Evaluating Treatment Options by Patient Type in Multiple Myeloma

Robert Z. Orlowski, MD, PhD

The University of Texas MD Anderson Cancer Center

Amrita Krishnan, MD

City of Hope

C. Ola Landgren, MD, PhD

University of Miami Health System

Ajay K. Nooka, MD, MPH, FACP

Emory Winship Cancer Institute

Cesar Rodriguez, MD

Mount Sinai

With the ever-changing treatment landscape in multiple myeloma, clinicians need to be able to determine which treatment options are best for their patients.

During a lively discussion regarding the current treatment landscape, experts in an Around the Practice^® panel convened to review available treatments and debate as to which would be best for different subgroups of patients. They touch on patients who have previously received a transplant, as well as those who have experienced a relapse. The panel was led by Robert Z. Orlowski, MD, PhD, chairman, ad interim director of Myeloma, and professor of medicine at The University of Texas MD Anderson Cancer Center.

He is joined by Amrita Krishnan, MD, executive medical director of Hematology, director of the Judy and Bernard Briskin Multiple Myeloma Center, and professor in the department of Hematology and Hematopoietic Cell Transplantation at City of Hope; C. Ola Landgren, MD, PhD, professor and leader of the Experimental Therapeutics Program and leader of Myeloma Service at the Sylvester Comprehensive Cancer Center at the University of Miami Health System; Ajay K. Nooka, MD, MPH, FACP, professor in the department of Hematology and Medical Oncology, director of the Myeloma Program, and scientific director of the Winship Data and Technology Applications Shared Resource at Emory Winship Cancer Institute; and Cesar Rodriguez, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, and Center of Excellence for Multiple Myeloma, as well as being the clinical director of Multiple Myeloma at Mount Sinai Hospital.

Determining Which Patients With Multiple Myeloma Should Undergo Transplantation

Orlowski: How do you decide who should get a transplant?

Rodriquez: Transplant seems to be put on the spot lately with all these novel therapies; now that anti-CD38s are moving up front, is it still relevant to do a transplant or not? Even though transplant is all a technique that stems from the 1980s—and it hasn’t changed much since then—it is still proving its worth.

The phase 3 DETERMINATION study [NCT01208662] and the phase 2 GRIFFIN study [NCT02874742] are showing that it is improving PFS. It is improving the depth of response.^1,2 Even though it’s still not showing an overall survival [OS; benefit], part of the reason is [because] these studies are still too early. We still need to let them mature a little bit more.

We have so many salvage therapies right now that whenever somebody relapses, we have another option for them. Before, we would see OS changes in studies more easily because we didn’t have that many salvage treatment options. My take on how we manage myeloma is that our first punch should be our best punch.

If we can get the best remission, the best disease control, and for the longest period of time, then that’s going to help us gain some time for the patient to recover their performance status, to enjoy the quality of life, and at the same time give us the opportunity to come up with new therapies that can potentially be more effective at controlling the disease or are safer to give.

Landgren: Transplant for sure is a valid treatment. Many patients benefit from it. I also think, with more and more new options, life will always change. There will always be new things. That’s how everything is [evolving]. New cell phones, new computers, new therapies, everything is moving forward. The DETERMINATION study did a good job. They captured the quality of life as part of the protocol and showed that there was a significantly better quality of life in the non-transplanted arm.

In 2020, our group published 3 papers showing with [the use of] whole genome sequencing that after exposure to melphalan [Evomela], you gain between 1000 and 2000 mutations in every cell in your body. Thinking about the fact that patients with myeloma have a high risk of developing AML [acute myeloid leukemia] and MDS [myelodysplastic syndrome] including in the DETERMINATION study; there were 10 patients with AML and MDS with this shorter follow-up, and they were all in the transplant arm. What will happen to patients who will live for 10 or 20 years? We don't know that.

Patients are going to live longer and longer with the newer drugs, so this is an area where I think we have to pay a lot of attention to the toxicity, as the long-term toxicity is not only [present with] transplant but is also going to [occur with] all the immunotherapies. I wanted to address the fact that efficacy is one thing, but the long-term toxicity is very important in particular for a disease like myeloma as patients live so long.

Krishnan: To your point about the future, the phase 3 CARTITUDE-6 trial [NCT05257083] excites me because it is going to incorporate cellular therapy in myeloma [which] is our future [along with] immunotherapy. Looking at that randomized [trial] comparing CAR T vs autologous transplant as a consolidated strategy up front will be very interesting.

To your MDS point, some of that has to do with understanding whom the patient is going into transplant first, in terms of clonal hematopoiesis risk factors predisposing for second malignancies. We haven’t done a good enough job of selecting patients for that. That’s also where the field is moving—to be able to help determine that for the individualized transplant decision.

