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Promising Multiple Myeloma Treatments ft. Dr. Saad Usmani

What’s Promising in Multiple Myeloma Treatment?

Dr. Saad Usmani & Cindy Chmielewski

Cindy Chmielewski

What are the emerging, most promising therapy options potentially available in 2022/2023?

Cindy Chmielewski (@MyelomaTeacher) talks with Dr. Saad Usmani, Chief of Myeloma Service at Memorial Sloan Kettering, about CAR T-cell therapy, bispecific antibodies, novel therapies and combination therapies, focusing on the relapsed/refractory patient population along with newly-diagnosed myeloma patients.

Dr. Saad Usmani

Thank you to Janssen for its support of our educational program. The Patient Story has full editorial control of our content. This interview has been edited for clarity. This is not medical advice. Please consult with your healthcare provider for treatment decisions.


Cindy Chmielewski, @MyelomaTeacher: I’ve been living with myeloma since 2008 and more recently, became a research advocate in the multiple myeloma community.

Saad Z. Usmani, MD, MBA, FACP: I’m the chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York. I’ve been involved with myeloma research both on the clinical and translational side for well over a decade. I’m looking forward to so many exciting things that we have in the field and how things are moving forward for our myeloma patients.

CAR T-cell therapy

What is it & who are they for?

CC: There have been some meetings going on. There’s ASCO and EHA and the IMW is coming up. There are a lot of things happening in multiple myeloma.

Let’s start talking about the CAR Ts because CAR Ts have been around for a while. There are two approved CAR Ts. Can you talk a little about them and who they’re for?

Dr. Usmani: CAR T-cell therapies have been around for a while. They started early on in another disease — ALL in children, actually — but the ones that have been developed in myeloma are targeting a specific surface protein on the myeloma cells called BCMA.

There are two that are FDA-approved for patients who have had four or more prior lines of treatment — including a proteasome inhibitor immunomodulatory drug as well as anti-CD 38 monoclonal antibodies — people who have had a lot of prior therapy.

Those two products are called ide-cel and cilta-cel and they both target BCMA, but they are unique products. The general side effects are similar but tend to happen at different time points. Both products actually show good clinical activity.

The patient’s T-cells are taught to recognize the cancer cell and they’re grown outside the patient’s body in the lab.

Dr. Usmani
Where can you get CAR T-cell therapy?

CC: These CAR T-cells have to be given in a center of excellence, is that correct? I can’t just go to my doctor and say I want some CAR T treatment.

Dr. Usmani: These are cell therapy products so they need to be given at a center that does transplant and cell therapies. Many of our myeloma patients go for a transplant evaluation and end up getting a stem cell transplant during the early course of their treatment.
The process is similar. Your doctor is going to refer you to a transplant center. They will do the evaluation and then get you those commercial products.

Typically, when you’re getting a stem cell transplant, you go through a process of getting growth factor shots and then getting the stem cells collected from your bloodstream through central venous access. In CAR T-cell therapy, we are selecting T-cells from the patient’s peripheral blood, but you don’t need growth factor shots so you can get those T-cells collected just off of the peripheral bloodstream.

Side effects of CAR T-cell therapy

CC: There are some unique side effects to CAR T-cell therapy that maybe myeloma patients haven’t experienced before. Can we talk a little bit about them?

Dr. Usmani: When you get these T-cells from the patients, you send them off to the specific company that’s manufacturing them. What happens is the patient’s T-cells are taught to recognize the cancer cell and they’re grown outside the patient’s body in the lab essentially; that production and expansion takes 3 to 4 weeks. When that product is ready, it’s shipped back to the center and patients get a certain lymphodepleting chemotherapy for three days before they get that product infused through the veins.

Those T-cells are active. They know how to recognize the cancer cells through the surface marker BCMA and they’re going to expand. There’s an expansion that happens in the patient’s bloodstream. These cells are growing and trying to go after the myeloma cells. It’s like introducing an inflammatory response in the patient.

The side effects are like the patient’s body is going through an inflammatory process. The two common side effects are what’s called cytokine release syndrome. These immune cells are releasing certain chemicals that enable them to go after the target. Due to that, patients can feel fevers [and] hypertension, as if they were infected with something. That tends to happen with ide-cel within the first two days. With cilta-cel, it tends to happen with a delay of 5 to 6 days typically.

We manage those side effects by giving antipyretics, fluids, sometimes steroids, or an antibody called Tocilizumab to patients. But for the most part, these side effects are grade one or two. They’re low-grade and are managed with those kinds of medications.

The other side effect that can happen because these T-cells are active is what we call neurologic side effects. Sometimes patients can feel loopy or have neuropathy. Very rarely, patients can have more serious neurologic side effects, such as seizures. Those tend to happen in a very low proportion of patients. Neurotoxicity tends to happen more commonly with ALL CAR T-cells rather than the myeloma CAR T-cells.

The side effects are like the patient’s body is going through an inflammatory process. But for the most part, these side effects are grade one or two. They’re low-grade and are managed with medications.

Dr. Usmani

Who might have a greater tendency for severe neurotoxicity?

CC: Are there any biomarkers that predict who might have a greater tendency for severe neurotoxicity? Or is that just up in the air?

Dr. Usmani: What we’ve observed is patients who have a higher burden of disease at the time of getting CAR T-cell therapy can be at a higher chance of developing these side effects. One can develop CRS and neurotoxicity independent of each other so it’s not that they come in as a package. In fact, CRS is more common. Neurotoxicity tends to happen in less than 10% of the patients. CRS tends to happen in almost all patients to some degree.

There aren’t typically specific markers that we can follow that are specific for CRS or neurotoxicity. There are certain markers that can give you a hint that there is a heightened sense of inflammation, like serum ferritin levels or CRP elevations in patients. We tend to follow some of those labs, but they’re not predictive. They’re just telling you that something is going on, just be careful.

Patients who have a higher burden of disease at the time of getting CAR T-cell therapy can be at a higher chance of developing these side effects.

Dr. Usmani
Are there any trials for more newly diagnosed patients or first relapse?

CC: The currently approved CAR Ts are for more heavily pre-treated patients who’ve exhausted many of the options. Are there any trials that have been reported for more newly diagnosed or first relapse? Are they coming closer?

Dr. Usmani: There are two randomized phase 3 studies that have looked at comparing each of these CAR Ts — both ide-cel as well as cilta-cel — in one to three prior lines of treatment comparing them to the standard of care triplet regimens. In fact, BMS (Bristol Myers Squibb) just announced that their phase 3 trial in one to three prior lines of treatment is coming out positive. Now, this was a company announcement so we haven’t seen the data but that is good news for our patients. I’m keen to hear more about this.

The key is the process [of] CAR T-cell therapy. It takes a while for that production time and so there are certain bottlenecks to the process.

Dr. Usmani

We do have smaller cohort studies that have reported out experience in one to three prior lines or early relapse patients with very high response rates of 80, 90% with Cilta-cel. In fact, well over 90% with Cilta-cel. We just need more updated data, though those are looking promising.

The key is the process [of] CAR T-cell therapy. It takes a while for that production time and so there are certain bottlenecks to the process. The big question is how applicable this technology will be to all patients that we treat.

Allogeneic CAR T-cell therapy

CC: What about allogeneic CAR Ts? Are they going anywhere? What are they? Can you explain? They seemed a little exciting.

Dr. Usmani: The idea of allo CAR Ts is you can take T-cells from a donor but knock out certain surface markers to make those T-cells more benign so that the recipient’s immune system is not recognizing them as the enemy and they’re not recognizing the recipient’s immune system as the enemy.

The advantage of having allo T-cells utilized to manufacture CARs is you can have one donor and make a product that can be given to a hundred different patients instead of taking the patient’s own T-cells. And those hundreds of products can be given in a very short duration of time. Essentially, if I see a patient today and I have an allo CAR T available, that patient can technically get that product three or four days from now. They can start getting lymphodepleting chemotherapy and they can get that product very quickly. Whereas if I were to see a patient today and try to collect their T-cells, even with everything aligning, it might take 5 to 6 weeks for them from today to get that product. That’s the major advantage of allo CAR T products, but they’re way behind in terms of clinical development and seeing the light of day.

The advantage of having allo T-cells utilized to manufacture CARs is you can have one donor and make a product that can be given to a hundred different patients… but they’re way behind in terms of clinical development and seeing the light of day.

Dr. Usmani

Efficacy of allogeneic CAR T-cell therapy

CC: Do we have any efficacy data? Are they working?

Dr. Usmani: They are working. We have seen some efficacy data. There’s an Allogene CAR product. In fact, Sham Mailankody from my program presented those data [in 2021] showing about 60% of the patients responding to that allo CAR product.

Now, the follow-up is short. We know that these patients, too, get CRS and neurologic side effects but the follow-up was only about three or four months so we need [a] longer follow-up to see. Is this activity long-lasting or just a short-duration activity? What kind of long-term side effects do we get from using this strategy?

Are there any CAR T-cell therapies that are looking at different targets on the myeloma cell?

CC: Right now, the approved ones go after BCMA. Are there any CAR T-cell therapies that are looking at different targets on the myeloma cell?

Dr. Usmani: Yes. Another target is called GPRC5D. That was a homegrown CAR T at MSK (Memorial Sloan Kettering) that Dr. Mailankody presented, showing good activity in patients who have had prior BCMA CAR Ts and BCMA therapies as well. The response rates, again, [are] in [the] high 60, 70% range looking at the various cell doses that the patients received. That CAR T is now being developed by BMS. There are other programs that are utilizing that CAR T.

We also have some very interesting dual CAR T data — BCMA and CD19 CAR T — that was presented by colleagues from China at the ASCO and EHA meeting showing high response rates.

The cool thing about that platform was the short production time. That product was manufactured within 48 hours. What we’re seeing is the new platforms are actually reducing the production time and that will be a good challenger to the allo CAR T strategy. If we are able to shorten that time, then there might not be as big an advantage for an allo CAR compared to [a] patient’s own T-cells.

