Participants Debate Which Combination Is Best for High-Risk Multiple Myeloma

Joshua Richter, MD (MODERATOR)

Associate Professor of Medicine

Tisch Cancer Institute

Icahn School of Medicine at Mount Sinai

Director of Multiple Myeloma

Blavatnik Family-Chelsea Medical Center at Mount Sinai

New York, NY

CASE SUMMARY:

A 60-year-old White woman received a diagnosis of stage II multiple myeloma. She had a history of being a heavy smoker, with gain (1q21) cytogenetics and an ECOG performance status of 0. At the time, she was treated with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induction therapy, followed by autologous stem cell transplantation (ASCT). She achieved a complete remission with VRd and ASCT and was minimal residual disease negative, then was placed on lenalidomide maintenance therapy.

At a follow-up after 2 years on lenalidomide maintenance, the patient reported having severe fatigue and pain in her back and legs, which disrupted her ability to continue working full time. A PET scan showed vertebral fracture at L1, lesions in both femurs, and an ECOG performance score of 1. Her current laboratory levels were the following:

• M protein: 1.98 g/dL (rapid increase from prior bloodwork)
• λ free light chain increase: from 47.5 mg/dL to 136.7 mg/dL
• Hemoglobin: 9.8 g/dL
• White blood cell counts and platelets: within normal limits
• Creatinine: 1.4 mg/dL (range, 0.59-1.04 mg/dL)
• eGFR: 45 mL/min/1.73m²
• Creatinine clearance: 40 mL/min

DISCUSSION QUESTIONS

• What is the trigger to initiate second-line therapy for this patient? How do you define early vs late relapse?
• When you think about an “aggressive” and/or “high-risk” relapse, what characteristics come to mind?

WIEDER: The trigger to initiate second-line therapy would be presence of symptoms or progression, based upon patient symptoms, blood work, or imaging. In terms of factors that influence decision-making, the decision would be dependent upon what kind of response the patient had—a complete response, a partial response, or refractory disease—and how long it was, an early relapse vs a late relapse. Those would all be factors that come into play in deciding the next line of therapy or options to use.

RICHTER: If the patient has no symptoms, does the speed of the rise of the M-protein matter?

WIEDER: Symptoms could be physical symptoms, or they could be symptoms in terms of laboratory results or radiologic results. It could be relapse or progression of disease based upon any number of factors, I would say. In terms of the speed, it’s more in terms of how much time had passed from when they completed their past therapy and what [therapy] they had. Did they respond? Did they not respond? If they did respond, if they had a transplant, maintenance therapy, and so on, how long were they on it before they had progression of disease?

MO: This patient had a relapse after more than 6 months. I think the previously used VRd can be used in the early relapse.

RICHTER: Is VRd your go-to for patients relapsing on lenalidomide maintenance?

WIEDER: If they had that initially for induction therapy, I wouldn’t go back to it.

BLOKH: If they relapse after 6 months on simple low-dose lenalidomide, seem like they don’t have any catastrophic emergencies, and they’re not presenting with cord compression or anything [severe], if you give daratumumab [Darzalex] and then the triplet, they could have a great response, and you’re not using up a lot of your other therapies. You could have multiple lines of therapies to go to when they relapse again.

RICHTER: Dr Blokh, you’re saying that you would give daratumumab plus lenalidomide? Or daratumumab plus something else?

BLOKH: No, I would give daratumumab, lenalidomide, dexamethasone, and bortezomib. If they relapsed on the single-agent lenalidomide, you have a lot of options, and that could be one of them if the relapse was past 6 months.

