Treatment Options for Patients With High-Risk NDMM


Concluding their discussion on newly diagnosed multiple myeloma, expert panelists consider treatment options for patients with high-risk disease.


Sagar Lonial, MD, FACP: Let’s get to our next case, Patient Case 2: a 57-year-old woman presents with persistent low-back pain, fatigue, and weakness. Her medical history includes hypertension, a hemoglobin of 7 g/dL, creatinine of 1.3 mg/dL, GFR [glomerular filtration rate] of 51 mL/min, LDH [lactate dehydrogenase] of 156 U/L, albumin of 2.7 g/dL, beta2-microglobulin of 3.3 mg/dL, immunofixation positive for IgM kappa, M-protein [monoclonal protein] of about 59.1 g/dL, free light chain of about 129 mg/L, multiple areas of lytic lesions, ECOG performance status of 1, and R-ISS [Revised Multiple Myeloma International Staging System] stage II. Cytogenetics by FISH [fluorescence in situ hybridization] shows 17p deletion and t(11;14). The patient is diagnosed with high-risk multiple myeloma and deemed transplant eligible.

What would be your choice of first-line therapy for this patient? Bortezomib-lenalidomide-dexamethasone, daratumumab–VRd [bortezomib, lenalidomide, dexamethasone], KRd [carfilzomib, lenalidomide, dexamethasone], daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone], isatuximab–KRd [carfilzomib, lenalidomide, dexamethasone], or other? Please take a moment to answer that, and I’m going to ask another question in the poll box. Do you have any thoughts about subcutaneous fixed dose vs IV [intravenous]? I’ll give a quick answer. Subcutaneous is the way to go unless you guys have caveats on why you wouldn’t use subcutaneous.

Andrzej Jakubowiak, MD, PhD: I agree.

Parameswaran Hari, MD, MRCP: Agreed.

Sagar Lonial, MD, FACP: Let’s see what we’ve got here. Most folks are saying daratumumab–VRd [bortezomib, lenalidomide, dexamethasone]. We’ve got a couple who are saying KRd [carfilzomib, lenalidomide, dexamethasone], and a couple who said daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone]. It’s a big mix, but we’re seeing a shift away from VRd [bortezomib, lenalidomide, dexamethasone], at least from what we saw in the previous case. Let’s start with Morie on this. What would you do in this case, Morie?

Morie A. Gertz, MD, MACP: I’d do daratumumab–VRd [bortezomib, lenalidomide, dexamethasone]. I’m not certain that patients with high-risk genetics will ultimately do better. I may be proven wrong, that these patients need carfilzomib if they’re in a high-risk situation. But right now, the data are awfully limited on this. The most important thing for this patient is determining what the maintenance therapy is going to be. This patient is going to need multidrug maintenance for a long time. That’s going to be key here.

Sagar Lonial, MD, FACP: OK. Dr Hari?

Parameswaran Hari, MD, MRCP: Daratumumab–VRd [bortezomib, lenalidomide, dexamethasone].

Sagar Lonial, MD, FACP: Andrzej?

Andrzej Jakubowiak, MD, PhD: I’ll stick to my previous opinions. I’d still favor daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone], with all the understanding of the limitations of where we are with comparisons. For high-risk patients, as I discussed earlier, I’d provide the best statistical chance of achieving MRD [minimal residual disease] negativity, which may improve the outcomes of patients in this patient population. It’s clearly shown in a number of studies.

Sagar Lonial, MD, FACP: Our standard approach is KRd [carfilzomib, lenalidomide, dexamethasone] for the high-risk patient population. We don’t introduce the daratumumab at this time point. It sounds like all 3 of you will, but we can talk through that later. Given all the information we have, how do you all define high risk and ultra-high risk? What are your institutional or practice-based definitions for that? We’ll start with Andrzej.