Bispecific antibodies


CC: Moving on to other types of T-cell redirection, there’s the bispecific antibody. There’s one that I hear it’s almost ready to be approved. Can we talk a little about Teclistamab?

Dr. Usmani: It got a favorable response from EMA, but it’s not yet approved. We’re waiting to hear from the FDA. I’ve been involved with Teclistamab from the very beginning. In fact, the first patient who was ever treated in the world was my patient. I’ve been with that program from cohort one, patient one.

CAR T-cell therapies are very effective, but bispecifics are therapies that will change how we manage patients in the community at large. They actually might challenge CAR T-cell therapies because they’re an off-the-shelf option, giving high response rates of, again, 60, 70% in relapse/refractory myelomas — [a] very similar patient population to CAR T-cell therapies — and it’s given subcutaneously.

Now, cytokine release syndrome is something that we see with the bispecific antibodies as well and that’s something that we have to watch out for.

The concept of this technology is very interesting. You’re going to hear TCE or T-cell engager as terminology. You’re going to hear bispecific antibody as terminology. The concept is the same. One part of that molecule recognizes the surface marker on myeloma cells. It could be anything. It could be BCMA, it could be GPRC5D, or something else. The other part of that molecule recognizes the T-cells. There is surface marker CD3 that recognizes.

The difference between [a] T-cell engager and bispecific antibody is the structure of that molecule. If it’s a whole antibody, then you call it a bispecific antibody. If it’s only a fragment of an antibody, you call it a T-cell engager.

Different companies and platforms have different molecule structures that are proprietary so the names are going to be different. Long explanation but a lot of excitement about that technology.

Teclistamab is the frontrunner. We might hear some good news about it later [in 2022] in the US and Europe. We’re all really excited about that platform.

Possibility of getting bispecific antibodies at a community hospital

CC: For patients, it’s exciting because it doesn’t involve having to probably relocate like the CAR T-cells. You have to go to a CAR T center and spend time away maybe from your home and family. Would the bispecifics be something that could be given maybe at [a] community hospital? Or is it something that you need to go away for?

Dr. Usmani: I think there will be a learning curve for our community physicians because giving bispecifics does require some education and comfort in managing cytokine release syndrome. It’s quite possible that they might ask the academic centers to give the first cycle of treatment.

Patients do need to be monitored during that first cycle as they’re going through the various step of dosing to full dose for that cytokine release syndrome. And because our community colleagues don’t see myeloma as frequently as some of the other solid tumors, they might ask us to give that first cycle.

Once patients are beyond that first cycle, it’s like getting any subcutaneous treatment so the short answer is yes, it will be possible for patients to receive this treatment out in the community. But I don’t see this happening during the first year of the FDA approval. It will be a steep learning curve for our community docs.

Side effects of bispecific antibodies

CC: Usually after the first cycle or two, the CRS and the neurotoxicity seem to go away?

Dr. Usmani: The likelihood of having those side effects is during the first three or four doses, so that first month. It’s really about engaging the T-cells.

Once the T-cells are active, they know exactly what to do, and they’re fine with the job assigned to them, it’s that early part where you’re trying to say go and kill the myeloma cells. They get revved up and release those cytokines. Once that process is done, the risk goes down to negligible.

Yes, it will be possible for patients to receive this treatment out in the community. But I don’t see this happening during the first year of the FDA approval.

Dr. Usmani

Frequency of subcutaneous injection

CC: For Teclistamab, is the infusion weekly [or] monthly? How often would I need to get this subcu injection?

Dr. Usmani: The subcu injection is on a weekly basis. [For] the first ten days, the step of dosing is given every fourth day for the first two doses before you get the full dose. That’s how it was done in the studies. I would be surprised if the FDA-approved label says something different. But again, we will know what the FDA says later [in 2022].

Very interesting and very encouraging data for our patients who have had triple-class refractory disease.

Dr. Usmani

Efficacy in comparison to CAR T-cell therapy

CC: What about the efficacy? How does it compare to CAR Ts?

Dr. Usmani: Response rates are around 63, 64%, which is very high. The median PFS (progression-free survival) is about a year, almost 12 months. The approvals for Carfilzomib, Pomalidomide, and even Daratumumab, the response rates were 25 to 30% for each of those products and the PFS for those products was about four months.

That gives you the context that you have this bispecific antibody, these are patients who have progressed on treatments like Carfilzomib, Pomalidomide, and Daratumumab, and you’re still seeing these high response rates and median PFS. In fact, the median PFS is similar to what was reported for ide-cel. Ide-cel’s PFS was less than a year and the response rates were over 70%, but median PFS was in a similar range. Very interesting and very encouraging data for our patients who have had triple-class refractory disease.


CC: There are other bispecifics besides Teclistamab. There’s Talquetamab. Is that going after the same target or a different target?

Dr. Usmani: It’s in the same patient population, but the target is GPRC5D. GPRC5D is a unique target to plasma cells. Talquetamab appears to be active. Response rates are up in the 60% as well.

We don’t have the PFS data because the development of that particular bispecific is a little behind Teclistamab, but we’re seeing activity of Talquetamab even in patients who have had BCMA-directed treatments, including CAR Ts and bispecific. It’s looking very promising.

Bispecifics with other targets

CC: There are many others, not just these two. There are a lot of bispecifics out there. Are they all doing quite as well?

Dr. Usmani: Yes. For BCMA-directed bispecifics, there are several options. Elranatamab is very active. ABBV-838 is very active. There’s a Regeneron bispecific. There’s a BMS Celgene T-cell engager that’s targeting BCMA as well. All of them are showing very similar activity. I think there are some differences in the safety profile percentage of patients getting cytokine release syndrome when they’re getting it. Some of those issues will be the distinguishing factors.

There are some that are given less frequently. I think the AbbVie bispecific, which was actually developed by a smaller company called Teneobio, is given every three weeks. There will be some nuances or differences between these BCMA-directed bispecific.

It’s good to know that there are other targets where we can see good clinical activity in patients.

Dr. Usmani

For GPRC5D, we only have one, but there are others that are in early development.

We have another target called FcRH5. There’s an antibody called Cevostamab, which appears to be active, [with] response rates of about 50% in patients who have relapsed/refractory myeloma beyond four lines of treatment.

It’s good to know that there are other targets where we see beyond BCMA and even GPRC5D where we can see good clinical activity in patients.

CC: As a patient, that makes me feel good. Even though some people say you might be able to use another BCMA-directed therapy, for me, I would like to have another target in my back pocket.

Combination therapy

TRIMM-2 Trial

CC: TRIMM trials are not only using the bispecifics, but they’re combining them with things. Can you talk a little bit about those?

Dr. Usmani: Once the efficacy and recommended phase 2 dose of both Teclistamab and Talquetamab were ascertained, the next step was can we combine them with other myeloma treatments and see if we get better clinical activity.

The TRIMM-2 study is looking at the subcutaneous Daratumumab administered with Talquetamab as well as with Teclistamab. There is a combination study of adding Pomalidomide to those combinations as well. We haven’t heard about the Pom combos, but we know the subcu data combinations. They have been reported out by my colleagues — Drs. Krishnan, Ajai Chari, van de Donk — each of them presented these data at different congresses over the past six or eight months, and I’ve participated in those studies as well. The overall response rate with each of those combinations is about 80 odd percent, which is remarkable because most of these patients were Daratumumab refractory in a previous line of treatment.

Why are we seeing a higher response rate compared to what we would expect with Teclistamab and Talquetamab? Daratumumab also is inhibitory to regulatory immune suppressive cells by virtue of blocking CD38 so it’s really acting as an immune modulator and enhancing the effects of these. I feel that’s probably the reason why we’re seeing this activity.

Those are very high response rates. With both Teclistamab and Talquetamab, the responses are in the 60%, but you’re seeing a higher percentage. Very encouraging. It means that we can potentially use this combination in earlier lines of treatment, even for newly diagnosed patients. It would be really cool to have a non-chemotherapy approach just using antibodies.

CC: Right now, is it still in that triple-class refractory population?

Dr. Usmani: Yes, but there are clinical trials in earlier relapse and even in the newly diagnosed setting being planned. They’re not in the public domain yet, but they’re planned and we are probably going to have these bispecifics examined for newly diagnosed patients.

CC: Yes, that might be something to consider for the high-risk group, which is really still quite an unmet need here in myeloma.

Earlier lines of treatment

CC: There was a trial that was presented that talked about RVd plus or minus Elotuzumab. Was that correct?

Dr. Usmani: Yes, this was an update from the SWOG-1211 trial.

To give you a context about high-risk patients in general, myeloma is a very heterogeneous disease. Biologically, we have eight or nine different subgroups depending on how you classify it on a molecular basis. From a clinical behavior standpoint, the way that we classify myeloma is patients who are at a higher risk of relapsing early after getting front-line treatment compared to those who have standard risk; in those patients, we don’t expect the myeloma to relapse early.

High risk is defined by certain clinical features, such as circulating plasma cells or extramedullary myeloma, or certain stereotypic abnormalities, like translocation for 14, 14;16, 14;20 or deletion 17p as well as amplification of 1q21. The SWOG-1211 was the first clinical trial that I had the privilege of designing and running when I was a junior faculty within the US cooperative group setting focused on high-risk myeloma. If you look at all the clinical trials, all the major studies that have been reported, they take all comers — any myeloma patient can participate. What we recognized as clinicians is high-risk patients don’t do well.

