Episode 143: Myeloma Series, Pt.4 - Myeloma Pharmacology (2025)

Summary

---

The Fellow on Call: The Heme/Onc Podcast

Episode 143: Myeloma Series, Pt. 4 – Myeloma Pharmacology (2025)

Release Date: December 24, 2025
Hosts: Ronuk (A), Vivek (B), Dan (C)
Guest Expert: Dr. Catherine Maples, PharmD (D), Clinical Pharmacy Specialist, Winship Cancer Institute at Emory Healthcare

---

Episode Overview

In this in-depth episode of The Fellow on Call, the hosts are joined by Dr. Catherine Maples, a myeloma-focused clinical pharmacist, to break down the pharmacology of multiple myeloma treatments. The discussion centers on understanding drug classes, mechanisms, side effects, patient counseling, and special considerations in both standard and complex clinical scenarios—offering practical pearls for trainees and practicing providers alike.

---

Key Discussion Points and Insights

1. Common Drug Classes and Regimens Used in Myeloma

• Triplet therapy is standard, usually comprising:
  • Immunomodulatory drugs (IMIDs): lenalidomide, pomalidomide (suffix "-omide")
  • Proteasome inhibitors: bortezomib, carfilzomib, ixazomib (suffix "-zomib")
  • Steroids: typically dexamethasone
• Brand/generic names: Bortezomib = Velcade (hence, VRD regimen is Velcade, Revlimid, Dexamethasone).

“In myeloma, the standard is triplet regimens. … Anything that has an omide, lenalidomide, pomalidomide, that is the immunomodulatory drug, also known as an imid."
—Vivek (B), [01:22]

---

2. Detailed Drug Profiles and Practical Tips

A. Bortezomib (Velcade): Neuropathy and Patient Counseling

• Main side effect: peripheral neuropathy—cannot be prevented, so close patient reporting is vital.
• Timing:
  • Neuropathy most often occurs within the first 5 cycles. If absent after 5 cycles, risk diminishes, though can rarely occur later.
  • Management: Hold or reduce dose if grade 2 neuropathy with pain. Start with gabapentin, escalate to pregabalin or add duloxetine as needed.
• Other key counseling points:
  • Herpes zoster/HSV reactivation risk—antiviral prophylaxis is a must.
  • Drug interactions with vitamin C (>500mg) and green tea can interfere with the drug.
  • GI issues can be constipation or diarrhea.
  • Unique side effect: styes (treated with doxycycline).
• Subcutaneous (SubQ) dosing reduces neuropathy compared to IV but still must be administered at a chemo center.

"We can't prevent it... So we really rely on the patient letting us know when they are experiencing it so that we can make interventions." —Dr. Maples (D), [06:28]
"Anything over 500 milligrams of vitamin C can cause the inhibition. So I ask them to look at their multivitamin..." —Dr. Maples (D), [11:00]

B. Lenalidomide (Revlimid): Mechanism, Side Effects, and REMS

• Mechanism: Multifactorial; direct tumor cytotoxicity, immunomodulation via T/NK cells, anti-angiogenesis. Newer agents target cereblon.
• Side effects:
  • Rash (immune based, can occur after steroids stopped; treat with topical steroids or Medrol dose pack).
  • Diarrhea (due to bile acid malabsorption; treat with cholestyramine/"bile acid sequestrant" over Imodium).
  • Myelosuppression (cytopenias)—manage with growth factors during induction if necessary, or dose reduce in maintenance.
  • Fatigue.
  • Dose reduction based on toxicity and patient frailty.
• REMS Program: Strict risk mitigation due to teratogenicity.
  • Requirements: negative pregnancy test before every fill, two forms of birth control (one barrier), patient surveys before dispensing.

"For a long time no one had any idea [how it works]…it does directly kill the myeloma cells, helps your immune system kill the myeloma cells and then also shrinks blood vessels..." —Dr. Maples (D), [15:59]
"REMS stands for Risk Evaluation and Mitigation Strategy...based off of the safety of the drug." —Dr. Maples (D), [22:50]

C. Dexamethasone: Dosing Simplification

• Schedules have improved and become less complex; aim to administer in-center and reduce take-home dosing.
• Side effects and patient “crash” can occur; doses can be split between infusion center and home.

"If we can try to make the dex easier for them and just give it to them when they're already here...that tends to be more successful." —Dr. Maples (D), [28:49]

D. Daratumumab (Dara): Mechanism, Administration, and Infections

• Mechanism: Depletes CD38-positive plasma cells, has multiple immune-mediated actions.
• Infusion reactions: SubQ dosing is preferred—lower rate of reactions, quick 5-min injection (no test dose required, unlike rituximab; but higher volume than typical SubQ drugs).
• Precautions: Causes pan-agglutination/interferes with blood typing (indirect Coombs).
• Vaccination: Ensure influenza, COVID, and pneumonia vaccines are updated. Consider IVIG if hypogammaglobulinemia or recurrent infections.

"Sub Q Daratumumab definitely has changed the game...it's a five-minute push...and there are significantly less infusion related reactions." —Dr. Maples (D), [31:43]
"Making sure patients are up to date on their vaccines, the flu vaccine, Covid and then pneumonia..." —Dr. Maples (D), [34:04]

E. Alkylators & Alternative Regimens for Renal Dysfunction

• CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) is used for patients with renal insufficiency, as lenalidomide is renally cleared.
• Cyclophosphamide: Oral and IV options—oral often preferred for shorter infusion, but large capsule burden.
• Thalidomide: Useful in severe renal impairment as it does not require renal adjustment and is still used in select regimens (esp. in European practice or for patients on dialysis).

"Lenalidomide is not nephrotoxic. It's just cleared renally...if a patient has impaired renal function, you're going to get a buildup of the drug and higher toxicities." —Dr. Maples (D), [38:21]

F. Carfilzomib (Kyprolis): Toxicities and Dosing

• Main concern: Cardiotoxicity (HTN, heart failure), possible TMA.
• Dosing: Once-weekly dosing (per A.R.R.O.W trial) is favored—no increase in cardiovascular events, more convenient.
• Rare neuropathy: Unlike bortezomib, carfilzomib has minimal neurotoxicity.