Andrzej Jakubowiak, MD, PhD: Like most, we apply IMWG [International Myeloma Working Group] criteria: 17p deletion, t(4;14), t(14;16), and we add to that 1q, at least in amplification, as it has been shown to also be considered high risk. I understand the limitation of that approach short of other approaches. We also like to see these patients’ Revised-ISS stage to see if we’re missing anything. For the most part, if we collect all the cytogenetics and beta-2-microglobulin, we can see that correlates quite well with outcome.

There are some other platforms that are GEP [gene expression profile] based, like SkylineDx, and previously the 1 developed in Little Rock [Arkansas], or even genetically based evaluations, which some places are using. Double-hit disease, where there are 2 significant abnormalities, are ultra-high risk. These are identifying the patients who require attention so we can aggressively treat them with the best strategy we have. But at the moment, in most places, we’re limited to cytogenetics. There was a wonderful discussion that I’d like to encourage everybody to listen to by Dr [Hervé] Avet-Loiseau, who is 1 of the experts in this field, in which he was questioning t(14;16) in the context of the French data and some other studies’ data. He qualified 17p deletion being high risk for only those who have it in more than 50% of cells. From some of the studies, there’s a difference between gain in 1q vs amplification of 1q, which is how many copies there are, but cytogenetics is still our standard approach.

Sagar Lonial, MD, FACP: Dr Hari, what do you use? How are you defining high risk?

Parameswaran Hari, MD, MRCP: Very similar to what Andrzej just described. The IMWG had its criteria: 17p, t(4;14), t(14;16), and t(14;20) would go into that. Then I’d use 1q amplification or gain—amplification meaning 4 or more copies—and I’d add all of them in the same pool. But if they have R-ISS 3, or 2 high-risk abnormalities in the same patient, I’d generally move them into the ultra-high-risk category. With double-hit in myeloma, there are a couple of definitions floating around: the original Arkansas definition and the mSMART [Stratification for Myeloma and Risk-Adapted Therapy] definition.

Then there are other things that people often overlook, such as a large number of circulating plasma cells, like 5% or more in the absence of t(11;14). Then there’s dynamic high risk, where you’re treating the patient and they’re not responding. If you’re not responding to a quadruplet or progressing in the interval between induction and collection of stem cells, those are all high-risk features. An early relapse after transplant on adequate maintenance is ultra-ultra-high risk, in my opinion.

Sagar Lonial, MD, FACP: Dr Gertz?

Morie A. Gertz, MD, MACP: You said it: extramedullary disease, circulating cells, primary induction failure, high proliferative index of the cells, and central nervous system involvement on top of everything else.

Andrzej Jakubowiak, MD, PhD: I agree with that. I just narrow it down to more standard evaluation in the short presentation.

Sagar Lonial, MD, FACP: There are 2 questions from the audience about a very high-risk subset of patients: plasma cell leukemia [PCL]. What’s your preferred go-to regimen as induction for plasma cell leukemia? We’ll start with Morie.

Morie A. Gertz, MD, MACP: It’s not VDT-PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide], which I never use. VDT-PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide] is an ablative regimen that’s 35 years old. It uses 5 drugs that have no activity as single agents in multiple myeloma. Everyone uses it. Our own experience is that progression-free survival is 2 months, and they spend 2 months in the hospital. For me, this is the time when the bortezomib is twice a week. This is when I might add a pulse of an alkylator, cyclophosphamide, 1.5 to 2 g/m2 on top of using dexamethasone. Sometimes I’ll substitute methylprednisolone, 2 g Monday, Wednesday, and Friday. I try to throw a lot of things, but I don’t use inactive agents in my myeloma, which includes cytarabine, doxorubicin, etoposide, and cisplatin.

Sagar Lonial, MD, FACP: Dr Hari, are you going to tell him he’s wrong or should I?

Parameswaran Hari, MD, MRCP: I do use VDT-PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide], but more and more I’m using daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone] in these patients and giving them weekly Cytoxan on top of that.

Sagar Lonial, MD, FACP: All right. That’s interesting.