The idea of the SWOG-1211 was [to] design a trial just for high-risk patients and see if we can make a difference for those patients; that was the first effort. The idea was [to give] RVd for induction and then [continue giving] RVd as maintenance — the dual PI/IMiD maintenance strategy. Then in the experimental arm, Elotuzumab was added to that same RVd backbone, both in induction as well as maintenance. It was a randomized phase 2 study and the study did not show a benefit of Elotuzumab adding anything to RVd. However, the trial showed better PFS than our historic control. The median PFS for just the RVd was about 34 months. Our assumption was that the median PFS for those patients would be about 26 months and that assumption was based on patients getting tandem transplant so this was from the total therapy time. The RVd arm actually performed better than the older therapy.

SWOG-1211 set up a benchmark for other high-risk trials to follow. At the ASCO meeting, we heard about a UK study looking at KRd-Dara for high-risk patients. There’s an IFM trial and there’s also a KRd-Isatuximab study from the German myeloma group. These are smaller single-arm studies that are trying to do the same thing — do enrichment design trials for high-risk patients.

I wanted to give the whole context of why that study is important. The results by themselves for SWOG-1211, it’s considered a negative study because Elo (Elotuzumab) didn’t add anything. But then it set up a very important benchmark for other studies to improve upon.

CC: That’s good to know. I really didn’t know that background and I’m glad to hear that more and more studies are just targeting that high-risk myeloma population. It’s so important to figure out how can we control that disease early on in that group of people.


CC: How about the DETERMINATION trial? I hear so much about it. I still haven’t quite figured out what the results mean. Can you try to clarify that?

Dr. Usmani: It’s very interesting. It’s a positive study. The primary endpoint for this particular trial was showing PFS benefit between doing an early transplant or delaying it at the time of the patient’s first relapse. There is a 21-month benefit in favor of doing [the] transplant early for that young myeloma patient.

The median age [in] this study for patients enrolled was 55 years so this is a young patient population. This is a sister trial to [the] IFM 2009 study that had already been reported out about five years ago.

The depth of response in terms of MRD (minimal residual disease) negativity and sustained MRD negativity appears to be higher in the transplant arm as well. The study has a median follow-up of about 70 months and, at that point, median OS (overall survival) has not been reached in either of the arms.

Some investigators, the way that they’re framing that is incorrect. They’re saying there’s no difference; that’s not how you read the statistics. You don’t say there’s no OS different at a time point when the median OS has not been reached in both arms because there’s not enough follow-up. If that was the case, we would be saying the same thing about the MAIA trial, the ALCYONE trial, the CASSIOPEIA trial… All of those trials had no OS benefit when they were reported out because the median OS had not been reached in those arms.

The new questions should be what about CAR Ts [and] what about bispecifics? We’re designing trials with that question in mind.

Dr. Usmani

The other important thing that we see is there is no difference between the two arms between second primary malignancies as well. The second primary malignancies that people get in one arm over the other are different, but the overall percentage is about 10-odd percent that was reported out. Again, that’s my take on the study. It really doesn’t add any new information. We already knew the IFM 2009 study data.

What it does augment is the use of Len (Lenalidomide) maintenance because the IFM 2009 study stopped maintenance after a year but the DETERMINATION trial continued maintenance for everyone until relapse, progression, or intolerance. The study really doesn’t add a lot more to what we already practice.

I hope that this is the last trial that we’re thinking about early versus late transplant because that is an old question. Now, the new questions should be what about CAR Ts [and] what about bispecifics? We’re designing trials with that question in mind. I think there’s a lot of hype around DETERMINATION but really it’s hype. I don’t think it adds much to what we are doing right now.

CC: Early transplant means transplant is part of your induction therapy. Late transplant means at first relapse. Is that what the trial was talking about?

Dr. Usmani: Yeah. Both arms did pretty good in terms of median PFS. Median PFS if you got [a] transplant was around 68 months. Median PFS if you just got RVd and delay transplant was about 47 months. There was a 21-month difference in favor of early transplants.

The follow-up is short on the study so you’re not going to have a lot of people even in the RVd arm relapsing to get their transplant.

Myeloma patients are doing so well today. The median OS is at least 10-plus years. You can just say after a four or five-year follow-up that we’re seeing OS differences. I’m hoping that by the time we get the DETERMINATION OS data, it’s going to be ten years from now. Because our patients are going to be doing so well that we’re going to be looking at this historic data and saying it was a good question at that time, but probably not relevant to us by the time that reads out.

CC: Exactly. In ten years, who knows what our induction therapy is going to look like? Much better, I’m thinking.


CC: What about the ENDURANCE trial? Can you talk a little bit about what that was?

Dr. Usmani: The ENDURANCE trial ran side by side [with] the SWOG-1211 study and it was asking an induction question for standard-risk patients. Is KRd better or RVd better for induction?

ENDURANCE was a randomized phase 3 study. Half of the patients got Carfilzomib with Len-Dex (Lenalidomide-Dexamethasone) as induction. The other half got VRd or Bortezomib with Len-Dex as induction for eight cycles. Then everyone got Len as maintenance.

This study enrolled standard-risk patients because high-risk patients were going on the SWOG-1211. Translocation for 14 patients were enrolled [in] this study as well.

Trial readout [showed] no differences between PFS on either arm of the study. Essentially for standard-risk patients, it established RVd as the right treatment choice just like the SWOG-777 trial had shared with us.

The other interesting thing about the median PFS of RVd on the ENDURANCE trial is the median PFS was around 34 months. Again, the SWOG-1211 with the PI/IMiD maintenance showed the same thing. My colleague, Shaji Kumar, presents this slide saying what makes the difference in high-risk patients is the dual maintenance if you look at the ENDURANCE trial and SWOG-1211 together because both of these were enrolling at the same time.

CC: So dual maintenance is what’s happening now in high risk?

Dr. Usmani: For high-risk patients.

New & exciting studies

CC: Anything else that we should be talking about? Anything else new and exciting?

Dr. Usmani: There are a lot of new trials that are in the works. There’s the CARTITUDE-5 study, which is looking at patients getting RVd as part of induction. These are patients who either are transplant ineligible or they’re deferring their stem cell transplant to first relapse. Everyone gets RVd as part of induction treatment but then half of the patients get randomized to getting CAR T-cell therapy; [the] other half move on to their maintenance treatment. The people who get the CAR T-cell therapy don’t get any maintenance. That’s a really cool study. We’re hoping that it can provide a good answer for those patients.

The second trial is actually looking at transplant-eligible patients. Everyone gets the quadruple regimen of Daratumumab with RVd and then patients get randomized to either a transplant or CAR T-cell therapy. That’s a very exciting study. We’re hoping we can get a positive answer for our patients.

High-dose Melphalan and transplants have been a part of myeloma treatment for a long time but if we can replace them with another cellular therapy approach, which is more specific to the myeloma cells, I would really welcome that.

CC: I would welcome that, too.

CAR T-cell therapy for transplant-ineligible patients

CC: When you talk about transplant-ineligible patients — there’s that group of patients that really are not eligible for transplant for whatever reason — would those group of patients not be eligible for CAR T-cell therapy or would they be possibly eligible? I know you have to look at them individually, but as a group, is it just like you’re not eligible for this or you’re not eligible for that?

Dr. Usmani: We are a little bit more lenient in CAR T-cell therapy eligibility compared with stem cell transplantation because patients are not getting the same level of myelosuppression with high-dose chemotherapy like a stem cell transplant. There might be patients who are in their mid-70s or even late 70s who are able to get CAR T-cell therapy that we would not necessarily pick for transplantation. We’re thinking about CAR T-cell therapy in a more lenient way because of the safety profile.

CC: That’s good to hear. It’s just amazing all these new therapies. When I was diagnosed back in 2008, most of the things we talked about weren’t FDA-approved except Revlimid and Velcade.

Words of wisdom

CC: When you see a newly diagnosed patient or even an older patient who may be relapsed/refractory, how do you provide them with hope with all these new treatments? What are your words of wisdom to these patients?

Dr. Usmani: I give them the context. I tell them about the time when I was starting in the field in the early 2000s and how the outcomes were for myeloma patients. I walk them through how things have improved, what our goals and expectations are today for our patients, and the treatment options we have. I provide them with measured hope.

We do recognize that myeloma is still not a disease that we can cure, but we can control it for a long duration of time. Even for patients who have high-risk myeloma, we’re thinking about things in a different way and trying to be proactive in giving different strategies for those patients rather than just treating them in a vanilla, one-size-fits-all way. I provide that context to patients and then it’s really about individualizing treatments based on patient preference as well. This is really a partnership. Our job is to provide patients with as much information as they can gather to make good, informed decisions.

I give them the context. I provide them with measured hope. We do recognize that myeloma is still not a disease that we can cure, but we can control it for a long duration of time.

Dr. Usmani

What will cure myeloma?

CC: Good. Now, you did mention the word cure. Do you think we’ll be curing any myeloma patients any time in the future? What do you think that would look like?

Dr. Usmani: I would say, yes. This is something that I’ve shared on other forums as well. If we’re able to get patients to MRD negativity and maintain them in that negativity for a certain period of time and then stop therapy at that time, then we can functionally cure [a] majority of patients.

Myeloma is a disease that tends to occur later in life. There are other competing health issues that patients have so a true cure cannot be determined in that situation compared to someone who was 20, got diagnosed with cancer, and dies of a heart attack at 90. You can say this person was cured [of] cancer. You can’t say that about a myeloma patient who’s getting diagnosed in their sixth or seventh decade of life.

If you can kick myeloma down to undetectable levels, start treatment, and patients continue to thrive for years and cancer doesn’t come back, in my mind, that’s functional cure.

My answer is yes, we’re going to get our patients there. The key would be finding the right recipe to get patients to that sustained MRD negativity before stopping.

CC: Right, and now we have so many ingredients for that recipe that I’m sure we’re going to find it soon.

It’s really about individualizing treatments based on patient preference as well. This is really a partnership. Our job is to provide patients with as much information as they can gather to make good, informed decisions.