"We can see a variety of different cardiotoxicity with carfilizomib ranging from hypertension all the way to heart failure." —Dr. Maples (D), [41:36]
"We use a lot more once weekly dosing regimens in the relapse setting for patients...and that can help with some of those day to day side effects..." —Dr. Maples (D), [43:59]

G. Pomalidomide (Pomalyst):

• Compared to lenalidomide, pomalidomide causes more myelosuppression but less diarrhea or rash.
• Adjustments needed in renal impairment; can be considered even in patients on dialysis.

"We do see much more neutropenia and thrombocytopenia compared to revlimid...the fatigue and the myelosuppression I think are much more potent with pom." —Dr. Maples (D), [44:49]

---

3. Supportive Care and Prophylaxis

A. Antiviral Prophylaxis

• HSV/VZV prophylaxis (e.g., acyclovir, valacyclovir) is mandatory with:
  • Proteasome inhibitors (bortezomib, carfilzomib)
  • Monoclonal antibodies (daratumumab, isatuximab, elotuzumab)

B. Thromboembolism Prophylaxis

• IMIDs increase risk of DVT/PE.
• Use validated risk scores (IMPEDE, SAVED) and clinical judgement.
  • Low risk: ASA 81 mg vs. high risk: low-dose apixaban or rivaroxaban.

"One of the biggest risk factors for a clot on an IMID is having any prior history of a clot...most of the time we do half-dose apixaban or rivaroxaban." —Dr. Maples (D), [26:43]

C. PJP Prophylaxis

• For patients on steroids equivalent to ≥20 mg prednisone daily for ≥30 days (e.g., dex 20 mg weekly).
• Also post-autologous stem cell transplant or for those receiving CAR-T/bispecifics.

"If they're on a regimen of dex 20 milligrams weekly or higher, then I would recommend PJP prophylaxis." —Dr. Maples (D), [46:17]

---

Notable Quotes & Memorable Moments

• "Don't suffer in silence. Let us know and inform us when you start to feel these sensations so that we can properly grade the peripheral neuropathy and make dose holds or dose reductions appropriately."
  —Dr. Maples (D), [06:28]

• “It's not like on their last day of revlimid they can stop practicing [contraception]. Four weeks later would be the cutoff for that.”
  —Dr. Maples (D), [25:05]

• “The paradigm really is just let's blast this disease out of water, see if we can't get some kidney function back.”
  —Dan (C), [38:06]

• “There are so many ways to treat multiple myeloma, so many different trials, there's so many ways to slice and dice this. But it's really good to know, to hear to how people practice differently.”
  —Vivek (B), [40:32]

---

Important Segment Timestamps

• [02:44] — Introductions and case setup
• [06:28] — Peripheral neuropathy counseling for bortezomib
• [11:00] — Unique drug interactions: Vitamin C and Velcade
• [15:59] — IMID mechanism of action explained
• [17:43] — Lenalidomide side effects and dose reduction strategies
• [22:50] — The REMS program for IMIDs
• [26:43] — DVT risk with IMIDs and prophylaxis
• [28:49] — Dexamethasone scheduling and patient guidance
• [31:43] — Daratumumab: subcutaneous administration, mechanisms, and reactions
• [38:21] — Myeloma therapy adjustments for renal dysfunction
• [41:36] — Carfilzomib: Cardiovascular risks and monitoring
• [44:49] — Pomalidomide vs. lenalidomide toxicity
• [46:17] — Antiviral and PJP prophylaxis in myeloma

---

Summary Tone

The conversation is collegial and educational, blending practical pearls from Dr. Maples' pharmacy expertise with the hosts’ clinical questions and curiosities. The episode makes complex pharmacology approachable for learners at any stage while emphasizing patient-centered care and multidisciplinary collaboration.

---

Listen to this episode if:

• You want a clear, practical walk-through of frontline and supportive myeloma drugs, their side effects, and real-world management.
• You need insights on how pharmacists collaborate in the care team.
• You’re a trainee seeking “the why” behind pharmacology choices or curious about evolving standards in myeloma therapy.

---

Transcript

[A]

Hey, friends. This episode of the Fellow on Call.

[B]

Is not meant to be used for.

[A]

Medical advice and is intended for educational purposes only.

[B]

Patient information has been modified to ensure privacy. The views expressed in this episode do.

[A]

Not necessarily reflect the views of our employers.

[B]

Enjoy.

[A]

Welcome to another episode of the Fellow on Call, the Hemong Podcast. We're coming at you from Rule University Medical Center. I'm Ronuk.

[B]

I'm Vivek.

[C]

And I'm Dan.

[A]

And in today's episode, we move to our pharmacology episode, talking all about the pharmacology of multiple myeloma. And we are so excited to share an episode that we recorded with Dr. Catherine Maples, who's a pharmacist at Emory in Atlanta. It was a fantastic discussion and we're really excited.

[B]

Yeah, this was such an amazing pharmacology episode. I learned so much about the pharmacology myeloma and treatments of myeloma and what to tell patients. It was fantastic.

[C]

Yeah, we were really lucky to be able to get her on the show. I think our listeners are really going to enjoy this one.

[A]

Guys, there's a couple of drugs and classes of drugs that we are using in this episode. Can you, in a few sentences, just kind of summarize what some of these drugs that our listeners are going to hear are just so that they can continue to follow this fantastic conversation?

[B]

Yeah, I'm going to do this very briefly and very quickly so that way we can get to the episode.

[D]

So.

[B]

So in myeloma, the standard is triplet regimens. And what we mean by triplet, we're saying that one of the drugs is something called an immunomodulatory agent or an imid. Another drug is a proteasome inhibitor, and the third drug is steroid. And that's what we're looking at. Know this, Anything that has an omide, lenolidomide, pomalidomide, that is the immunomodulatory drug, also known as an imid. So here I say imids, and they end in omide. For the proteasome inhibitors, those end in zomib. So bortezomib, carfilzomib, ixazomib, so simple proteasome inhibitors, and enzomib. The other thing you'll hear us say is that we'll try to introduce some of the brand and generic names because you'll hear these things, and some of the regimens are abbreviated that way.

[D]

So.