Nooka: [With regard to quality of life], there is a dip in the transplant arm that was transient for 3 months. In clinical practice, yes, we see that dip in the quality of life for 3 months, but they get back to normalcy by the end of the 3 months. That’s a clarification.

In terms of the transplant, I still feel that the transplant is the one that is able to get us to the response that we are anticipating. If we are looking for MRD [minimal residual disease] negativity, I know we are looking for MRD negativity; what is the best approach to reach there that isn’t transplant? If that goal is what we’re all looking for and that has translated into a PFS [progression-free survival] benefit of more than 2 years, I’d want to use that approach for my patients.

I also want to talk about secondary primary malignancies. The devil lies in the details. Yes, there is an AML signal that you’re seeing at 10 vs 0; 10 patients had AML. If you look at the contrary, what is the best approach in the non-transplant arm? Seven of them had ALL [acute lymphoblastic leukemia] in the non-transplant arm vs zero in the transplant arms. Could we say melphalan is protective for ALL? We don’t know; as you just said, we [may find out] as the field evolves. If you’re learning more, we’re all amenable to the change. At this point in time, to gain that MRD negativity rate, I’m all in for the transplant.

Orlowski: Is there a correct number of treatment cycles? Do you individualize based on the patient? How do you go about this?

Landgren: There is no right number. At least, we have not yet figured it out. There may be a secret number somewhere, but we don’t know that. We used to give 4 cycles of say, RVd [lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone], and that stemmed back to the good old days with the increase in [doxorubicin] and dexamethasone because if you gave more than that, you would damage the heart of the patients.

When that went away, the new therapy was just replacing the old, but the numbers remained the same. Data emerged after showing that there was money on the table. You could keep on giving more cycles and deepen the response before you transplant. Groups found that you could use 6 cycles of RVd. We published a paper years ago where we looked at 4…, all the way up to 8 cycles.

We found that the yield for stem cell collection was not different if you went even further. At our institution [Memorial Sloan Kettering Cancer Center] and different institutions I worked at, we have instituted a long time ago 6 cycles as our default, but different groups do different things.

When we have used KRd [carfilzomib (Krypolis), lenalidomide, and dexamethasone] and daratumumab (Darzalex) [plus] KRd, we have very high rates of MRD negativity. After we collect the stem cells, we would typically give 2 more cycles; that would give us a total of eight. That’s a number of out of the blue. We pulled that out of a hat.

A lot of studies have used 8, so we have done that too. After that, we put the patient on maintenance. There is also the question of if you do 2-drug maintenance­­ like the GRIFFIN study that used 2 years of daratumumab plus lenalidomide. Then the patient continues just with lenalidomide, but there are other studies that continue 2-drug combinations. There are also trials that have a single drug.

Now they’re also coming in [and using] bispecifics in combination with lenalidomide, or a bispecific alone. I’m not sure what I going to do long term, but right now, in my practice, I use daratumumab with lenalidomide, and I give daratumumab once a month for 1 year, then I tend to repeat the bone marrow to confirm MRD negativity. [From there], I go forward with lenalidomide maintenance. I may change that in the future; I do that because I want to limit the immunosuppression and the development of hypogammaglobulinemia.

Treatment Options for Patients With Relapsed Myeloma

Orlowski: Would you use daratumumab until disease progression and not use it again in the second line, or would you stop and then try to reuse it in the second line?

Landgren: In my practice, I use it frequently up front. We talked about DRd [daratumumab, lenalidomide, and dexamethasone]. I use that a lot, or daratumumab/CyBorD [cyclophosphamide, bortezomib, and dexamethasone] sometimes. As I mentioned, I have started switching from just lenalidomide maintenance, a single drug, to having daratumumab with lenalidomide in my practice as one of my defaults. I know there is not a final study proving how long to do it, but I started doing that about 1 year. The protocols have been done for 2 years or continuously.

My rationale has been that I deepen the response beyond what I do with the combination up front. Then if the patient relapses later on lenalidomide maintenance, I can then go back to the daratumumab-containing regimen. If the patient sadly relapses just a few months after you stop the combination, that is probably not a good drug to go back to. We all probably have the same experience here. If it's 6 months or 12 or say more than 12 months, I think you can safely go back and use it in other combinations. That’s what I frequently do.

Orlowski: In the past, there were studies showing that patients who were CD38-refractory with regard to their disease and had poor outcomes. Now we’ve got some BCMA [B-cell maturation antigen]–targeted therapies, specifically teclistamab-cqyv [Tecyvali], how does this work?

Nooka: It’s a great advancement that we had from a bispecific standpoint. These are slightly different from the naked antibodies that we’re used to with the daratumumab or isatuximab-irfc [Sarclisa] which are targeting CD38.