Dr. Usmani

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Multiple myeloma

Multiple Myeloma Research | Moffitt Cancer Center

Multiple Myeloma Research

How a Rocket Scientist is Trying to Help Cancer Patients

Our hope is that when we do this at every juncture through a patient’s journey through multiple myeloma, potentially we could extend their survival to maybe like 10 to 15, maybe even 20 years.

We’ve been hearing about emerging treatments for multiple myeloma, in particular for relapsed/refractory patients. There are novel therapies, new combinations, and more about CAR T-cell therapy and bispecifics.

There’s a lesser known area of study, helmed in part by someone with fresh eyes – Praneeth Sudalagunta, Ph.D., a former aerospace engineer who specialized in computational models to help solve programs.

So the question is: can we use computers and patient data to help them figure out the next best treatment for them? Explore below.

Thanks to Karyopharm Therapeutics for its support of our educational program.


Stephanie Chuang: Hi, everyone, this is Stephanie with The Patient Story, and I am hoping that you’re doing well wherever you’re joining us from. I’m really excited. This is actually a first of its kind interview for us because it features a rocket scientist, and I know that that’s a little joke that you’ve heard before. So I’ll welcome, without further ado, Praneeth Sudalagunta, Ph.D., applied research scientist at Moffitt Cancer Center. So welcome, Praneeth.

Praneeth Sudalagunta, PhD: Thank you for having me. I’m really happy to be here and talk to you today.

Then there comes my mother or my brother or my uncle, my father – everybody knows somebody who has cancer and that hits them at a very personal level.

What drew you to work in cancer research?

Stephanie Chuang:  I’m excited because this is a different angle we’re talking about. Usually, we’re talking to, as I’d mentioned, patients and people in that area and then also to a lot of specialists, myeloma specialists, people who are studying and researching it, as well as treating patients in the clinic. You come from a different background. The way you’re studying to help myeloma patients and their families is very different. It’s unique, and that’s why I’m excited to dive in. 

You’re studying these myeloma cells and plasma cells and everything in the lab. What drew you to be a scientist at a cancer center?  Because you could do this in a number of different settings.

Praneeth Sudalagunta, PhD: Yes. That’s a fantastic question, because there’s actually an anecdote that I usually tell people because I do get this question a lot, especially because of the transition that I’ve made from aerospace engineering to cancer research.

A specific setting is when I’m taking an Uber ride. Then the driver just really makes small talk and then they ask, What do you do? I say, I work at a cancer hospital and then here at Tampa, Moffitt is kind of like your neighborhood cancer hospital where everybody knows Moffitt.

The moment I say that I do cancer research, there’s usually like a three to four second pause. And then there comes like my mother or my brother or my uncle, my father, somebody everybody knows somebody who has cancer and that hits them at a very personal level. That is something that is incredibly compelling about working at a cancer center because it puts you literally close to patients and you have access to patient data in a way that maybe a research facility at a university may not have. So I think that’s what’s really exciting about being at a cancer center.

Stephanie Chuang: Wonderful, and yeah, it’s so true. Unfortunately, there are very few degrees of separation. Lots of people who are  impacted in some way by cancer. I had non-Hodgkin lymphoma, a blood cancer, and so very grateful for any research that’s happening in this space. 

You and I agreed that there’s a need to translate this medical scientific jargon into understandable, digestible information for people. We know that myeloma is not curable right now. There is no cure. But what we do know and why we have so many of these series now is because there’s so much going on in the landscape of myeloma drug research and a lot of that in combination, which we’ll talk about later. It makes it tricky to understand how people are really responding to a particular drug, and that’s where you come in. 

Moffitt: Studying myeloma outside the body

The focus on relapsed/refractory myeloma patients

Praneeth Sudalagunta, PhD:  When you have a newly diagnosed patient who has never seen any therapy, they typically respond to the frontline therapy they get. And what happens after that is that once they relapse to that, it happens at some point. For some patients, it’s very quickly. For some patients, it may take a while. But whenever they do relapse, it’s kind of all bets are off really because you really don’t know what they get. 

Then as they keep relapsing, the complexity keeps increasing exponentially because now you have different sets of patients who have received different treatments in different sequences, right? And a lot of patients we’ve noticed that over the several lines of therapy, develop what we refer to as multi-drug resistant state, which basically is that they might have been exposed to four or maybe six, four lines of therapy. And then they’re all of a sudden refractory to like 20 drugs. 

This is something that we are able to figure out because what what was developed here at Moffitt Cancer Center by Dr. Ariosto Silva and Dr. Ken Shain, whose lab I work in, is that they’ve pioneered this technology where they take cancer cells from a patient, which is donated by these patients at Moffitt Cancer Center.

Method of studying tumors outside the body (ex-vivo)

Praneeth Sudalagunta, PhD: What we do is that we culture them outside the human body, basically in a petri dish. We trick the cancer cells into thinking that they’re still inside the patient’s body by giving them enough resources to survive, and then we treat these cells with various drugs. This is an incredibly powerful piece of information because this is something that you wouldn’t otherwise get in a clinical setting because these patients, they always receive combination therapies. 

So if a patient has responded, you don’t know if they’ve responded to one particular drug or of the three drugs that they’ve received. Or is it like a combination. You basically have six possibilities. That’s why this platform that was developed here at Moffitt Cancer Center is so powerful is because we were able to characterize drug sensitivity for a given patient to various drugs individually. That’s what really powers my research project.

Stephanie Chuang:  The way that people are figuring out resistance or sensitivity to drugs, meaning if they respond to a drug is by having to go into this clinical trial or just taking the combination if it’s already approved and then figuring out that way. Does it work? Does it not work?

That’s hard, right? It’s hard for people in so many different ways, especially when you’re dealing with something that’s chronic, this relapsed refractory multiple myeloma population. They are physically going through a lot and mentally and emotionally, they’re not really getting a break. So being able to test all these things in a lab is incredible. 

How do you work with the physicians?

Praneeth Sudalagunta, PhD:  Right now, what we do is that we generate a PDF report for a physician here at Moffitt, for every patient who donates their bone marrow specimen. And then we actually have these bar plots, which are like, okay, for this particular combination, this is what the response is going to be like, so there’s a predictive response. That kind of gives the physician a relative view of these are the different drugs. And relatively speaking, this is how these drugs respond compared to each other. So that is something that we want to develop.

Stephanie Chuang: Ok, great, we’ll dive more into this in a bit, but let’s rewind a little bit into talking about personalized medicine and predictive, right? We keep hearing predictive and this is promising for people for all the reasons we mentioned earlier.

Can you talk about what it means to identify predictive biomarkers like what are you looking at? How is it being studied in the lab effectively?

In myeloma, there’s no real baseline for this. There’s really not a lot of data, so there’s a lot of potential for improvement.

What exactly are predictive biomarkers in multiple myeloma?

Praneeth Sudalagunta, PhD: Absolutely. So in order for predictive biomarkers, on one hand, we have the the readout, which is the drug sensitivity, right? So we have this drug sensitivity for each of the patients. And in order to be able to predict the drug sensitivity, we need to identify a feature in a given patient.

So the question is, what are these features now? What we rely on is that there are certain genetic features and there are certain other cancers where there are certain mutations, for example, that make a particular patient more sensitive or more resistant to a given drug. And this information is widely known in those cancers. 

But in myeloma, there’s no real baseline for this. There’s really not a lot of data, so there’s a lot of potential for improvement. And what we do is that we use gene expression data. Now, gene expression might sound like a very absurd scientific jargon term, so I will try my best, again an aerospace engineer’s perspective of what a gene expression is. 

What is gene expression?

Let’s think about a cell as a factory. Now, every factory produces something. Let’s say, this factory produces T-shirts, right? And there are other factories that might be producing belts, another factory that may be producing trousers. And collectively, what they do is they clothe the population, the society. It’s what happens inside a complex organism’s tissue and an organ is that you have these different types of cells and they all are doing their part in making sure that the organ functions in a certain way.

But sometimes when there is a particular type of cell that’s not functioning as expected, which is typically what happens when that particular cell turns malignant is that you have a supply chain issue like kind of we’re all experiencing right now. What happens in that organ is that you have too much of something and then relatively you have too little of something else. And that’s what leads to potentially organ failure, and it could be very catastrophic.

Now let’s zoom into what happens inside the cell. Now the cell, like I said, it’s a factory that makes T-shirts. It has something like a family recipe. It’s like your grandmother’s recipe for biscuits or something like that. It’s hardcoded and written into a giant world which is called the nucleus, and this family recipe is basically the DNA. Then on the floor of the factory, you have a lot of machines, and these machines are known as proteins.

Proteins are aptly termed as molecular machines, and they do all the work inside the cell. So you have this giant family recipe that’s inside the vault that is locked, not everybody can walk in there because it’s protected and then you have all these machines on the floor. So how does this information, this recipe from the vault go into these machines because these machines need to know what to do, right?

Because they need to be a machine that draws the cloth, another machine that cuts it, another one that folds it and then stitches and then prints. So all this needs to happen in the sequence, and they all have to be done in a particular way because you need to have t-shirts which are big or small and so on and so forth.

What happens is that these messages are being sent from inside the nucleus using basically you can call them supervisors, these are managers. These are upper manager level people who have access to the vault. They have exclusive access to the vault. And then they send this information down to the factory workers on the floor. And what gene expression really is wire tapping that information that comes from inside the nucleus to these molecular machines.

What we do is that before they go into that, we capture that information just like wire tapping. Then we’re trying to estimate what the cell is telling. It’s trying to estimate basically sequence mRNA, which is messenger RNA. That’s what gene expression is, and it’s like it says – messenger, right? So it’s the messages that are going to these proteins and that’s what we captured. 

So this gene expression we capture for over 20,000 genes. Now you have a problem – you have 20,000 genes and you just don’t know which genes are really important for you. That is something that we figured out.

Using our approach is that we try to figure out which genes are actually driving resistance to a given drug and which genes are driving sensitivity to given drug. And we are able to do that because we have gene expression for 500 patients on one hand. 