[B]

So, for example, bortezomib, remember the zomib for a proteasome inhibitor that's the same as Velcade. So you could see vrd the V being Velcade or you could see Cybor d the bor being bortezomib. We'll go through that. It's something that'll get ingrained in your head soon. We'll have charts in our show notes. You gotta commit this to memory. It'll make this whole talk make so much more sense. But let's get to it and excited to have you guys listen to this episode.

[A]

Welcome back to another fantastic episode of the Fellow on call. This time we are so excited to have a guest with us. This is Dr. Catherine Maples. She's a clinical pharmacist at the Winship Cancer Institute at Emory Healthcare in Atlanta, Georgia. Katherine, thank you so much for being here today.

[D]

Thank you so much for having me. I'm very excited to join you guys.

[A]

We love having our pharmacists on our show and we love learning about what it is that you guys do. And it is going to be, I'm sure, a fantastic episode as we get into the nuances of myeloma. There's a lot of drugs and I know that I struggle with a lot of them, so hopefully you can help us better understand a little bit more about them. We would love if you could tell us a little bit about yourself. And we love asking our guests one fun fact about themselves as well.

[D]

Yeah, for sure. So I am, like you said, a clinical pharmacy specialist in multiple myeloma. So I am kind of in that little niche area of myeloma, which I love. I went to pharmacy school at the University of Georgia. So I'm going to go ahead and give a go dogs. And I did my residency in at VCU in Virginia and I spent some time at Memorial Stone Kettering before returning back home to my roots at Emory. So I, I have flown the coop and returned back home. A little fun fact about me is that I have an obsession with my German short hair pointer dog named Duke. He is my whole little world and I never knew I could be so obsessed with a dog. So that's my fun fact.

[B]

I totally feel that. We have a red heeler and Australian cattle dog and exactly the same. Did you get Santa pictures with him?

[D]

We tried. He had, he had no interest in sitting still for that, but it made for a good laugh.

[B]

Yeah, yeah, yeah. You got, you got to do the obligatory trial of the Santa picture with.

[D]

The dog, for sure.

[A]

That's awesome. Well, you know, we, we do want to kind of kick things off for our, Myeloma pharmacology discussion today. In order to do that, we do have a case for you, Catherine, if you're ready.

[D]

Let's dive in.

[B]

All right, perfect. All right, I'll give us the case this time. I know listeners. Roanoke usually does it, but we're gonna switch it up a little bit. This is the pharmacy episode. And again, thanks again. This is gonna be awesome. So in general, our current approach to induction therapy in our patients that we're gonna talk about in our episodes that we have the triplet or a quad therapy, meaning either a three or a four drug combination, and one of those drugs being high dose dexamethasone. And that's really where we're at right now in myeloma. So let me start with a case. So let's say we have a 63 year old male with newly diagnosed IgA Kappa multiple myeloma, who's otherwise healthy at baseline and deemed transplant eligible. He had standard risk disease based on a cytogenetic evaluation from his bone marrow biopsy. And we decided to treat him with induction VRD times four cycles and planned for high dose melphalan followed by autologous stem cell transplant. So this is something that you might see, listeners as you go through fellowship, that VRD is a common regimen. You'll see things like dara, vrd. And we'll get to that later on our discussion. First thing I wanted to focus on, so what do these letters mean? What is the V and the R and the D? So first we want to focus on V. And this is for Velcade where the generic name is bortezomib. And like the intro in the episode, we kind of gave you guys some mnemonics for that. The major class side effect of this is neuropathy. But I want to ask you, can you tell us a little bit about when to expect neuropathy? And is there some point that we feel like we're cleared from the neuropathy because we talk about in some high risk patients using Velcade in the maintenance setting as well. So can you tell us a little bit about that and what's your approach to dealing with the neuropathy and when would you hold the drug?

[D]

Yes, I think that that is a very important question and a very important side effect to counsel patients on. Because I think one of the problems with peripheral neuropathy, especially bortezumib induced peripheral neuropathy, is we, we can't prevent it. So there's nothing we can really do to prevent it. So we really rely on the patient, letting us know when they are experiencing it so that we can make interventions. So I try to tell my patients when I'm counseling them on this side effect that I need them to not suffer in silence, but let us know and inform us when they start to feel these sensations so that we can properly grade the peripheral neuropathy and make dose holds or dose reductions appropriately. So in terms of timing, I would say it's most common that we're going to see that neuropathy if they are going to have it occur within the first five cycles. If we kind of get beyond those five cycles and they don't have neuropathy, it's likely not going to worsen at that point. And if there's someone who's going to experience it, it does happen early, but it can be a cumulative side effect and we can see it worsen over time. So you will have that patient who's been on Velcade maintenance for years and all of a sudden they develop neuropathy. So it's not to say that it can't happen, but I would say most commonly, if we can get past cycle five, we're okay. And then in terms of how to manage it, the prescribing information also on Lexicomp or any drug information resource has the grading broken down really well. So I think it's, it's good to follow that in terms of do they have grade two with pain, grade two without pain, or grade three or grade four. Typically, once we get to a grade two with pain, we need to think about dose holding and definitely dose reducing grade two without pain, depending on where they are in their treatment. You can also talk about a dose reduction, but I think asking the questions of is it numbness, is it pain, can you button your shirt, can you open a water bottle? Trying to get a feel for how it's impacting their daily is key and management is, you know, your, your standard neuropathy medications. So I would say the most common approach is to start with gabapentin. If gabapentin becomes too sedating, then we will switch it to pregabalin. And then once we kind of titrate up on those, on those doses, then we would think about adding in duloxetine. Nothing wrong with your vitamin B complex complexes or some of the other herbal products. They just don't have a ton of data associated with them. But most of the time we can manage it with kind of those typical neuropathy medications.

[B]

Yeah, that makes a lot of sense and just for our listeners that when you think about grade one, grade two, grade three, there's the ctcae and you can just Google it. And definitely if you're new at this or if you're a new pharmacist, whatever level you are, I still do it myself. It's always good to just google what it looks like so that way you get a better sense of what these grades are. What's another thing? So you guys the pharmacists. And for people who haven't been in fellowship or maybe starting fellowship, pharmacists do so much with patient education. They teach us as fellows all the time. What are some other side effects that you counsel patients on for Velcade in particular?

