Novel Triplets Shed New Light on Sequencing in Relapsed/Refractory Myeloma

Ajai Chari, MD

New triplet combinations anchored by anti-CD38 antibodies are expanding the therapeutic landscape for relapsed or refractory (R/R) multiple myeloma, providing exciting options that extend progression-free survival (PFS) windows from months to years for heavily pretreated patients, according to a panel of hematologic experts. Nevertheless, the regimens come with complex questions about how best to sequence and personalize treatment.

In August 2020, the FDA approved a new indication for KdD—daratumumab (Darzalex), a CD38-directed monoclonal antibody in combination with carfilzomib (Kyprolis) plus dexamethasone—for adult patients with R/R multiple myeloma who have previously received 1 to 3 lines of therapy.¹ In March, the FDA approved isatuximab-irfc (Sarclisa), another anti-CD38 antibody, in combination with Kd—carfilzomib plus dexamethasone—also for the treatment of adult patients with R/R multiple myeloma who have previously received 1 to 3 lines of therapy.²

Daratumumab and isatuximab both were previously approved in the R/R setting in combination with pomalidomide (Pomalyst), an immunomodulatory drug (IMiD), plus dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including the IMiD lenalidomide (Revlimid) and a proteasome inhibitor (PI).

“We’ve made a lot of progress with induction therapy, transplant, and lenalidomide maintenance therapy,” said Ajai Chari, MD, during a recent OncLive^® The Talk program on multiple myeloma. “Unfortunately, in the relapsed setting many patients are lenalidomide refractory. I think what’s not well appreciated is how that independently is a negative prognostic factor even with regimens that do not contain lenalidomide.”

However, as triplets continue to stake their claim in the armamentarium, exploratory analyses seek to offer more answers for individualized treatment considerations, including prior therapy, comorbidities, and perhaps the identification of future predictive markers.

Chari moderated the discussion based on the latest data from the 62nd American Society of Hematology Annual Meeting and Exposition in December 2020, which include f indings from these pivotal studies involving patients with R/R multiple myeloma:

• CANDOR (NCT03158688): a phase 3 study that compared KdD with Kd in patients who relapsed after 1 to 3 prior lines of therapy³;
• IKEMA (NCT03275285): a phase 3 study that compared the combination of isatuximab, carfilzomib plus dexamethasone with Kd, also in patients who relapsed after 1 to 3 prior lines of therapy⁴; and
• APOLLO (NCT03180736): a phase 3 study that evaluated subcutaneous daratumumab (Darzalex Faspro) plus pomalidomide vs pomalidomide alone in patients who received at least 1 prior line of therapy including lenalidomide and a PI.⁵

Panelists C. Ola Landgren, MD, PhD; Saad Usmani, MD; and Meletios A. Dimopoulos, MD, joined Chari to unpack the role of these regimens, including dosing considerations, for patients with advanced disease.

C. Ola Landgren, MD, PhD

Chari: Moving to a very complicated part of the disease, because of the increasing drug availability, [let’s discuss] updates in relapsed or refractory myeloma. Let’s get things started with Dr Dimopoulos, who has some very exciting updates on the combination of daratumumab, carfilzomib, and dexamethasone.

Dimopoulos: Yes, the [CANDOR] trial, which Dr Usmani had a very significant role in the design and the conduction of the follow-up of the study, compared KdD [versus] Kd given on the approved schedule of 56 mg for 2 consecutive days. The main finding of this study and the follow-up was that there was a significant improvement, a sustained improvement, in PFS in favor of KdD.

Of particular interest were the patients who were pretreated with lenalidomide and those who progressed on lenalidomide, where we saw, for the first time, a median PFS exceeding 2 years in this specific subset of patients. This is the best PFS that we have seen. We know that Kd and daratumumab/ bortezomib/dexamethasone are really not optimal for these patients with a median PFS of [typically] no more than 10 months. We have seen some improvement [in PFS] with pomalidomide/bortezomib/dexamethasone of up to 18 months, and now a PFS of 26 to 28 months is really encouraging [Table^1-6].

Table. Updated Efficacy Data of Triplet Combos for Patients With Relapsed or Refractory Multiple Myeloma^1-6

Chari: Dr Usmani, you published these data recently, congratulations. Any comments on other updates that you heard about at ASH on CANDOR?

Usmani: I think from a practical standpoint, one of the things that we struggle with is treating patients who are lenalidomide refractory in the US because many patients receive lenalidomide maintenance. The data for the lenalidomide refractory population are probably the key takeaway for me. Many of us have been big fans of the data on the dexamethasone combination for that patient population based on the phase 1b experience that you had published, Dr Chari.