On the other hand, we have the drug sensitivity for all those patients, so we’re able to match them, use computational methods and say these patterns lead to resistance to this drug and these patterns lead to the sensitivity to the other drug and so on and so forth. That’s basically not in a nutshell what a predictive biomarker is.

Stephanie Chuang: Well, it’s hard to do in a nutshell for that topic! If I’m hearing correctly again boiling it down to the very essence of what you’re saying, you’re studying the messaging that’s happening from the nucleus or the vault to the proteins, which are the machines, the molecular machines, right? You’re capturing this somehow.

And some of the messaging allows for a pattern of sensitivity to a particular drug and other messaging with a certain pattern shows you, oh, they’re more resistant to this drug or something like that. Is that ball park?

Praneeth Sudalagunta, PhD: Perfect.

Testing tumor behaviors outside of the body

Stephanie Chuang: It’s very interesting because it’s fresh eyes, a different perspective with that background, using the mathematical, computational models that you have from one field applying it here, I think that’s fabulous. 

So again, what I’m hearing, you had mentioned the two things you’re studying the drug sensitivity and the gene expression as part of this research, those are the two important parts. Now specifically, first of all, you had mentioned the actual process. 

So these patients at Moffitt, they were getting bone marrow biopsies or basically they were getting extractions to get those cells from the bone marrow right? And that was what’s being studied in the petri dish. Is the experimental the pioneered approach with the tumor microenvironment. So making sure that they would stay alive outside of the body?

We found that daratumumab… and selinexor… actually have this anti correlative profile, where the fingerprint of one drug is exactly the opposite of the fingerprint of the other.

Praneeth Sudalagunta, PhD:  What we do is that we take these cells and we culture them in a petri dish. But the actual term is that it’s a multi-well plate. It has (about) 384 wells. Now we’re trying to use a 1536-well plate where you’re able to test 1536 experimental conditions on one patient simultaneously. So this is allows you to test several drugs at different concentrations. You need some technical replicates in case there are any issues. And we need to make sure that if there’s any variation to account for things like that.

So what we do there is that in that well, we culture these cells with bone marrow stromal cells. These are from the patients. It’s not from the same patient. It’s usually from another patient a few months ago or like a few weeks ago. We capture these cells in a flask and then allow them to replicate.

Then we use those cells to kind of give them that microenvironment. It provides them those growth factors to survive. You also use that patient’s plasma and then we add that into that. We think that they’re still in that microenvironment for them to survive.

Stephanie Chuang: Wonderful. Thank you for that. I know that there was a recent – it’s ASH, so it’s a huge blood disease blood cancer conference where brilliant minds gather, and there was a presentation specifically about this kind of research applied to daratumumab and selinexor. I’d love to hear about that research.

New study: the relationship between selinexor & daratumumab

Praneeth Sudalagunta, PhD:  There are these predictive biomarkers. So what we’ve done is we’ve tested 500 patients with one 180 drugs,  some of them being used in multiple myeloma but most of them are drugs that are used in other cancers. And what we did is for these 500 patients, we also have their gene expression data and we combine the two of them to identify basically like a fingerprint, like a genetic fingerprint for each drug. And we did this for all the 180 drugs. 

We were particularly interested in those pairs of drugs which had an exact opposite fingerprint, like if there are certain genes which have which are implicated in resistance to one drug. Are those exact same genes implicated in sensitivity to another drug?

We did this massive analysis with all these 180 drugs, and then we found that daratumumab, which is a monoclonal antibody, anti-CD38 monoclonal antibody that’s currently approved for use in multiple myeloma and selinexor, which is a selective nuclear export inhibitor, also approved for use in relapsed multiple myeloma, is that these two drugs actually have this anti correlative profile, where the fingerprint of one drug is exactly the opposite of the fingerprint of the other. That is something that caught our eye and then what we did is that we basically reached out to and have an active collaboration with Karyopharm Therapeutics.

We reached out to them and said, in your trials where you’re treating selinexor patients, could you look at the treatment history of the patients and split them into patients who have been exposed to an anti-CD38 monoclonal antibody and those who did not and then compare their survival?

Clinical validation of computational, data-driven approach

What they did is they essentially compared the two. In two clinical trials, STOMP and XPO028 , they noticed that patients who received an anti-CD38 monoclonal antibody survived longer versus those who did not. That’s basically a clinical validation of an inference that we’ve made based on a completely data-driven approach where we did not use any known biological knowledge or any mechanism. 

None of that. We just used this data and then we fed it into this computational system. It basically spits out this pair of drugs and we go into a trial and see if there is any difference. Lo and behold, we find that difference. And it’s a validation that this whole computational approach does work. That’s what the ASH talk that you were referring to is focused on.

Stephanie Chuang: Wow. So what I’m hearing you say is there’s all the computational models, the data that’s coming out. And then this was verified by the clinical research data, real world data from patients and how they had performed on the the daratumumab type drugs, so the anti CD38 monoclonal antibodies. What you’re saying is what you found with your data was that those with the daratumumab resistance were sensitive to the selinexor. So was it vice versa as well?

Determining if patients with selinexor resistance are sensitive to daratumumab 

Praneeth Sudalagunta, PhD: That’s a very good question. So based on our inference, we expect it to work both ways because we don’t know… I mean, it’s a correlation, so we don’t know off directionality. Since we reached out to Karyopharm Therapeutics and since they looked back in time, they were able to because their trials involve selinexor and they can always look back in time and say whether a patient has received daratumumab or not. 

You could always flip that question and look at a patient who’s enrolled in a daratumumab trial and see if the patient has prior exposure to selinexor and so on and so forth, potentially if it works both ways. We don’t know this yet, but potentially as a hypothesis, it works both ways. 

In research: could you alternate 2 drugs like daratumumab & selinexor and prolong patient survival?

You could have daratumumab-selinexor, and once the patient is exposed to selinexor now, something that commonly happens when you expose the patient cells to a particular drug, they acquire resistance to that drug. So the first we’re exposed to daratumumab, now they acquire less resistance to daratumumab. 

And now you treat them with selienxor since we know that they’re sensitive to selinexor, then they acquire resistance to selinexor, could you then treat with daratumumab again? Right? So basically, what we would be doing is that from a patient’s perspective, we would be taking them back in time in terms of the tumor. The tumor would go back in time to the point where they were first treated with daratumumab, and that’s essentially prolonging survival by that much amount. 

And could we do this over and over again? Could we do this once?  These are all open questions and this is something that we’re actively investigating, but based on our data, itself, we don’t know off directionality, we just know this much that there is a negative relationship. We just don’t know what’s the extent of it. And that’s something that’s worth investigating. It’s a very good question.

Stephanie Chuang: Yeah, it’s fascinating, all of the different questions that this poses. So if I’m a patient and a caregiver now listening to this, it’s like, OK, so now you know that daratumumab resistance, you may respond well to selinexor. So that’s one data point that might be helpful, although I think right now a lot of specialists and physicians are trying to do these different combinations. If you haven’t, we’ll add this as the next regimen. What else can patients take away from just that part? It’s so fascinating if you were able to kind of do both back and forth.

I just want to be very clear. So one, is according to both your data and also the selinexor clinical trial data, people who were on daratumumab and then selinexor did better than those right who were just on selinexor themselves.

Praneeth Sudalagunta, PhD: Yes.

Stephanie Chuang: So you have that data, OK, which is really important. Then the second question that came up that needs to be studied is well, we need to figure out the directionality of it. And could it be if you could figure out with daratumumab that the inverse is true, that then you could do daratumumab, then selinexor and then daratumumab again? And then it’s like, well, how many times could you do that to prolong survival? Right? And of course, this is all without talking about side effects. And of course, people develop those. But just purely on the scientific sort of level, that would be the line of questioning to follow.

Praneeth Sudalagunta, PhD: Yes. That’s something that we’re actively investigating. So based on our data, like I said, we don’t infer directionality and we’re thinking about that. Could we develop some kind of a computational approach? Can we use a particular type of data set to infer this directionality? That’s basically something that we are looking at. 

Could we look at a patient who has the gene expression of a patient before they were exposed to selinexor versus after exposure? They can look at this difference between their gene expression and what difference does that make? Does it flip this fingerprint from one side to the other? That is something that we’re actively investigating.

Looking ahead with this kind of research

Stephanie Chuang:  So you’re actively investigating a lot of different things. And I know you said there were a lot of drugs, but in myeloma, we know the four major classes of drugs. Then you also have the novel mechanisms of action like selinexor, so is there going to be testing like, it’s really a function of how these different drugs act and you’ll also test the proteasome inhibitor versus the monoclonal antibody versus the IMiDs, that kind of thing.

How do you approach this research with the different classes of myeloma drugs?

Praneeth Sudalagunta, PhD: Yes. When we look at these drugs first, we look at them in an agnostic sense. We don’t really classify them based on classes because what we know is that drugs which belong to the same class, they sometimes have a different pharmacodynamic effect, which is basically if a drug has a particular target, how does that inhibit that particular target and how does that vary across time?

That effect that the targeted effect of a particular drug that’s basically the pharmacodynamics and the pharmacokinetics is when a patient takes a pill like, basically equal to the ADME process, it gets absorbed. You have that drug available at the site of the tumor. And how does that vary as a function of time? So a few years ago, I was reading this textbook just to understand pharmacokinetics and pharmacodynamics. Then the author wrote a really nice statement which made a lot of sense to me and stayed with me. 

It’s that pharmacokinetics is what the body does to the drug, and pharmacodynamics is what the drug does to the body. There’s a yin yang effect there, which is really cool for me to remember.

Stephanie Chuang: That is really interesting. And so I just want to make sure I’m understanding this correctly. So what that means is it’s agnostic to the classes because while you can say how the drug is supposed to react to the body, we actually don’t know how the body will – we don’t know the other part of it. So it is very patient specific, and that’s why it’s personalized medicine.