[D]

Yes, for sure. So I first one of the class effects of all the proteasome inhibitors is going to be the risk for any of the herpes simplex or zoster reactivation. So I do make a point to counsel them on that and tie in the fact that they're going to be on a prophylactic antiviral as part of this therapy as well. So making sure that they understand that they will need to be taking that antiviral prophylaxis at home every single day. Bortezomib can cause both diarrhea or constipation. Patients can kind of go one way or the other. We tend to see more diarrhea just because it's often being given in combination with revlimid. But we definitely can see some of the autonomic side effect with some constip as well. One of the more unique side effects, I think with bortezomib that you don't read it as much in the literature, but I definitely see it in practice, is dyes, and they can really recur. So we will use doxycycline to to treat the styes for patients if they have multiple. And then of course, the pharmacist and me is going to make sure to talk about drug interactions because there's a few unique ones. These aren't necessarily side effects, but I think it's worth noting there are drug interactions with vitamin C and green tea. And I think that, especially in the COVID era, think vitamin C is no harm, no foul. It's great. Everyone needs vitamin C. Exactly. And so I make a point to ask that because I don't think people put that on their medication list. So I'll ask, do you take vitamin C supplements? The data shows that anything over 500 milligrams of vitamin C can cause the inhibition So I ask them to look at their multivitamin and see how much vitamin C is in it. So those are kind of the other big things that I like to talk to patients about now.

[C]

That's great to know. I had no idea about the vitamin C thing, if I'm honest. I also take a fair amount of that stuff every day. So super, super good to know and great to keep in mind.

[B]

You got to prevent scurvy.

[C]

Yeah, that's the thing. We're seeing a lot of it these days. It's no good. And so, you know, one thing I was wondering about. One of the pivotal trials that we really want to emphasize over the course of our treatment episodes is the SWOG trial. SWOG S0777. It compared VRD to RD showing superior OS for the triplet for VRD and kind of established that triplet as a standard of care. That trial was constructed such that patients got their Velcade twice weekly for two weeks and daily Revlimid over the course of that two weeks. So for days one through 14 on a 21 day cycle, I know there are also options out there for weekly velcade with 28 day cycles. What are your thoughts on the difference between these two regimens? Is there a difference between twice weekly Velcade and weekly Velcade? It's just, it seems like kind of a lot for a patient to come in that frequently for treatment.

[D]

Yes, for sure. And I think this is a really good question. So we, we do have mostly retrospective data that looks at this question where we see when twice weekly Velcade is compared to once weekly Velcade that the dose intensity factor oftentimes comes out to be very similar because twice weekly Velcade has higher rates of that neuropathy we talked about. So patients end up getting held or dose reduced. So when you map out the dose intensity, you can see similar dose intensities in the tricly versus once weekly. You can see of course, lower rates of those toxicities and efficacy appears to be similar. These have again mostly been retrospective. But one thing that I think makes me pause and, and want to push for twice weekly Velcade and especially our younger fit transplant eligible patients, is that we do know that the depth of response in myeloma tends to correlate with duration of response. And this patient we were talking about, he's, he's young, he's transplant eligible, we want to get disease control and get a deep response. I, that's someone that I would push for twice weekly Velcade and Someone who is more frail, maybe not transplant eligible or really can't tolerate it. Starting with once weekly I think would be completely appropriate.

[C]

Okay, cool. You know, as a predominantly benign hematologist, I prescribe a lot of Lovenox, but this kind of. Even though this drug can be Sub Q, this Velcade can be Sub Q, this isn't something that we're letting patients give to themselves at home, is it?

[D]

No, unfortunately it does still need to be mixed in a chemo hood in the pharmacy. So it's unfortunately not able to be given Sub Q. But it is nice because it was previously an IV therapy and the sub Q formulation actually has reduced amount of peripheral neuropathy. So it is the preferred route and it's a quick two second injection so patients can, can come and hopefully be in and out as fast as possible. But unfortunately no, we're not, we're not quite there yet with the home injection.

[C]

Yeah, it makes sense. You wouldn't want patients getting this kind of without labs or without. Or having a fridge full of chemo either is, doesn't sound like a great idea.

[B]

And this is a shout back. When we talked to Renee on our last pharmacy episodes that we had of the amount of work it takes to get the drug to the patient. What we do is we just type in the treatment plan and really oftentimes our clinical pharmacists are amazing and somewhat do it for us in a lot of cases that they fix it, they check everything. But there's so much work that goes into the mixing of chemo, delivering the chemo to the patient. So it's good to know here it's the same stuff, right? We can't. It's not like Lovenox where you have pre filled syringes and you just give the injection and go home.

[A]

Absolutely. Yeah. I mean I've already learned so much about Velcade that I didn't know previously. And so I'm curious to kind of switch gears a little bit and move to the R in vrd. So that is Revlimid or Lenalidomide as our listeners may know. And as everyone probably also knows, this falls into the class of drugs known as the Imids. And you know, we'll talk a little bit more about this, especially in patients with renal dysfunction later in the episode. But, but let's just focus on our patient here with, with normal renal function. So Catherine, could you just kind of explain to us how this class of drugs actually works? Because quite frankly, I have no idea.

[D]

Yes, I think for a long Time no one had any idea. So we have definitely learned a lot more about these drugs over the last several years. And I would say the mechanism of action of the image is definitely multifactorial. So do know that there is some direct cytotoxicity on the myeloma cell. So they are directly killing. And we now have learned that this is largely due to the Cereblon target. So our, our new novel image that are coming down the pipeline like CC220 and CC92480 are classified as the Cereblon inhibitors, like small molecular inhibitors. So there is some direct cytotoxicity. We also know that Revlimid has some anti angiogenesis properties, so shrinking those blood vessel vessels and preventing tumor growth that way. We also know there is some immune properties so increasing natural killer T cells and T cell modulating activity. So it's kind of multifactorial. And I kind of tell patients, you know, it does directly kill the myeloma cells, it helps your immune system kill the myeloma cells and then it also shrinks those blood vessels just to prevent growth.

[A]

That's, that's really good to know. And you know again we give this drug quite frequently. And so there are some toxicities that, that come to mind that I counsel patients about. Things like cytopenia, fatigue, some GI issues as well. I recently had a patient that, that essentially lost his appetite because he had altered taste related to the Revlimid. So what are, what are some toxicities that, that you counsel patients on and you know, more specifically toxicities that would or should prompt us to dose reduce.