But daratumumab plus Kd adds a very good alternative to that particular regimen and speaks to that class switch that we had talked about for 15 years when all we had were the first-generation PIs and IMiDs.

The depth of response data that Dr Landgren shared was also very encouraging. CANDOR was the first study that looked at a time-dependent MRD [minimal residual disease]-negative CR [complete response] rate at 12 months.⁶ [That’s] keeping in mind the International Myeloma Working Group response criteria. These data showed very good MRD-negative CR rates with sustained MRD negativity, as well, and that’s something unique to this 3-drug combination.

Saad Usmani, MD

Chari: Dr Landgren, any more thoughts on your presentation? And perhaps you could share the data for IKEMA study?

Landgren: [The data from the] CANDOR study showed that the PFS rates for patients who received daratumumab Kd was 12.5% [compared with] 1.3% for Kd. We also look for different ways to analyze MRD, the best overall MRD at any time [vs] different time points. The highest rate was in the best overall MRD-negative rate at any time. And for the 3-drug combination, that was 22.8% for the 3-drug combination vs 5.8% for Kd.

[These data] feed right into the same type of pattern that we have seen for other daratumumab-based combinations and also carfilzomib-based combinations in that they are quite tolerable, and if patients stay on them, the response can deepen. Unlike other drugs such as bortezomib [because] when you run into neuropathy you have to stop the drug, you cannot see this continued deepening.

The IKEMA study is very similar to the CANDOR study. It used the CD38targeted drug isatuximab in combination with carfilzomib/dexamethasone. It’s the same carfilzomib/dexamethasone dosing in the experimental and the control arms. Results showed that patients had a higher rate of MRD negativity in the IKEMA study for both the 3-drug combination and the 2-drug combination compared with [the same patient populations in] the CANDOR study. So why is that? Is that the better combination?

Because the carfilzomib/dexamethasone regimen is the same control arm in the 2 studies and the results are better in the IKEMA study, it probably is reflective of the fact that there are [fewer] patients enrolled on that study. So, as always, when we compare across studies, we have to be careful.

Usmani: There are a lot of similarities between CANDOR and IKEMA. Many feel that daratumumab and isatuximab are similar in terms of their activity. [Results of] both studies prove their point that when they are adding an anti-CD38 agent to Kd, you’re getting really good depth of response and good PFS. There might be numerical differences between the numbers in PFS benefit or MRD negativity. But if you look at the difference between the standard-of-care arms of the study and the experimental arms, there are a lot of similarities in the delta and the difference that you’re seeing.

You know when you add an anti-CD38 agent to Kd, you’re going to get good responses. I would be keen to look into the lenalidomide-refractory population specifically, as well as the high-risk population and see what the differences are there as the data mature on both these studies.

Chari: You know when you add an anti-CD38 agent to Kd, you’re going to get good responses. I would be keen to look into the lenalidomide-refractory population specifically, as well as the high-risk population and see what the differences are there as the data mature on both these studies.

Landgren: I dose once a week. And although the 2 studies show 56 mg twice a week vs 70 mg once a week, I many times do 56 mg once a week. I think that’s an easier dose to give; it’s well tolerated. I know the [data on] 70 mg are out there, but I do once a week, and I have a tendency to go for the 56-mg dose in my clinic.

Usmani: Depending on the patient, it’s either 56 mg weekly or 70 mg weekly. Again, based on the famous Dr Chari phase 1 experiment with daratumumab and Kd,⁷ I think it depends on the clinical situation and what the patient can tolerate, but in general I haven’t found any difference in efficacy in my patients.

Dimopoulos: We use 70 [mg]. I think the concern [about whether] to lower the dose of carfilzomib on a weekly basis [depends on] when we combine it with lenalidomide. Without lenalidomide, we feel pretty comfortable to use 70 mg with anti-CD38 monoclonal antibodies.

Meletios A. Dimopoulos, MD

Chari: I’ll just add that we did an analysis comparing the weekly 70-mg [dose] vs the twice weekly 56-mg [dose] in CANDOR and the outcomes were comparable. From a cost perspective, it’s actually [less expensive] because 70 mg weekly is less drug than 56 mg twice weekly. I think that is something to keep in mind.

But let’s move on to perhaps one of the most eagerly awaited abstracts for relapsed or refractory disease, which Dr Dimopoulos presented beautifully. This is the APOLLO trial of daratumumab/pomalidomide/dexamethasone vs pomalidomide/dexamethasone.