These bispecifics that were just approved, which is teclistamab, is targeting not just the BCMA, but also targets the CD3 that is present on the T cells and makes the T-cell–directed killing of the myeloma cell happen.³ This is a unique technology and is very effective. It has been transferred into clinical practice and, clearly, we are seeing those responses in these refractory patients, who had unprecedented responses that we’ve never seen before.

Orlowski: What is the role of teclistamab in relapsed/refractory myeloma?

Rodriguez: Teclistamab, at the moment, is FDA-approved for [patients] who have had 4 prior lines of therapy and have been exposed to a proteasome inhibitor, an immune modulator [IMID], and an anti-CD38 agent. It is currently going to be used in people who are heavily pretreated, which is an area that before CAR T therapy and bispecific therapy was available, we were having very poor success in having a good response and control of the disease.

We were approving drugs that had only 30% response rates and we were getting very excited with a 30% response rate as a single agent. Teclistamab is showing response rates at 63% as a single agent. That’s a benefit. It's something that we’re all excited about, and everybody wants to start treating patients with this agent.

There’s a long waitlist to try to get patients started on this regimen for everybody who is either refractory to the 3 classes or who is heavily pretreated. Do I think that this is the niche where teclistamab is going to stay? I don’t think so. It’s going to probably move up front. For now, anybody who is shown to be refractory to IMIDs [immunomodulatory drugs], proteasome inhibitors, and anti-CD38, is an excellent option for them.

Krishnan: If you see a patient who has had 4 prior lines of therapy and you can give either talquetamab, teclistamab, CAR T-cell therapy, a BCMA agent, or a GPRC5D CAR T, what will you do?

Orlwoski: Additionally, at some point, they will relapse. What would you offer them after that?

Landgren: I would do what I said before. I would have a conversation with the patient. What’s the goal of the therapy? If the patient says ‘I’ve been on so many months or years of therapy, I am treatment-fatigued,’ I think that patient could be a good candidate for CAR T-cell therapy.

The patient could also say I would like to have outpatient therapy. I know that for a lot of these antibodies, you can do them subcutaneously or I don’t mind having a shorter infusion. From all we know right now, I would pick the BCMA because there is less known about the GPRC5D. The majority of patients probably would go to the antibody in my clinic because of the availability of CAR T-cell [therapy], but I would have that conversation.

Nooka: I would like to stick with the facts so that it helps us to make the most informed decision. As of today, we only have 1 bispecific approved. I’ll be happy to choose the bispecific for somebody that may not be able to wait for a couple of months, to allow for the CAR T manufacturing.

Clearly, we can easily identify the CAR T patients and the bispecific patients in our clinics. The good thing in the future is that myeloma is a place with a plethora of options. We will have them in the future. With GPRC5D and BCMA as targets, we clearly are seeing the development of these new CAR Ts. [We need to] understand what the future holds, how do I want to treat this patient when the patient is relapsing, and how to sequence these treatments is going to be a huge question and the data will be coming in.

What we have currently is that these are not mutually exclusive so if somebody gets treated with a BCMA bispecific they could get a BCMA CAR T down the line which probably may not be my approach. I would do the opposite way going on with a bispecific, going on with a CAR T targeting BCMA followed by a bispecific targeting BCMA.

Rodriguez: There’s 2 factors I would take into account. One is the disease. If it’s a rapidly progressing disease and you can’t afford to wait these 6 to 10 weeks for the CAR T to be produced and re-infused, go for a bispecific; teclistamab is the only one that’s FDA-approved for a clinical trial. We’re seeing these prolonged cytopenias [with CAR Ts]. We’re seeing these bio-reactivations and the potential neurotoxicity or Parkinson-like movements.

It has some potential risks so it’s on the patient's comfort level. If they’re willing to do a one-and-done dose so that they can take a nice break from therapy and feel like they’re not myeloma patients for a while knowing that there’s potential they might have to deal with cytopenias. In terms of one or the other, I think all options are great. It’s just which one is available at that moment.

Orlowski: Anything else to discuss regarding relapsed or refractory disease?

Landgren: One thing I would like to bring up is that there are all these new drugs. We talked about it all the way from newly diagnosed to relapsed [disease]. There are some patients who have not had a lot of benefit from all these amazing drug developments. I think the big missing piece in the puzzle is to be better at identifying high-risk [disease] to dissect it biologically.

I think we need to apply more precision medicine to these patients. Clearly, these are different subgroups of patients, but they need other drugs than we currently have. There are patients who will have a much shorter lifespan and they have not benefited from all the existing drugs. I think that’s a very important task for the field.

References

1. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925
2. Sborov DW, Laubach J, Kaufman JL, et al. Daratumumab (dara) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-057
3. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. News release. FDA. October 25, 2022. Accessed March 22, 2022. https://bit.ly/42vEiIJ