[D]

So a couple of things that come to mind for me first with Revlimid is we can see a rash and it is kind of a unique rash. You can definitely google pictures of it. And what I find interesting about the Revlimid rash is it is more immune based. And so it's not necessarily that they're allergic, but where patients freak out a little bit is more in the maintenance setting and they, they start back on maintenance Revlimid and they develop this rash and they're like, I didn't have this before. And it's probably because they were on high decks before and it was covering up the rash. A lot of times we don't see that revlimid rash up front, but we can see the rebel mid rash later. And you can treat that with topical corticosteroids or even sometimes a Medrol dose pack might be needed. But oftentimes we can quiet down the rash and patients Continue on the rebel man. No problem. The diarrhea is one we definitely see and can be limiting for patients and I. The mechanism of revelment diarrhea is unique and it's been found to be due to bile acid malabsorption. So using a bile acid sequestrant like cholesterol or well call often better for rebel men induced diarrhea than imodium or lomodil. So having patients take that and they can kind of self titrate it. We usually start with like 2 grams bid of cholesterol and they can kind of titrate themselves up and down based off of their bowel movements. And then I think the cytopenias are often the big one where I would say we, we talk about dose reducing. And I think that conversation definitely depends on where we are in treatment. If this is induction therapy for this, you know, like for this patient, especially if they're someone who had a packed marrow so their counts were low to, to start. Our inclination is oftentimes to add growth factor. And unlike other cancers in chemo where you can't give growth factor on the same day, you can give growth factor on the same day as rvd. So we'll give them twice weekly, three times weekly growth factor to support them through and not have to dose reduce the revlimid while we get through induction. Now if we're in the maintenance setting, their ANC is constantly less than 5,000 or in the 700, 800 range and they're in remission, then less important to push that dose. And I think that's when we would talk about a dose reduction and going to 5 or even 2.5. But I think the counts and the fatigue would be more of reasons that I see the need to dose reduce. The diarrhea can often be managed and the rash can often be managed with some other pharmacologic interventions. And I think it just depends, like I said, on where they are in their treatment.

[A]

That's, that's really helpful. And you know, I actually didn't know about the GCSF component either. So that's, that's really helpful. Now, you know, kind of going off of that though. Do you ever kind of assess a patient and just have like a gestalt that maybe we shouldn't start at the maximum dose and you dose reduce based on what they look like or is it the recommendation and the preference to always start with the max dose of 25 and then you know, should something arise, then have a low threshold to decrease that dose?

[D]

Yeah, for sure. I think that's a really good question. I would say there's definitely those patients that you just have a feel for. They're not going to tolerate 25 especially, especially if we're talking about doing like Dara Revdex, like the Maya trial and a transplant ineligible patient. And so they're, they're, you know, they're probably in their late 70s, 80s, and they may have a poor performance status. I would say definitely more inclined to start that patient at 10 to 15. And if they' tolerating things, then great, we can go up. But if they're transplant eligible and their performance status is relatively okay outside of renal function, we need to dose reduce for that. Then I would say we try to start at 25 and dose reduce from there. But I think it's definitely an eyeball and gut feeling as well.

[B]

Yeah, it makes so much sense. And I know that for me, you know, here at Rouleau, we. I've seen a fair amount of myeloma patients in my panel and it took me a long time to figure out that gestalt. But now I feel like I'm getting a better grasp of this older, more frail person. Let's start low and go slow, right? I mean, we still have things like Dara that we're giving them so many other options in myeloma now that we can give them. So you don't necessarily need to blast them with revlimid, but you got a young fit patient. Push through. Push through. Because that PFS one that Catherine was saying, I mean, that's so important, right? To keep that depth of response and duration of response is critical in these patients. So one of the other things that just from our perspective as fellows, that we just have no idea what goes on behind the scenes of getting something like these IMIDs approved, whether that's revlimid or pomalidomide. And people talk about a REMS program and I have no idea what any of that means. So can you tell us a little bit about what goes on on your end to get the drug approved? And what exactly does a REMS program mean?

[D]

Yes, for sure. We have so many REMS programs in myeloma now. So REMS stands for Risk Evaluation and Mitigation Strategy. And this is something that is mandated for a drug by the FDA based off of the safety of the, of the drug. So lenolidomide and pomalidomide have their REMS program developed due to the original IMIT of thalidomide, which caused the embryo fetal harm. And when it was given to mother for nausea. So thalidomide was taken off the market. And then later when lenalidomide and pomelet pomalidomide were developed and approved. This REMS program was developed because of that history. So what kind of goes beyond behind the scenes? So first for all oral chemo you have to get the prior authorization. So that's going to be the first step of getting that submitted to the insurance. That typically takes around a week to get approved and get turned around. And then if they have any copay issues making finding copay assistance, which can be done through the specialty pharmacy. So that's, that's an oral chemo general topic that happens in terms of the REMs. So female females of childbearing age with lenalidomide and pomalidomide have to get a pregnancy test prior to each refill. And you cannot put any refills on the immunomodulatory agent. So prior to each, every 21 day cycle or every 28 day cycle, whatever it is, they have to come in and get their pregnancy test. And you have to then log into the REMS portal, document that the pregnancy test was negative and you get a unique authorization code that has to be put on the prescription which is sent to the pharmacy. So the pharmacy has to have that authorization code before they can dispense the drug. And that authorization code does accept aspire. And then women of non childbearing age do not have to do the pregnancy test. But all patients, men and female, are counseled that they must use two forms of birth control and one has to be a barrier method for the duration of the time that they are on an immunomodulatory agent if they, if their partner is of childbearing age. That's two forms of birth control, one being a barrier method. And the recommendation is that practice must continue for four weeks after discontinuing discontinuing the drug. So it's not like on their last day of revlimid they can stop practicing. That four weeks later would be the cutoff for that. So that's the counseling portion. And then the last step of all of this is all the patients, men and women, have to complete a survey before the pharmacy can dispense the drug to them. So they have to answer questions that they understand the REMs, they understand the pregnancy risk and answer all the questions correctly before the pharmacy can release the drug. Sometimes what we will see happen is a patient will accidentally answer that question wrong and the pharmacy won't dispense the drug. And then you have to call the REMS program and have them reset the survey or the questionnaire. It can go back to the patient at that point and then the drug can be dispensed. But it is a lot of steps to make sure that the pregnancy test is done, the survey is done, and the prescriptions are filled in a timely manner.