Praneeth Sudalagunta, PhD:  It’s patient specific, but also it’s drug specific because drugs within a class, they behave very differently. And this is kind of known but not very well known in the field. So there’s a lot of complexity that’s associated with it.

Stephanie Chuang: That answers my question because I was asking, if you test one class, does it apply to all? And the answer is no. This has to be research that’s done with each drug in different classes. 

Praneeth Sudalagunta, PhD: Exactly. 

Stephanie Chuang:  You have different sequences.  What’s the goal? I know that this study has been ongoing, so it’s been 500 plus myeloma patients. That’s a great number. What’s the next hallmark moment for for the study? What are the goals here to expand to? The major goals – you talked about some, but what are the next major steps here?

The hope and what we’ve shown in our study is that when you do things this way, the patients do survive longer. 

What are the next major steps in this research?

Praneeth Sudalagunta, PhD:  Right now, the way traditional treatment is given in the clinic is that a newly diagnosed patient comes in or the patient is early relapsed or refractory or late relapsed refractory. You know where they stand in terms of that timeline.

Then those patients are given a certain treatment that’s for an established clinical pathway system. What we want to do with this particular research is that transformed that into a predictive, biomarker driven decision making system. 

When a patient comes in, you’re able to identify this fingerprint that the patient has, and that’s from the gene expression data. And then we are able to tell that this particular patient would be best suited with this drug. It’s not something that’s defined by this sort of clinical pathway system. The hope and what we’ve shown in our study is that when you do things this way, the patients do survive longer. 

That’s what we’ve showed with the daratumumab-selienxor study in a microcosm. But potentially if you could apply this to all kinds of fingerprints that might exist out there for different patients, you could potentially match them to a drug that they would best respond to.

So you have subsets of patients responding to subclasses of drugs and then you’d kind of have treatment prescribed in that particular fashion. It’s kind of a predictive, biomarker driven therapeutic intervention. That’s how I would put it with respect to the next step for this study, yes.

Stephanie Chuang: A couple of follow ups there. You would just need a bone marrow biopsy from patients to be able to do this research right for the gene expression? 

Praneeth Sudalagunta, PhD: Yes, so that’s the cool thing. So what we need here is since we’ve already done ex vivo drug sensitivity characterization on a cohort of patients, that’s kind of the patient. It’s like a training set and we’ve learned a lot of things from that training set.

We no longer would need to do that going forward with a new patient. So the new patient would basically give us, would donate their bone marrow specimen and we would get the gene expression data from it. We would not need to do the ex vivo drug sensitivity characterization. And the idea is purely based on gene expression.

Could we make a certain conclusion in terms of which drug or which particular subclass of drugs the patient would be best suited to? And alternatively, what we could do is if we can have cells to be able to characterize their ex vivo drug sensitivity, they can also match drugs. 

Ex vivo drug sensitivity screening also does the same thing, but in a very different way, right? So even there, you can identify a particular drug that the patient is more sensitive to, just like this fingerprint from the gene expression data does. And what I personally think is that the future is really in a multimodal imaging or decision making system where you have these multiple modalities kind of coming together and informing a particular common decision making system. So that’s what I would say that that’s really where I kind of foresee the future of cancer treatment really is.

Stephanie Chuang:  Which is exciting. I want to clarify just in terms of what patients would need. So as a new patient wanting to be part of this process to see if it would work for them. You’re saying you would still need bone marrow cells from the bone marrow, right? But you wouldn’t need for them to have to go through a treatment like that data, is that what you’re saying to show the sensitivity or resistance?

Praneeth Sudalagunta, PhD:  If you go back to the the prime objective of the study is that we have two sets of data, ex vivo drug sensitivity and gene expression. So we have this for 500 patients and we use this to inform the model. Going forward,we just use the gene expression data from a patient and then that just informs the process.

Stephanie Chuang: Perfect. So that saves the time, of course, a huge amount of time.

Praneeth Sudalagunta, PhD: And definitely cost because the gene expression data is something that is a lot more affordable than doing this ex vivo drug sensitivity screening because it involves a lot of personnel, a lot of equipment. That kind of brings up the cost. So you’ll be able to do more with less money.

Future possibilities with other combinations of myeloma drugs

Stephanie Chuang: So you were mentioning before, too, about how this particular part of research came about, which actually started with another study looking at four combinations with selinexor and different drug combinations, right? What was the result of that that prompted this study and what are the possibilities with other pairs of drugs?

Praneeth Sudalagunta, PhD: So basically, we looked at four two-drug combinations involving selinexor. They are:

  • Selinexor-dexamethasone, which is already FDA approved combination
  • Selinexor-pomalidomide, which is currently being studied in the STOMP trial
  • Selinexor-elotuzumab
  • Selinexor-daratumumab, which are (both) also being studied in the STOMP trial because it’s a multi-arm clinical trial

What we’ve observed is that in our ex vivo drug sensitivity cohort, in the patient cohort that we looked at, we noticed statistically significant synergy.

Synergy is basically it’s better than it’s not better than one drug, it’s basically better than the additive effect. So what is an additive effect? Additive effect is if one drug kills 50 percent of the cells, the other drug kills 50 percent of the cells. The additive effect is 75 percent. When drug kills 50 percent, the other one killed 50 percent of the remaining 50 percent, and now you have 75 percent. If the combination kills 87 percent, then you could say the 12 percent is a synergistic effect. So that’s synergistic effect. It’s kind of like a high bar when we think about combination therapies and that high bar was what we used to characterize these two drug combinations. 

What we noticed is that out of the four combinations that we looked at, selinexor dexamethasone, selinexor pomalidomide, selinexor elotuzumab, was statistically significantly synergistic. And selinexor daratumumab was synergistic in a sub cohort of patients, which was very interesting to us because whenever we see that we’re thinking there is some kind of a predictive biomarker. There is something that is common among these patients that’s driving them to be synergistic and not in the other patients. 

That is really exciting from a research standpoint, and that’s when we really got interested in looking at selinexor and daratumumab as a possible sequential therapy and basically looking at these predictive biomarkers. And this can be potentially applied to other drugs.

Basically, there are several drugs that are available currently in multiple myeloma. And if you think about the possible combinations, it just basically explodes combinatorially. All of that can be done using a simple computational model, which kind of prunes all these different pairs and gives you this curated list of pairs that you could look at for combination therapy and also for sequential therapy. And this could potentially be tested in a preclinical setting first and then in a clinical setting, and that’s when it would translate into clinical practice eventually.

Stephanie Chuang: Yes, which is an important point to make – a lot of this needs to still go into clinical trials, and after that data is when you’d see the practice happening at your health care provider.

But all this to say that this research is really exciting because you’re able to do the studies without having people actually have to go through everything first to get the data which again, is just so big if we can save people that stress and that weight of having to endure all of the treatments that they already have to anyway, then I think this is great for not just their survival, but their quality of life. So thank you.

Praneeth Sudalagunta, PhD: Thank you so much.

Stephanie Chuang:  So my last question for you is what is the high level message and takeaway,  especially relapsed refractory multiple myeloma patients and their families, with this kind of data? Big question, because we talked to a lot of people who do clinical trial research, and it’s always, how far away is this from me benefiting in real life? And what’s the five year, 10 year sort of picture for for patients?

How might myeloma patients benefit from this research in real life?

Praneeth Sudalagunta, PhD: That’s a great question, and the short answer is whatever study that we are doing right now, we’re putting all this information out there. The first step is always to go to a clinical trial,  because a clinical trial would ensure that it’s actually done in a controlled condition. It’s basically proven, you know, like there’s a lot of thoroughness associated with it. 

Once it goes to a clinical trial, that’s when it’s available to patients for improving their treatment therapy. So the idea here is to put out several novel therapeutic strategies based on these genetic fingerprints that we are trying to capture from gene expression data. And the idea would be matching patients to these fingerprints and then identifying them and matching them to the drug that they would best respond to. 

And this drug would potentially prolong their survival, through that particular treatment and also this would be done the next time they would have to get treated so it would prolong their survival then, and the next time and the next time.

It has this compounding effect, and our hope is that when we do this at every juncture through a patient’s journey through multiple myeloma, potentially we could extend their survival to maybe like 10 to 15, maybe even 20 years. And that’s at that point. It’s kind of a new life, and that’s that’s that’s kind of the idea behind that.

Stephanie Chuang:  Thank you so much for sharing this is exciting research. It’s so nice to have the aerospace engineer, rocket scientist, you know, perspective as fresh eyes and fresh knowledge in the cancer space. So thank you for the work you do.

Praneeth Sudalagunta, PhD: Thank you so much for giving an opportunity to talk about my research. Thank you.

Calquence (acalabrutinib) CAR T-Cell Therapy Caregivers CLL Hematology Ibrutinib (Imbruvica) Leukemia & Lymphoma Oncologist Venetoclax Zydelig (idelalisib)

Dr. Tim Fenske, CLL Treatment

Tim Fenske, M.D., M.S.

Chronic Lymphocytic Leukemia (CLL) Treatment

Dr. Tim Fenske is a hematologist-oncologist who specializes in cancers like lymphoma, leukemia, and CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma). In this interview with The Patient Story, Dr. Fenske describes the basics of CLL and latest treatment options, including immunotherapy and targeted therapy.

  • Name: Tim Fenske, M.D., M.S.
  • Role: Professor, Medical Oncologist, Researcher
  • Experience: ~15 years
  • Hematology/Medical Oncology
    • Cancer Center – Froedtert Hospital, Moorland Reserve Health Center
  • Associate Professor
    • Medical College of Wisconsin
  • Fellowship
    • Hematology/Oncology – Washington University – St. Louis, MO (2002-2005)
  • Approach with patients: Education & including patient perspective

Patients who are nervous about a clinical trial typically say things like, “I don’t want to be a guinea pig.” The thing is, that’s not really the case. In most trials, you will not be the first person to have taken a drug. There are very few scenarios in which the patient would be the first.

