Insights from Experts at Mayo Clinic on Translating Evidence to Clinical Practice - Episode 9

Selecting and Sequencing Therapy in Relapsed/Refractory MM

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Panelists take a broad look at treatment selection and sequencing through multiple lines of therapy in patients with multiple myeloma.


Shaji Kumar, MD: Prashant, you previously alluded to the role of quadruplets in the high-risk patient population. If this patient’s head effusion was a 1q gain or amplification, would you have changed the therapy? Would you have used a different approach?

Prashant Kapoor, MD: Because the patient’s performance status wasn’t as good when I saw her, I wouldn’t have necessarily changed it, but now I feel more comfortable as more data are emerging about the triplet that even frail patients can tolerate. Regarding somebody who is responding well to a regimen that they’re already on and tolerating well, I wouldn’t necessarily make changes to it.

Shaji Kumar, MD: We talked a lot about adding a monoclonal antibody in the up-front setting for patients with newly diagnosed myeloma. There are some data prompting the question: should we keep some of the effective drugs in store for the later therapy, or should we be using all the effective treatments or as many of them in the up-front setting to get the best outcomes? What are your thoughts?

David Dingli, MD: These are very interesting questions, and they’re best addressed by clinical trials. Sometimes the best trials are not conducted. We probably all agree that our best shot at treating this disease is with first-line therapy. Historically, if we look at what happens with each subsequent therapy, the duration of the response and the quality of the responses goes down. We’re at risk every time we lose patients because their performance status worsens, they develop comorbidities, or they don’t get subsequent lines of therapy for other reasons.

I’d argue that first-line therapy is probably going to be the main determinant of long-term outcome of patients. For example, take a patient with standard-risk disease who’s transplant eligible. As Morie said earlier, that patient can be expected to have a survival of about 10 years. Half of that is decided with first-line therapy. This involves 4 cycles of induction, transplant, maintenance—perhaps with lenalidomide—and that response is about 4½, 5 years. With the first-line therapy, assuming there are no developments in the field, that’s half the survival time.

One can argue that this is true whether the patient is transplant eligible or not. Interestingly, Dr Rafael Fonseca at ASH [American Society of Hematology Annual Meeting] recently reported an interesting analysis of a bortezomib-based induction regimen or a doublet vs a daratumumab-containing regimen. Of course, this gets statistically complex. We’re using real-world data to try to understand what will happen to these patients. In that analysis, he could show that the daratumumab to first line improves OS [overall survival] and PFS [progression-free survival] by 2½ to 3 years, which is quite thought-provoking.

Morie Gertz, MD: I’m a big proponent of quads up front, but it’s getting out of hand related to reimbursement. Let’s say you eventually want to take your patient for CAR [chimeric antigen receptor] T-cell therapy, ide-cel [idecabtagene vicleucel], or cilta-cel [ciltacabtagene autoleucel]. Under current labeling, you have to fail 4 lines of therapy. If line 1 is daratumumab-VRd, [bortezomib, lenalidomide, dexamethasone], and line 2 is KPd [carfilzomib, pomalidomide, dexamethasone], and you don’t want to give belantamab because it’s anti-BCMA, then what are lines 3 and 4 to make the patient eligible? It’s a bad argument about not overusing everything early. If I could use CAR T in the third line, it would be OK. I can’t, so I’m making up inferior concoctions that are meant to fail to get to CAR T eligibility.

Shaji Kumar, MD: The reality is that most of these patients who start on a quadruplet don’t stay on a quadruplet until progression, so there’s clearly a role for reusing some of these drugs later on if they’re not refractory to that.

Morie Gertz, MD: Point taken.

Shaji Kumar, MD: Hopefully that will help us with some of those as well. We’re talking about relapse and being refractory to all these proteasome inhibitors, IMiDs [immunomodulatory imide drugs], and the anti-CD38 monoclonal antibodies, and now we have other new drug classes available for treating this highly refractory patient population, particularly the BCMA-targeted therapies. The 3 platforms we have in the clinic for targeting BCMA on the myeloma cells appear to be quite effective, particularly CAR T, as you pointed out. The data are still emerging in terms of the ideal sequence of using different BCMA-targeted agents. Will 1 work after another platform or even within the same platform going after different antigens? Will that be of benefit? Would you want to speak a little about the specifics?

Morie Gertz, MD: You have to be circumspect. At ASH, Mount Sinai [Hospital] reported everything they did with BCMA. They found high levels of cross-resistance. You’re not going to use 1, then use a BiTE [bispecific T-cell engager] and go to CAR T, not if they’re both directed at BCMA. You have to think about it. Of course, we have 2 approved CAR T therapies that are highly effective and have, considering how heavily treated these patients are, a reasonable MRD [minimal residual disease]–negativity. On research trials, we have BiTEs. For most patients, CAR T means they’ll spend time away from home, bridging chemotherapy, lympho-depleting chemotherapy, and 1 shot. With BiTEs off the shelf—they’re not approved yet, but they will be—the home physician can keep them at home, repetitive dosing is permitted, bridging chemotherapy is a nonissue, and lympho-depleting chemotherapy is a nonissue just from the logistics of it unless the CAR T is shown to be much superior. There’s a lot speaking for the use of BiTE therapy.

Transcript edited for clarity.