[C]

Yeah, that makes sense. It's definitely a big deal. You want to make sure that you're preventing any chance of pregnancy when people are on these drugs. Again, putting my benign hematologist hat on here. Beyond the teratogenicity aspect of these drugs, the big thing I always think about with IMIDS is DVT risk. And so we were taught to just prescribe DVT prophylaxis. And I feel like again, some of your younger, fitter patients can get away with a baby. Aspirin, 81 milligrams a day of aspirin. But when do you think about escalating to something more intense?

[D]

Yes, I think this is a really good question. So there are two scoring systems that are in the myeloma MCCN guidelines as well, the impede score and the saved score. And these are two different scoring systems that you can use that incorporate other known VT risk factors. So you know, obesity, smoking, any, anything else that you would normally think of. So you can use those scoring systems and tease out if they need something a little bit higher than an aspirin. I think for my practice, we, we don't follow those scores exactly, but thinking about, definitely thinking about the risk of the patient. And one of the biggest risk factors for a clot on an IMID is having any prior history of a clot, whether it was provoked or unprovoked. So if there's someone who's had a provoked blood clot in the past from a long flight or whatever it may be, then we would do something more than aspirin in that patient. And most of the time we do half dose apixaban or rivaroxaban. So not full dose anticoagulation, but a little bit more than an aspirin. And I think we use those impede and save scores as our guiding factors to assess each patient individually. And if there's someone who's immobile, they've just had a kypoplasty, they're not, they're not walking very well or they're not active. Those would all be things we think about doing apixaban 2.5 bid or something, or something like that.

[C]

That's a great point. Thinking about how common orthopedic complications from myeloma are, it's definitely something to keep in mind.

[A]

So, Catherine, again, switching gears then, to the last drug in our triplet therapy that we talked about for our patient. So the D in VRD is for dexamethasone. So it is from, from experience. It's a kind of a complicated schedule about how to get patients to take their dex. And so I think something that'd be really helpful to us is how you counsel your patients about keeping all of it straight, because I barely can keep it straight. So what do you, what do you normally talk to them about?

[D]

Yeah, I think we've seen dexamethasone dosing evolve in myeloma over the last couple of years. So it used in. It used to be a lot more confusing than I think we can make it now. So some of the older regimens is where we see the dex being dosed on, you know, days 1, 2, 4, 5, 8, 9, 11, 12. And it was just insane. When we see some of the more novel regimens like DARA RVV or DARA VTV and those trials, the dex dosing is a little bit more simplified. And there's data that has shown that the super, super high doses of dex that were in the old school RVV dosing don't provide superior outcomes and they do have higher toxicity. So I would say we have seen trying to simplify the dexamethasone for patients, and we try to give it in the infusion center only so that there isn't a need for them to take it at home. So, for example, in the Griffin study, dexamethasone was dosed 20 milligrams on days 1, 2, 8, 9, 15, 16, 16. And we consolidated that and just do dex 40 milligrams on days 1, 8 and 15. So they get it when they're in the infusion center and they don't have to take anything at home. Now if there's someone who has that dexamethasone crash and the next day is really hard for them, we will, we can split it and they can do their 20 in the infusion center and their 20 at home the next day and then counseling them on how to do that. But I think if we can try to make the dex easier for them and just give it to them when they're already here for their Velcade or their dara, that tends to be more successful.

[A]

That's awesome. That's a great reminder for all of us.

[B]

And Catherine, let's switch things up just a little bit. So let's say that instead we really wanted to shoot for MRD negative disease and we wanted to add that daratumumab on. And so let's say that instead we gave this patient the regimen that you just referenced. Dara vrd. I want to talk a little bit about daratumumab. So that's what we call dara for those who aren't familiar. And one thing that everyone should remember is to get the type in screen. I think we learn about this a lot as fellows, so don't want to harp on that too much. But CD38 is the target for daratumumab and that's found on the surface of red blood cells. So it will affect the indirect Coombs test. So this is why it's just important for us to get that type and screen ahead of time, particularly if a patient's not going to a blood bank at an academic center. Now for the most part, many blood banks can get around this with reagent testing. But just something to keep in mind, but our two big questions for you. First question, we know this is a CD38 monoclonal antibody, but what's its mechanism of action? And then the second thing is we know there's a high rate of infusion reactions with daratumumab IV and we wanted to know if you're doing it sub Q, do you have to do a test dose first or can you just start with sub Q?

[D]

Yes, we love our daratumumab and myeloma. So these are great questions. So the mechanism of action with DARA. So first it does deplete the CD38 positive immunosuppressive regulatory cells. So the myeloma cells express CB38. So it's going to target and kill those CB38 expressing cells. But it will also target all cells that express CD38. So we do see some of our healthy regulatory cells be affected there. It also promotes T. CE expansion and activation. So we can have the T cell engagement and then some of the other immune system properties are it, it works through antibody dependent cellular cytotoxicity, antibody dependent cellular phagocytosis and then CDC or complement dependent cytotoxicity. So kind of a multifactorial approach similar to our immunomodulatory agents. And then in terms of the IV versus sub Q, sub Q, Daratumumab definitely has changed the game. As you said, the, the IV Dara, the infusion related reactions were quite high. That first infusion could take eight to ten hours to complete. Getting an infusion chair that blocked up that much time can be hard to find. Scheduling purposes wise, sub QDera does not require a test dose with IV so that's, that's different to Rituximab. You can just go straight to subcudera. It's a five minute push, which I think is a bit unique to a sub Q drug. And it's 15mls in volume so it's not your typical sub Q small volume. So it does take a little bit longer than the Velcade shot that they're oftentimes getting. But you can go straight to sub Q. So we have, we have adopted that practice. And the other benefit to Subcudera is that there are significantly less infusion related reactions with sub qtera compared to iv. So it's a shorter administration, shorter reaction rate and kind of an all around win.