Tim Fenske, MD, MS

Introduction & CLL Basics

Can you introduce yourself?

My name is Tim Fenske. I am a part of the faculty at the medical college at Wisconsin University in Milwaukee where I’ve been practicing for about 14 years. My practice is focused on lymphoma (Hodgkin’s, non-Hodgkin’s) and leukemia.

I came to medicine from the research side of things. I had spent several years doing lab research and became very fascinated with the immune system and the idea of bone marrow and stem cell transplants as well as immunotherapy as ways to treat cancer. That’s how I got interested in this field.

Then, after all the years of training, residency, and fellowship, I ended up as a specialist in blood cancers with my research area being more focused on clinical trials and testing new agents.

What is CLL? Is it leukemia or lymphoma?

With CLL, they actually call it CLL/SLL. That’s a way to make the distinction that it can present in different ways. There’s a leukemic presentation where there are a lot of cells in the blood, and then with SLL it’s more of a lymphoma where they have enlarged lymph nodes and not a lot of cells in the blood.

The distinction for CLL is a certain number of cells in the blood. You can have enlarged lymph nodes with CLL, but if you just have the lymph nodes and not so much the cells in the blood, that’s gonna be called SLL. The cells themselves look the same. The diseases are the same. It just has more to do with where the cells are living.

»MORE: Learn more about CLL →

What is the difference between leukemia and lymphoma?

The short answer is leukemia means you have cancer cells circulating in the blood. Lymphoma is when you tend to have the cells in lymph nodes or other organs that are part of the blood system like the spleen.

There are, of course, exceptions. You can see lymphoma show up in just about any organ. Leukemia can present as almost like tumors in the blood.

The most common scenario is that leukemia is circulating in the blood and there are detectable cancer cells in the blood. Whereas a straight lymphoma is when the cells aren’t so much detectable in the blood, but they’re in the lymph nodes.

Testing & Treatment

What determines when someone with CLL will get treatment?

In many cases you can wait. We check a lot of biomarkers and run a lot of tests on patients when they’re first diagnosed. We run chromosome tests, protein stains, mutation analyses, and things like that. Those things are useful for predicting prognosis.

Within patients with CLL, there are some who have a more aggressive form of the disease and can’t do watch and wait very long. There are others who won’t get treatment until five or 10 years after they were diagnosed.

These biomarkers are reasonably good at predicting whose disease is going to be a slow mover versus a fast mover, but they don’t actually tell us who needs treatment at that moment. These biomarkers are more for giving us an overall idea of how the disease is going to go: fast or slow.

The actual decision to treat or not treat is based on more basic things like whether or not the patient is anemic or has a low platelet count. Other symptoms might include fevers, drenching sweats, weight loss, extreme fatigue, or pain from enlarged lymph nodes.

Those kinds of things would influence a decision of whether to treat or wait.

What are some of those biomarker tests?

There’s something they do on the immunoglobulin gene called a gene mutation analysis. That’s a little confusing. The normal counterpart cells that CLL cells come from are called lymphocytes.

Those cells go through a normal maturation process as part of the immune system. In that process, there’s a normal mutation process that happens.

A cell that’s further along in the B cell development pathway will have these mutations, and a cell that’s not as far along won’t have those mutations.

It’s a way of assessing how far down the B cell development pathway that cell got before it turned into a CLL cell. It’s not a mutation that drove the cell to be cancerous. Those are different.

Immunoglobulin mutation analysis has been a good way to cluster patients. If they’re mutated, they have a better prognosis as it turns out. If they’re unmutated, those cases tend to be a little harder.

Then there’s a panel we do called a fish panel. It looks for structural abnormalities in the chromosomes of CLL cells. One of the things we look for is chromosome 17p. That’s where the p53 gene resides. If that is deleted, that’s been shown to be associated with a less favorable prognosis in CLL.

If you have a deletion of part of chromosome 13 and that’s the only abnormality, those cases actually do better than normal. There’s another abnormality they look for in chromosome 11. That’s associated with adverse prognosis as well. So, the fish panel is another way to risk-stratify patients. It doesn’t necessarily influence the treatment, but it tells us what risks there are.

Why do genetic testing if it doesn’t influence treatment?

Some of those studies like with p53 and others, a lot of that data was generated years ago using treatments that were not as good as what we have now. It’ll be interesting to see if those risk assessments will still hold up nowadays with some of the new treatments. We’ll see. What used to be a really high-risk group may not be as bad as it used to be.

Newer Options

Can you talk about some of the new treatments?

Chemotherapy drugs are small drugs that block something that any dividing cell has to do, so that would be how it copies its DNA, unwinds its DNA, how one big cell physically separates into two smaller cells. All the proteins and enzymes that makes that machinery work, those are the things that chemotherapy blocks. 

Rituxan is a big antibody molecule that’s much larger than a chemotherapy drug. It sticks on the outside of the cell, and it flags it to your immune system in a number of ways.

Then you’ve got these newer, more targeted agents like Ibrutinib, Venetoclax, Acalbrutinib, Idelalisib, and many others in development. These are smaller drug molecules that go inside the cells. Instead of blocking something that any cell has to do, they tend to be more selective. They target enzymes that are more active in CLL cells.

We’re in this new era where we have these novel or targeted agents. That really started about 10 years ago with Ibrutinib and more recently we’ve had Venetoclax. Before that, we really only had chemotherapy and Rituxan, which is more of an immunotherapy drug.


Ibrutinib blocks an enzyme called bruton’s tyrosine kinase or BTK. This is an enzyme that does play a role in normal B cells, but it’s a very important enzyme in CLL cells, too.

You don’t get all the same chemotherapy side effects. It’s a highly effective way of treated CLL. It does still have possible side effects, but it does a good job.


Venetoclax works in a different way. It works on a pathway of proteins. When you have cancer, the problem can be that the cells are growing too much or that they don’t die when they’re supposed to die. CLL, in large part, sees cells not dying when they’re supposed to, so they’re accumulating. Venetoclax blocks a protein and turns a death signal back on in the cells, triggering apoptosis. That’s just a fancy term for programmed cell death. It restores the cell’s ability to die.


Then you’ve got this other class of drugs called PI3 kinase inhibitors like Idelalisib. It blocks a different enzyme in the cell.


Recently, we’re seeing second and third drugs in each of these categories. So, at first we had Ibrutinib, and now we also have Acalabrutinib. It isn’t technically approved for CLL yet, but it’s probably going to be approved in the coming year. It seems to be more selective for BTK than Ibrutinib. We believe that some of the side effects from Ibrutininb are due to what we call “off-target effects,” so in theory, Acalabrutinib might have a more favorable side effect profile.

What is the difference in side effects with these drugs versus chemotherapy?

You don’t lose your hair, typically you don’t have as big of a drop in blood counts, and in general you don’t see nausea and vomiting. So, with these targeted agents, you don’t have typical chemo side effects, but they can still have side effects.

For example, Ibrutinib can cause rashes, diarrhea, heart rhythm disruptions, muscle and joint aches, and things like that. About 20% of people wind up having to come off of these drugs because of some side effects. It really depends on the person.

Do you see chemotherapy becoming a thing of the past?

Targeted agents are definitely where the field has moved. For several years there was a debate about which patients should still get chemo.

Really, in the last year based on some recent studies, most experts in the field agree that there’s very little if any role for conventional chemotherapy in the frontline for CLL.

Maybe in the third or fourth line, you might start to think of some chemo. It’s going to be very rarely used moving forward.

There are some newer immune therapies like CAR-T cell therapy that are on the rise too. We never really did a whole lot of stem cell transplants for CLL, but we used to do some. Those numbers are going down. We still get an occasional patient where it makes sense, but that’s not very often.

When is CAR-T cell therapy a viable option for a CLL patient?

It’s not approved as a treatment for CLL yet. It’s something that would be done in the context of a clinical trial. That being said, there are three main classes of targeted agents. There are BTK inhibitors like Ibrutinib or Acalabrutinib. There’s Venetoclax. Then there’s the PI3 kinase inhibitors like Idelalisib.

If somebody has had all three of those classes and they’re still having problems with their CLL, that’s somebody we should be thinking about putting in a CAR-T trial.

Other Advice

How do you handle patients who have questions about holistic or alternative treatments?

In the old days, the doctor told the patient what to do, and the patient did it no questions asked. Doctors these days try to be more collaborative and take the patient’s perspective into account. That can be kind of tricky when the patient is bringing in all sorts of things they read on the internet.

As a doctor, you want to be respectful of the fact that it was important enough to the patient that they brought it up, but at the same time, a lot of these things don’t have nearly enough scientific evidence for us to recommend them.

Diets, supplements, fasting, and things like that are brought up a lot. We don’t have enough good scientific data to support a lot of that.

It’s not to say that those things are worthless; it’s just that we don’t have enough data.

Diet is a big one. For every one special diet that someone is touting, there are hundreds of others saying the same thing. All we can do is give people generalizations of healthy diet, exercise, stress management, support systems, good sleep, and all these things people know to be doing anyways.

I think some patients get frustrated because they just want some simple answers and things they can do. I try to walk through that with them. If a patient is really set on a certain supplement or something, I have our pharmacists look at it and make sure there’s nothing harmful that would interact with their other treatment.

I make sure it would be safe for them to take, and then I’ll tell them as far as I know, it’s okay for them to take it, but we can’t always know for sure how something is going to affect them.

Do you have any advice on clinical trials?

A lot of patients are not very well informed about clinical trials. It’s on the doctor to educate them.

Many people seem to think that trials are a last resort after there’s nothing left for them to try. That’s not true.

There are all different kinds of trials. There are phase 1 trials which means you could be getting a really new drug. Ibrutinib, Venetoclax, and all our new drugs were a phase 1 trial at some point. If patients hadn’t signed up for those trials, those drugs wouldn’t have made it to market. Those patients’ willingness has helped a lot of people.