Andrzej Jakubowiak, MD, PhD: I’m also evolving from VDT-PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide] to daratumumab–KRd [carfilzomib, lenalidomide, dexamethasone]. There are rare cases with VDT-PACE [bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide]—maybe it was luck—where following the following principles—good, quick reduction of the disease; preferably tandem transplant without breaks; and immediately resuming treatment, preferably with what worked before and until progression—I had patients in 4 and more years in remission. I had patients who failed 2 or 3 months later too. But it’s achievable in plasma cell leukemia. It’s an understudied entity, so it’s very difficult to advise what’s best.

Sagar Lonial, MD, FACP: It sounds like other than that PCL situation, regardless of whether it’s high risk or ultra-high risk, you guys have already decided what you’re going to use. Keeping people on schedule is an important part of that treatment approach. That makes a lot of sense. The last question I’m going to ask you is, what do you think are the remaining unmet medical needs in myeloma? Dr Jakubowiak?

Andrzej Jakubowiak, MD, PhD: The most important unmet medical need is how we treat high-risk disease. It’s not well established.Dropping a bomb and using everything that we have to achieve MRD negativity is simplistic. We should be able to get there, so that’s probably the biggest unmet need. The same applies in penta-refractory patients. We didn’t talk about that today, but we have the emergence of new modalities with CAR [chimeric antigen receptor] T-cell therapy and other immunotherapies. This is something that needs to be addressed more urgently than anything else.

Sagar Lonial, MD, FACP: Thanks, Andrzej. Dr Hari, what are the key takeaways, future directions, and unmet needs?

Parameswaran Hari, MD, MRCP: I agree with Andrzej that the biggest unmet need from a patient and provider standpoint is high-risk disease, where we haven’t made the same gains. But then the future, as I see it, is figuring out how we use immunotherapy. We have powerful immunotherapeutic agents. Only 1 of them has been approved so far: the BCMA [B-cell maturation agent] CAR T-cell agent. But BCMA BiTEs [bispecific T-cell engagers], non-BCMA BiTEs, and other CAR T-cell therapies are coming. Using those early, we might make an impact on the natural history of high-risk disease. That’s going to be the biggest unmet need as far as trials that we have to do. If we make an impact in high-risk disease, we’ll cure a substantial proportion of cases of standard-risk disease using that same approach.

Sagar Lonial, MD, FACP: Great. Thank you so much, Dr Hari. Dr Gertz, you get the last philosophical word. What are the takeaways, future perspectives, and unmet needs?

Morie A. Gertz, MD, MACP: The unmet need is clearly in the relapsed/refractory setting, where every trial excludes patients with platelets under 50,000 per mm3, under GFR of 50 mL/min, and with plasma cell leukemia, which is a substantial proportion of relapsed/refractory. These patients are denied access to investigational drugs, and no one knows how to treat the relapsed patient with their 22,000 per mm3 platelet count because they’ve been excluded from trials. Clearly, the future is immunotherapy. As we go forward, it’s not necessarily going to be combinations of chemotherapy with transplant, but it will be chemotherapy plus BiTEs or chemotherapy plus CAR T-cell therapy.

Andrzej Jakubowiak, MD, PhD: Agreed.

Sagar Lonial, MD, FACP: All right. This was a great discussion. Thank you, Drs Gertz, Hari, and Jakubowiak for joining us in this lively discussion on the treatment of patients with newly diagnosed myeloma, including those with high-risk disease, brought to you by CancerNetwork®. And thank you to our viewing audience. We hope you found this interactive discussion to be informative and beneficial to your clinical practice. Thank you again, and have a good night.

Transcript edited for clarity.

Related Videos
Ursula Linne-McLaren, RN, an expert on multiple myeloma
Amir Ali, PharmD, BCOP, an expert on multiple myeloma
Amir Ali, PharmD, BCOP, an expert on multiple myeloma
Amir Ali, PharmD, BCOP, an expert on multiple myeloma
Amir Ali, PharmD, BCOP, an expert on multiple myeloma
Amir Ali, PharmD, BCOP, an expert on multiple myeloma
Related Content