[B]

And then in terms of other side effects with dara, we always talk about just the URI risk, particularly in these patients getting Carfilzomib and things like that. So what are your thoughts on vaccine? Do we need to get vaccines? Is there something in particular that we need to be concerned about when we give our patients Daratumumab?

[D]

Yes, the, the, the urtis with a DARA based regimen I think are definitely something we need to be careful with. So making sure that patients are up to the, up to date on their vaccines, the flu vaccine, Covid and then pneumonia are the ones that we try to make sure that they're up to date. The pneumonia vaccine, we are going to think about revaccinating all of our post transplant patients with their childhood vaccines anyway. So sometimes giving that during induction isn't of utmost importance because you're going to be giving it on the back end. But depending on when they're diagnosed and if it's in the middle of flu season or respiratory viral season, making sure that they're on those vaccines and then less so in the induction setting just because the period is much shorter. But if you're using DARA and the relapse setting and they're going to be on DARA for potentially hopefully many, many months to years. We will use IVIG if their IGG is less than 400 or if there's someone who gets recurrent infections, you can, you can supplement with ivig.

[C]

Makes sense. You can't just blast away someone's plasma cells and just expect them to be able to be immunologically normal for the rest of their life. You know, want to change things up just a little bit so that we can get into a discussion of some of the second generation drugs out there and alkylators when we're older classes of drugs. Drugs and particularly in the setting of renal dysfunction, as we know, unfortunately, renal dysfunction is a very common complication of myeloma as well. Let's say our 63 year old guy that we are talking about in our case was diagnosed during an admission for hypercalcemia. And Aki creatinine's up to three and a half. It only comes down to three after a lot of fluid resuscitation and correcting that hypercalcemia. So when you have a patient in renal dysfunction, I've been taught to stay away from, from Lenalidomide, from Revlimid and instead give one of these older regimens Sibor D. So remember that triplet is sort of what we usually go to and the D in that triplet is in this triplet. For many of our myeloma triplets is dexamethasone. The bore in this case is for bortezomib or Velcade and the PSI is for cyclophosphamide which is an alkylator drug. So in Cybor D, I think there is an option for both weekly and bi weekly bortezomib, just like we had talked about in our VRD regimen. Is there a sort of similar signal for improved disease response or improved depth of response rather with the biweekly dosing or is that different in this regimen?

[D]

Yeah, so I think what we are trying to accomplish a lot of times in a patient that is newly diagnosed with renal dysfunction is to see if we can reverse some of that renal dysfunction and save some of the kidneys. And so getting rapid disease control for the myeloma is what can accomplish that. So I would say we oftentimes are starting with twice weekly Velcade because we're trying to get rapid control of the myeloma and try to reverse some of the renal impairment. So I would say probably going with twice weekly unless they're more of a frail.

[C]

That makes a lot of sense. And similarly for, for oral versus IV cyclophosphamide, do you have a preference there? Do you feel like one of those is more effective?

[D]

Yeah, I don't have a preference in terms of effectiveness. We tend to try to start with oral because it's faster and the dose that you're the dose of cyclophosphamide in These regimens is not a dose that's going to need a lot of fluid, hydration or mesme or anything like that. So you can do the oral dosing. The only time that that gets challenging is that they only come in 50 milligram capsules. So your dose of Cytoxan is typically 300 milligrams or 500 milligrams in these regimens. So that can be six to ten capsules for patients to swallow. And so if patients kind of struggle with that, then totally fine, we'll switch them to iv. Not a big deal. But it's IV infusions usually take an hour. So a lot of times patients are like, it's fine, I'll swallow the pills because it's faster.

[C]

Gotcha.

[A]

Yeah.

[C]

I mean, so the paradigm really is just let's blast this disease out of water, see if we can't get some kidney function back. If you do start to see some improvement in renal function, is there a specific threshold in GFR that you're looking for to get somebody transitioned over to something like vrd?

[D]

Yeah, I think this is a really good question, and it's one of my soapbox that all of my residents and students are probably tired of me talking about. But lenolidomide is not nephrotic toxic. It's just cleared renally. So the dose adjustments that are provided in the package insert for linoleum I are really aggressive. If you see like PI recommendations are creating clearance of less than 60, it's like a 60% dose reduction. You go from 25 to 10 on Revlimid. And so there is a phase two, smaller precog study in myeloma patients with renal dysfunction that have different recommendations. So I tend to try to follow that study when I'm dosing revlimid in a renally impaired patient. But I just try to remember that it's not nephrotoxic, it's just cleared renally. And so if a patient has impaired renal function, you're going to get a buildup of the drug and higher toxicities, most notably the cytopenias. So if they're creatinine can stabilize, you know, above 30 in the 40 range, then I think we oftentimes will feel comfortable switching them over to a revlimid based regimen. And then you can also always think about thalidomide. I know we tend to kind of forget about thalidomide, but the beauty of thalidomide is that it does not have any renal adjustments. So you can give Thalidomide to anybody on dialysis or any issues. So if you want to avoid the alkylator then you can also transition them to a thalidomide based regimen until you see some improvement and then go to Rev.

[B]

That's, that's fascinating. I think one of the interesting things some of our listeners are in Europe and thalidomide's very, I mean Cassiopeia, right. Very commonly used in Europe. So do you guys use it?

[D]

Yeah, we do use. We. So we tend to do a lot of DARA for our patients that have poor kidney function on diagnosis, we tend to do a lot of DARA VD to try to reverse some of that kidney impairment and then add in the revlimid maybe with cycle two. So do just one cycle of Dara Veldex and then add in the IMID in cycle two. But if they are not someone that we think their renal function is going to recover, then we do a lot of DARAB ETD like Cassiopeia.

[B]

So interesting that, you know, and this is the thing that we want our listeners to know, that there are so many ways to treat multiple myeloma, so many different trials, there's so many ways to slice and dice this. But it's really good to know, to hear to how people practice differently and to know that there's an option for thinking about daravd adding in the revlimid later if it gets better. And the other option is DARA VTD and the thalidomide doesn't matter as much on renal dysfunction, which is huge.