VESOLE: This patient has biologically very aggressive disease and they have a 1q [alteration]. The idea of going back to the original therapy is certainly reasonable, but VRd is not what most physicians would use for first relapse. I think that an anti-CD38 monoclonal antibody with a proteasome inhibitor [PI] and dexamethasone would probably be the best way to manage this. Somebody could argue about carfilzomib [Kyprolis; K] vs bortezomib. It was the ENDURANCE trial [NCT01863550] that compared KRd vs VRd for frontline therapy, and we’re extrapolating from those data, which showed that for KRd and VRd, the progression-free survival [PFS] was similar between the 2 groups. KRd worked faster and had deeper responses than VRd. The more important thing is that the KRd was more effective for the high-risk patients or those with 1q gain. That wasn’t necessarily seen with the 1q amplification group.¹ I’d give carfilzomib over bortezomib because it’s probably more potent for high-risk patients. Of the [proteasome inhibitors], I think that’s more appropriate.

Then you have to decide on which anti-CD38 monoclonal antibody to use. You have to compare the results of the CANDOR study [NCT03158688] with the results of the IKEMA study [NCT03275285]. Sanofi says that the PFS for isatuximab-irfc [Sarclisa] plus Kd [IKd] is approximately 41 months² vs 28 months with daratumumab³ plus Kd [DKd]. And they’ll tell you specifically that they had high activity in patients with a 1q [alteration].²

However, the CANDOR trial never looked at the 1q patients. [In the IKEMA trial], there was some statistical manipulation of dropouts, of how they censored some of the patients with the IKd trial. I think that they dropped out 8 patients because the original [PFS] was 35 months,4 not 41 months.² They dropped 8 patients out and it ended up being 41 months, which is what they promote now.²

I’m not convinced that isatuximab is better than daratumumab. I have no qualms with either one. That would be my route. I’d go with an anti-CD38 antibody, either isatuximab or daratumumab. If I gave them carfilzomib plus dexamethasone, I would be very concerned about this patient’s long-term prognosis.

RICHTER: I agree, [but] I would ask you this: Does the duration of the remission impact it? Is there ever a patient to whom you would give an anti-CD38 antibody and pomalidomide [Pomalyst], even with a 1q [alteration]?

VESOLE: There are some data that pomalidomide has more activity… and that pomalidomide worked in the high-risk patients. I’m not convinced. PIs have a much higher likelihood to be effective in the patients with high-risk cytogenetics than do the immunomodulatory drugs. So I’m going to go with the PI.

RICHTER: That is very reasonable. Is there any reason to consider something like bortezomib, pomalidomide, and dexamethasone [VPd] from the OPTIMISMM trial [NCT01734928]?

VESOLE: I’m not going that route.

DISCUSSION QUESTIONS

• Would you use a monoclonal antibody at first relapse or hold for a later line of therapy for those patients who haven’t seen one yet? If yes, which would you use?
• What backbone partner would you choose for this patient with aggressive early relapse on lenalidomide maintenance?

RICHTER: Would you use a monoclonal antibody here or would you save that for later? Maybe carfilzomib, pomalidomide, and dexamethasone for a patient like this? And if you’re using an anti-CD38 antibody, is it isatuximab or daratumumab, and do you use it with carfilzomib or pomalidomide?

BRAUNSTEIN: [In my opinion], a monoclonal antibody is definitely indicated here. It’s well tolerated for a patient who may have residual comorbidities from prior treatment. We can only cross-compare the studies of what companion drug to use in the monoclonal antibody regimen, whether it’s DPd or DKd. Both of those studies were triplet vs doublet, but nevertheless showed PFS advantage.^3,5 I agree with Dr Vesole about IKEMA and the 1q subgroup, that there may be a benefit in that high-risk group. But if the patient doesn’t have any cardiovascular comorbidities, I’d probably lean more toward DKd. If they were intolerant to an immunomodulatory drug or had challenges with that, again I’d probably lean more toward DKd. I would also tailor to their comorbidities as well as perceived benefit.

SUAREZ LONDONO: I agree with Dr Braunstein. I think an anti-CD38 monoclonal antibody is what we need to use in this patient. This is a high-risk patient. He’s responding poorly and relapsed very quickly. The question is about the companion drug. DKd is what I’m used to using, although the PFS in the IKEMA trial was larger [than in CANDOR].^2,3 If there were contraindications, I would use daratumumab in this setting.