Then you have trials where we’re testing out how we use drugs and maybe using them in a new combination. It really depends on where a patient is in their disease.

Patients who are nervous about a clinical trial typically say things like, “I don’t want to be a guinea pig.” The thing is, that’s not really the case. In most trials, you will not be the first person to have taken a drug. There are very few scenarios in which the patient would be the first. Like I said, many trials are looking at drugs that have already been approved and just tweaking how we use them.

Getting the word out about being involved in clinical trials is important because it not only pushes the field forward, but it also could give patients access to cutting edge therapies a little sooner.

Do you have any advice for newly diagnosed patients?

First of all, try to understand your disease as well as you can. A lot of people think leukemia is just one thing or lymphoma is just Hodgkin’s or non-Hodgkin’s. Within non-Hodgkin’s, there are about 50 different kinds.

So make sure you understand your disease process and how it’s normally managed so they have an idea of what to expect.

If a patient has something that’s less common, it never hurts to get a second opinion from a specialist who sees more of that disease. We have people who live in more rural areas and don’t want to drive two or three hours when they want treatment.

I understand that, but they could see that specialist every once in a while in addition to their local doctor. That specialist can collaborate with their local oncologist in many cases.

Thank you Dr. Fenske!

Hematologist Oncologist Experts

Rafael Fonseca, MD

Role: Interim executive director, hematologist-oncologist
Focus: Multiple myeloma, new drug development
Institution: Mayo Clinic

Farrukh Awan, MD

Role:Hematologist-oncologist, associate professor
Focus:Leukemias, Lymphomas, BMT
Institution:UT Southwestern

Nina Shah, MD

Role: Hematologist-oncologist, researcher
Focus: Multiple Myeloma
Institution: University of California, San Francisco (UCSF)

Kerry Rogers, MD

Role: Hematologist, researcher
Focus: Chronic lymphocytic leukemia (CLL), Hairy Cell Leukemia (HCL)
Institution: OSUCCC-The James

Tim Fenske, MD, MS

Role: Hematologist-Oncologist
Focus: chronic lymphocytic leukemia (CLL) & leukemia and lymphoma | CAR T, targeted therapy
Provider: Medical College of Wisconsin

Irene Ghobrial, MD

Role: Clinical investigator and professor of hematological oncology
Focus: Multiple myeloma, Waldenström’s Macroglobulinemia, early screening, clinical trials
Provider:Dana-Farber Cancer Institute (Boston)

Edmund Tai, M.D.

Role: General oncologist, hematologist
Focus: Specialist in treating Chinese-speaking patients
Provider: Sutter Health (Bay Area, CA)

Jacqueline Barrientos, MD

Role: Hematologist, researcher
Focus: Chronic lymphocytic leukemia (CLL), lymphoma, 17p Deletion (Ibrutinib, Acalabrutinib, Venetoclax), IgHV mutation
Provider: Northwell Health (NYC)

James Berenson, MD

Oncologist: Specializing in myeloma and other blood and bone disorders
Experience: 35+ years
Institution: Berenson Cancer Center
Darzalex (daratumumab) Harvard Medical School Hematology Medical Experts Myeloma Oncologist

Dr. Irene Ghobrial, Multiple Myeloma

Irene Ghobrial, MD

Multiple Myeloma Treatment

Dr. Irene Ghobrial is an experienced hematologist and oncologist who specializes in myeloma. In this interview with The Patient Story, Dr. Ghobrial talks about treatment for those with MGUS, smoldering, and active myeloma, and where she thinks research is headed.

  • Name: Dr. Irene Ghobrial, MD
  • Roles
    • Clinical Researcher
    • Professor of Medicine
  • Experience: ~15 years
    • Professor of Medicine, Harvard Medical School
    • Director, Clinical Investigator Research Program
    • Fellowship
      • Mayo Clinic, Graduate Medical Education, Hematology & Oncology
    • Residency
      • Cairo University School of Medicine, Pediatrics
      • Sinai-Grace Hospital of Detroit, Internal Medicine
    • MD – Medical School Education
      • Cairo University School of Medicine
  • Approach with patients: Unique approach for each patient in order to prevent disease progression

We’re trying to develop better targeted therapies so we’re not just using myeloma drugs earlier.

We’re actually trying to develop what’s called prevision intervention which are new therapies, vaccines, and other ways to make the immune system stronger so it can prevent progression without any chemotherapy.

Can you introduce yourself?

My name is Dr. Irene Ghobrial. I’m a professor of medicine at the Dana-Farber Institute and Harvard Medical School. I’ve been here for about 15 years.

Over the last few years, we’ve said multiple myeloma is a cancer where treatment doesn’t start until a patient is symptomatic. These symptoms are lytic lesions, fractures, anemia, and kidney failure.

It didn’t make any sense. We were all trained this way. But for any other cancer, it’s not like that. If you have a woman with early breast cancer, you never tell this woman, “Wait until you have metastasis everywhere.”

At Dana-Farber, we’ve said, “Why don’t we change that?” We are finding better biomarkers and developing clinical trials for earlier intervention and prevention of precursor conditions like Monoclonal Gammopathy of Undetermined Significance (MGUS) and smoldering myeloma.

Can you talk about The Promise Study?

We expanded that to start the first screening study. It’s called The Promise Study. We got 10 million dollars to start the first screening study in the US that looks for myeloma in individuals who are at risk.

Those at high risk are African Americans and first-degree relatives of those who have myeloma. 

We’re screening 50,000 individuals. We’re trying to encourage people to sign up online. It’s really simple. They get a kit, and take it to a lab. They take care of the rest. If they’re positive, we call them and help them. If they’re negative, of course, we let them know. 

The hope is that we screen early, prevent early, and in the future, we don’t even diagnose myeloma. The goal is to always prevent it early.

»MORE: What is multiple myeloma?

What does the treatment look like for someone with MGUS?

If they are low-risk, we don’t want to treat them. We just observe them, and we try to figure out why their myeloma isn’t progressing and learn from that to help others.

Maybe there is something in their immune system that is so good that it’s preventing the disease? Is there something in the early tumor cells that we can understand?

For higher risk MGUS, we have an antibody treatment called Daratumumab. We have more studies coming along.

What about treatment for smoldering myeloma?

For smoldering myeloma, we have multiple clinical trials including active myeloma treatment, but we’re just starting it earlier. If someone is extremely high-risk, then we go ahead and start them even if they have smoldering myeloma.

Are you curing people before they have active disease?

The word cure is very hard. We don’t have evidence that we have cured anyone, but we are definitely delaying progression.

Instead of having fractures in two years, can we maybe prevent them for 10 to 15 years. In that case, hopefully we’ll have even better drugs and options at that point. The hope is to cure people, but we’re not there yet.

What does it mean for someone to be high-risk?

Currently, the markers are all tumor markers, meaning your M-protein is very high, your light chain ratio is high, or your cancer cell count in your marrow is high. Of course if your tumor cells are high, you are at high risk, but there are people whose numbers aren’t that high who progress really fast. 

We’re developing better genetic markers to find out just how high someone’s risk is based on more than just tumor cell count, but more biologically.

We’re trying to see if they have a bad cytogenetic abnormality or bad DNA changes that predict whether the cells like to proliferate more quickly. 

We already did something called next generation sequencing with 200 patients. We have data already that shows those patients who have certain markers would progress much faster. We’re ready to put that in publication.

We’re hoping this would be a test we can provide clinically so people can find out at their own physician’s office if they have those markers and be labeled as high-risk in the future.

What other tests are you working on?

We have something called liquid biopsy where instead of doing it as a bone marrow biopsy, we test the blood sample. You can test all those markers in the blood.

That would be much easier because the last thing you want is multiple bone marrow biopsies for patients. Hopefully, we can just use the blood in the future for testing. 

Because MGUS and smoldering myeloma have minimal DNA in the blood, we’re working on better technologies that can detect in a much more sensitive way. We still have some work to do before those tests and screenings can be launched to patients.

Can you make a distinction between MGUS, smoldering myeloma, and active myeloma?

Active myeloma is characterized by four criteria. Those are hypercalcemia, anemia, lytic lesions, and renal failure. We have a few more now like having a high tumor burden or having lesions on the MRI. Something like this would be considered active myeloma and should be treated. 

Anything before that would be a precursor condition. The difference between MGUS or smoldering myeloma is having 10% of plasma cells in the bone marrow. Less than 10% is MGUS, and more than 10% is smoldering. 

The chances of progression are very different. For MGUS, it’s a 1% chance per year. For smoldering, it’s a 10% chance per year.

Where do you see the research going next?

First, we need to develop better biomarkers. We’re not there yet. This is just the first step. We’re trying to understand a lot of different things. 

We’re trying to develop better targeted therapies so we’re not just using myeloma drugs earlier, but we’re actually trying to develop what’s called prevision intervention which are new therapies, vaccines, and other ways to make the immune system stronger so it can prevent progression without any chemotherapy. 

The hope with that is that they will preventative and non-toxic. We’re hoping to make the screening study the standard of care where you go to the doctor at age 40 or 45 and get screened for myeloma.

We’re trying to understand why certain families have a higher chance of myeloma, why African Americans have a higher chance, and whether what we eat and the microbiome plays a factor.

What’s your advice for someone who is newly diagnosed with smoldering myeloma?

First, I would say go see a specialist. Not everyone knows smoldering myeloma. Do your homework, research, and look into clinical trials. We’re happy to assist everyone. This is why we have a whole center for prevention of progression. 

Having patients engaged and empowered is important. Patients can play a huge role in research, so get involved. If you have been diagnosed, get qualifying immediate family members to enroll in the Promise Study.

If everyone is involved and excited about the research, we will move much faster.

Thank you, Dr. Ghobrial!

Myeloma Specialists

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