[A]

Yeah, that's absolutely fascinating. And I've only ever known the negative side effects of thalidomide. So the idea of us still using that drug is actually quite mind blowing. But it's good to know that it still has a lot of utility in these patients. You know Catherine, one of the drugs that we had mentioned I think earlier in this episode is Carfilzomib or Kyprolis. And so one of the common things that we learn about with this drug is that it causes cardio toxins toxicity. Are there any other side effects that you think about with carfilzomib or you know, is cardiotoxicity really the main one that we should be worried about?

[D]

Yeah, I think the cardiotoxicity of Carfilzomib is definitely one of the big ones. I think about. We can see a variety of different cardiotoxicity with carfilizomib ranging from hypertension all the way to heart failure. So you can have someone that has, has maybe they have hypertension at baseline and you see it get worse and you have to adjust their blood pressure medications or you can have someone who didn't have any issues and they ultimately end up on a blood pressure medication. So I think that's something that we do commonly see a little bit more of the more rare side effects. But the more serious cardio side effects of course is heart failure. And unlike some of our other chemos like Dr. Rubicin where it's recommended that you get a baseline echo, it's not a hard and fast that you, you have to get a baseline echo with with carfilzomib. But I would say I, I feel like we're starting to do that a little bit more just so that we do have a baseline of where they're at and if they do start to develop symptoms, we can repeat it and get, have a better idea for if this is carfilzomib related or not. I think some of the other more rare side effects with carfilzomib, thinking about any TMA that can occur, you can see a handful of that and we've had a few patients that we've had to treat with ecolizumab for their carfilizumib induced tma. So those are definitely more rare. I think some of the more common side effects we see and that patients struggle with are headache on day of infusion. Carfilzomib can have an infusion reaction as well. So we, we never fully eliminate oftentimes the dexamethasone premed with Carfilzomib. Oftentimes we'll at least give like a low dose 4 milligram pre med. And then thrombocytopenia is the other thing I think is more common with a carfilzomib based regimen. And so we may have to make some dose holds or dose adjustments. But I think one study that's been helpful for us is the arrow study comparing the once weekly versus twice weekly dosing of Carfilzomib. Because that showed that PFS was, was not different. It actually favored the once weekly dosing arm and the concern of using the higher dose all at once, there was not higher incidence of heart failure. So I would say we use a lot more once weekly dosing regimens in the relapse setting for patients on carfilazomib and that can help with some of those day to day side effects that.

[A]

People may have with, with bortezomib. Our big concern was Neuropathy. Do we see any of that with the Carfilzomib at all?

[D]

Very little to none. It's really not something we see with Carfilzomib. You can, you have those, the rare patient that will have had a history of neuropathy and then we start them on, you know, a Carvel's mid based regimen and relapse and we see their neuropathy worsen a little. But that's very rare. And most of the time neuropathy is not a concern.

[A]

That's great. And so switching gears a little bit then to the IMIDs. And so in, in the relapse refractory situation, one of the drugs that we've been taught to consider using is the drug pomalidomide or Pomalyst. So just briefly, what does the side effect profile of, of pomalidomide look like compared to like lenolidomide?

[D]

Yeah, I think one of the biggest differences with palm is the myelosuppression. So we do see much more neutropenia thrombocytopenia compared to revlimid. The, the diarrhea is, tends to be a little better with palm. So a lot of patients, if they're coming off rev maintenance and you're switching them to palm, you can, can see their diarrhea improve. And we don't see much of the rash either. But the fatigue and the myelosuppression I think are much more potent with pom.

[A]

That's good to know. And and lastly specifically to this patient, can these drugs be considered so in someone with renal dysfunction, so specifically like carfilzomib or pomalidomide, so they, they both.

[D]

Can be considered with Carfilzomib. There are dose adjustments been suggested if someone has an acute renal toxicity on therapy. So not necessarily that you need to dose reduce up front, but monitoring closely to see if there are creatinine changes and you may need to dose reduce with palm, there are dose adjustments recommended for someone on dialysis.

[B]

So one other really common thing that we see in our myeloma patients is the use of acyclovir or Valtrex for HSV prophylaxis, which you had mentioned before, which with Velcade and I just wanted to get a sense for our listeners a couple things. One, which drugs really require the use for HSV prophylaxis and myeloma? And then two, these patients are getting a lot of steroids many times. When would you consider something like a PJP prophylaxis?

[D]

Yes, very important. Things. I think it's oftentimes hard for myeloma patients because we are starting a triplet or a quad regimen for their myeloma, but also adding two to three more supportive care medications on top of that. So it's not just their myeloma therapy, but HSV prophylaxis is recommended for anybody on a proteasome inhibitor based regimen or a monoclonal antibody based regimen. So our Velcade, Carfilzomib, Daratumumab, Isatuximab, elotuzumab, you would wanna make sure that they're on HSV prophylaxis and then in terms of PJP prophylaxis. So fortunately we don't see a lot of PGP prophylaxis, but I recommend and would recommend doing it off of the steroid dosing. So kind of translating the NCCN guideline regimen of prednisone 20 milligrams a day for 30 days or more, that kind of translates into dex 20 milligrams weekly or higher. So that's kind of the general rule of that I recommend and follow is if they're on a regimen of DEX 20 milligrams weekly or higher, then I would recommend PJP prophylaxis. If their dexamethasone dose falls below that, then you can think about discontinuing it. And then of course, PJP prophylaxis is recommended for six months after autologous stem cell transplant. And in patients that are on bispecific antibodies and CAR T cell therapy, we are seeing more opportunistic infections in that patient population. So I would consider PJP prophylaxis for those patients.

[B]

Awesome. That was really one of the last questions we had. I wanted to remind everybody we have such an awesome myeloma expert, Dr. Catherine Maples, who just gave us a masterclass in pharmacy. For her, it's probably very simple, but for us and our listeners and all the hemochs out there listening to this, it's so, so helpful.

[A]

This was absolutely fantastic. Catherine, thank you so, so, so much for taking the time to join us for this special episode. Guys, any final questions for.

[B]

For Catherine now? That was fantastic.

[C]

I learned a ton. That was fantastic reviews. Thank you again for being here.

[B]

Yeah, we both got to get back to our dogs, I think, so I think that's the, that's the key thing right here.

[A]

All right, everybody, so until next time, we'll see you all later.

[B]

See you later.

[C]

Peace.