Noa Biran, MD: Yeah.

Peter Salgo, MD: This is all exciting stuff.

Noa Biran, MD: Yeah, it’s all exciting. And they are used throughout the entire course of treatment.

Peter Salgo, MD: So you use them to induce, you use them to maintain, do you use them for relapse?

Noa Biran, MD: Yes.

Peter Salgo, MD: Can you just sort of quickly run down which drugs are used for what?

Noa Biran, MD: The -imide... the Revlimid, and the pomalidomide are, for the most part, a backbone of almost every treatment regimen. So they are part of induction. There’s lenalidomide maintenance, and then in the relapsed setting almost all regimens involve an IMiD, and the rest of the drugs are kind of and add-on to the IMiD backbone.

Peter Salgo, MD: So let’s talk about safety. Let’s talk about, oh, I guess, convenience, efficacy. How do the oral oncolytics compare to the older parenteral drugs in terms of all of this? Are they safer, less safe, the same, what?

Cheryl Allen, BPharm, MBA: Well the newer drugs are targeted therapies, but they’re used in combination, right? So we use NCCN [National Comprehensive Cancer Network] as the guideline and for drug therapies. NCCN is continually updated. I went back to look at what we were using for training in October, and it’s changed just in 4 months.

Noa Biran, MD: It changes it all the time.

Cheryl Allen, BPharm, MBA: What categories 1 will be.

Peter Salgo, MD: Just when you thought it was safe to go back in the water, hey?

Cheryl Allen, BPharm, MBA: Right, right. But lenalidomide is, it continues to be category 1A, so we use lenalidomide in combination for maintenance as well as some of the primary therapies.

Peter Salgo, MD: Given that you can use them together, given that this is not binary, what are the advantages and disadvantages of the oral agents versus the parenteral agents?

Noa Biran, MD: So the obvious one is convenience, right? When you’re a cancer patient who has a chronic disease, do you really want to be coming in to your physician’s office once a week, every other week, once a month even for an infusion? No. So they offer the advantage of convenience. They can be taken at home, which also presents a whole set of issues in itself because you have to make sure the patients are taking it correctly. You have to make sure the blood counts don’t drop. You have a little bit less supervision.

Peter Salgo, MD: I was about to say that 1 of the advantages is the inconvenience of the parenterals, which is you’ve got to show up, right?

Noa Biran, MD: Right.

Peter Salgo, MD: Someone’s got to look at you. Someone’s got to, probably if they’re going to give it to you via IV [intravenous], get some blood and check your white count, and check a whole bunch of other stuff.

Noa Biran, MD: Yeah.

Peter Salgo, MD: So, you’re out there in the ozone a bit on the orals, aren’t you?

Noa Biran, MD: Yes, absolutely. And in the first couple cycles we tend to keep a closer eye on patients. But the other disadvantage, and people often think, oh, I’m taking a pill, it’s going to be less toxic. No, that’s not necessarily the case.

Peter Salgo, MD: Nice try with that one.

Noa Biran, MD: Sometimes you see cumulative toxicities such as cytopenias, because they’re daily or weekly dosing and you get more cytopenias. Sometimes you have more GI [gastrointestinal] toxicities because they’re orally absorbed. So certainly they, they offer an advantage, they don’t always offer fewer adverse effects.

Cheryl Allen, BPharm, MBA: And I think it’s also good to note that the majority of our patients are, outside of maintenance, they are on infused therapies as well as the oral therapies.

Noa Biran, MD: Exactly.

Cheryl Allen, BPharm, MBA: In combination.

Peter Salgo, MD: So, if it’s got to come in anyway, is, there’s no, unless I’m misreading this, there’s no real convenience issue. I guess your choice at that point if you’re going to use both is efficacy.

Cheryl Allen, BPharm, MBA: It is. It’s targeted nature.

Peter Salgo, MD: In other words, is it better, use it together. What do the patients like better? Do they like coming in or do they like staying home taking pills?

Noa Biran, MD: Honestly, they’ve done studies on this and the quality of life is not better for patients who take all orals. In patient reported outcome studies where they looked at patient-reported-outcomes, there’s not always a benefit to staying on all oral pills. Some people work. Some people you know can’t get to the office because they rely on their son or their daughter to drive them in. And for those people hands-down they prefer all oral. But.

Peter Salgo, MD: Sure.

Cheryl Allen, BPharm, MBA: Yeah, I think, overall, it’s a challenge for our patients. As Dr. Biran said, this is chronic illness that our patients have. And they’re living years and decades with this disease, and they’re cycling through many therapies. So understanding what therapy they’re on, how the cycle will work, how the oral may work in conjunction with that is really important. And I think the other thing to note is our patients, sometimes the therapy depends on how old our patient is, how frail our patient may be.

Noa Biran, MD: Absolutely.

Cheryl Allen, BPharm, MBA: You know, average age of our patient is somewhere between say 65 and 74. It’s rare. It’s less than one percent of the time that we have a patient less than 50 years of age.

Peter Salgo, MD: OK. But from the perspective of the patient now, if I hear you correctly, the obvious advantage is I can stay home and take my pills.

Noa Biran, MD: Yeah.

Peter Salgo, MD: I don’t have to go to the doctor’s office as often. I don’t have to get stuck. I don’t need an IV infusion for hours—I’m assuming they take an hour or 2 or 3 or whatever. Right?

Noa Biran, MD: Yeah, absolutely.

Peter Salgo, MD: But, in contradistinction, you don’t get seen. You’re not going to get something picked up that a doctor or a nurse or a doctor’s extender might see that a patient at home might not. So there is a trade-off here, right?

Noa Biran, MD: Yeah. And to me the biggest trade-off is cost. I mean you know I think it’s incredible that we have even now have an oral triplet regimen—ixazomib, lenalidomide, and DEX [dexamethasone], for example. A triplet-based therapy that’s all oral. That’s amazing that you can treat somebody for cancer with met with pills.

But I think cost is a big problem because patients have a very, very high out-of-pocket cost, and not all patients can afford it.