RICHTER: Is there any particular reason why you would choose daratumumab as opposed to isatuximab here? Is it the subcutaneous administration or the monthly dosing schedule?⁶

SUAREZ LONDONO: It’s just that I’m more used to it. But if you look at the data, the data are better. The PFS is longer.^2,3

RICHTER: That’s all reasonable. Does someone want to argue for the CASTOR [NCT02136134] regimen of DVd?

WIEDER: I think that all these are very reasonable choices. The patient initially had VRd. I assume they had a complete response and then went to transplant, which tells me that the patient is very sensitive to bortezomib, and then they progressed on lenalidomide maintenance. I try to maximize many of the medications I use initially before I go to new choices, just to increase as many options as possible. In this case, bortezomib is very reasonable because the patient had it before and tolerated it well and is sensitive to it, so why not go back to bortezomib before I try to switch to something else?

RICHTER: That’s fair.

CASE UPDATE

The patient was started on IKd and achieved a very good partial response.

DISCUSSION QUESTION

• Have you used the IKEMA regimen of IKd? If not, have you used any other isatuximab-containing regimen (eg, isatuximab plus pomalidomide)?

BLOKH: I haven’t, only because daratumumab came out first and we’re used to it. From what I understand, there are no data saying that isatuximab would rescue anyone who progressed on daratumumab, at least [when used] consecutively. Maybe if there were a couple of regimens in between, and the patient was offered an anti-CD38 agent, then I would consider giving isatuximab in a subsequent line, but I would not use it immediately after daratumumab. I would give daratumumab up front, or I would give it in relapse if the patient hadn’t been exposed to daratumumab up front.

WIEDER: I was going to say something similar. I agree, based on personal experience. daratumumab came out first. It started with the intravenous formulation⁷ and switched over to the subcutaneous injection.⁶ I just think it’s easy and I have had good experience with that, so I just haven’t had the opportunity to switch to something else.

NG: [I agree] the subcutaneous administration and the every- 4-week maintenance schedule make it easier to give.

DISCUSSION QUESTION

• What do you think of the updated PFS data from the IKEMA clinical trial of IKd vs Kd?

RICHTER: Dr Lal, do you have any thoughts about the IKEMA trial so far?

LAL: It seems to be impressive compared with dexamethasone alone, and I think isatuximab is also going to be available in a subcutaneous, on-body injector, so that will be impressive and easy for the patients to use. I think when you use daratumumab there is a problem with the collection of the stem cells sometimes, but with the isatuximab we don’t see that problem. So if this patient is going to go on to transplant, then this regimen will be probably more suitable, based upon the improved PFS, a better chance to collect the stem cells, and the possibility of using this subcutaneously in the future.

RICHTER: All very interesting and valid points. Regarding the effect on stem cell collection, you can still collect stem cells. Daratumumab has 1 FDA [regimen] approved on the basis of the results of the CASSIOPEIA study [NCT02451383] of daratumumab plus VTd [bortezomib, thalidomide, dexamethasone]⁸ and 1 National Comprehensive Cancer Network [NCCN] guideline regimen approved on the basis of the results from the GRIFFIN trial [NCT02874742].⁹ The patients were able to have stem cells collected. On average, they just take an extra day to collect. This is more of a class issue, not a drug issue. So because CD38 is located on just about everything, you would theoretically have the same issues with isatuximab; it’s just that isatuximab doesn’t have any of the approvals yet in the up-front setting.

CASE DISCUSSION QUESTIONS

• What is your reaction to the updated data from the IKEMA study?
• How do you view the efficacy of this regimen?
• Do you agree with this treatment approach?

RICHTER: Do you have any reactions to the updated safety and efficacy data for this regimen or any thoughts about how this compares to what you often do with other triplets?

SUAREZ LONDONO: These data only [recently] came out. The minimal residual disease rates are higher. It seems to be a better regimen. I echo my colleagues when they say that daratumumab was first, and we have a lot of patients who received daratumumab in the beginning, and we have patients who are currently on daratumumab. I think that’s the 1 barrier. But I think these are very convincing data; the PFS is good.⁴ It’s a good regimen.

_REFERENCES

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