Dimopoulos: For this particular study, first we have to clarify that the patient population [had more advanced [disease] than the CANDOR or the IKEMA studies, where half of the patients received only 1 prior line of therapy. In the APOLLO trial, patients had to be refractory progressing on both lenalidomide and bortezomib. However, 10% of the patients had received 1 prior line of therapy.⁵

These were patients who have received [bortezomib/lenalidomide/dexamethasone] and who have progressed. The results of this study confirmed what your study, Dr Chari, had shown several years ago: the large phase 2 study [NCT01998971; EQUULEUS], which led to the approval of daratumumab/ pomalidomide/dexamethasone in the United States.

APOLLO was a formal prospective randomized trial that needed to demonstrate that this treatment was more active than pomalidomide/dexamethasone, as well as [to provide the] opportunity for this treatment to be approved outside the United States. That was the main end point, and results showed an improvement in PFS with an HR of 0.68. Additionally, the toxicity profile was acceptable with a slight increase in grade 3 or 4 neutropenia and the rate of infections, especially pneumonias.

This study established daratumumab/ pomalidomide/dexamethasone as a salvage therapy for patients who have received at least 1 [prior line of therapy], but most of the patients had received a median of 2 lines of therapy. Hopefully, the results will lead to the approval of this combination outside the United States.

Chari: Dr Usmani, you referred earlier to daratumumab/pomalidomide/ dexamethasone as one of your go-to regimens. How do these results compare with what you were expecting?

Usmani: I agree with Dr Dimopoulos’ comment about the APOLLO study having a more advanced patient population than CANDOR or IKEMA and probably the same is true for those data that were presented last year. You know my general impression of daratumumab/ pomalidomide/dexamethasone—if used in earlier line of treatment [it] was somewhat similar to the experience that you had shared. I think even in the MM 014 study [NCT01946477] for earlier lines of daratumumab/pomalidomide/dexamethasone use, the median PFS was north of 20 months for those patients, and they were all lenalidomide refractory. I was a bit surprised that you would see that kind of an overall drop in PFS.

But I suspect it probably has to do with how refractory patients were and that they had more median lines of treatment. I was surprised [by the results]; I was expecting similar results from APOLLO as we had seen with CANDOR, for example. I was a little underwhelmed with the outcomes.

Chari: Dr Landgren, what were your expectations with the additional nuance that since you use so much carfilzomib up front, what do you do in relapse?

Landgren: Every study population is different, so if you have more or less patients [with advanced disease], that is going to always affect the results. That’s why you can never compare results across studies. We already know it, but we do it all the time, and we always ask the same question, but that is the simple answer. It also reminds me of the fact that we are probably going to see more of these types of studies because there are more drugs.

It is going to be harder to develop new therapies in the future because patients [who progress] to later lines have gone through so many more therapies. I think we could maybe project in the future that the differences may not be as profound as they used to be in the past because of the fact [that we have] more drugs available. It will obviously dilute [data] on the back end, and there will not be overall survival differences because patients are going to go through every therapy in the end.

In general, development in the field is changing. So, to answer your question, I use the best drugs up front, but what do I do if the disease comes back? Well, I do the same thing again—I’m sure you do the same: I give the best drugs up front, go to maintenance, then, of course, patients [have] PFS for so long, for, say, 5, 6, 7, 8, 9 years. If the disease progresses, I give the same drugs 1 more time, they work 1 more time. Just because you gave a therapy up front doesn’t mean that it doesn’t work later.

If you give a drug and the disease progresses and you start 6 months later with the same therapy, of course that’s not going to work. But if you have years between treatments, it’s not a problem clinically. Therefore, I give the best drugs every time.

Chari: Who would be the ideal candidate for a CD38 antibody in combination with pomalidomide/dexamethasone?

Dimopoulos: I believe that patients who progress on bortezomib/lenalidomide/dexamethasone may be treated with an anti-CD38 [antibody]/pomalidomide/dexamethasone. Based on the data from the IKEMA and CANDOR studies, I am more in favor [of using those regimens in] earlier lines of therapy. Then, for patients who have more advanced disease, I would use the other [available] treatments. However, we’ve been seeing more patients who progress on both lenalidomide and daratumumab. In that setting, a type of treatment such as carfilzomib/ pomalidomide/dexamethasone may be of interest.

Chari: I think what we are seeing here is that the pomalidomide/ dexamethasone backbone was perhaps just a little bit disappointing for this population. And, again, we caution that they are much more heavily treated patients, more double refractory. So it’s not appropriate to compare, but it brings up the question of class switching. If you [see a patient who is progressing] on lenalidomide, should you switch to carfilzomib?

I think [there are] very compelling data for Kd. Further, a CD38 antibody plus pomalidomide/dexamethasone would be another option.

The last point, of course, is keeping in mind toxicity. I think carfilzomib’s cardiac toxicity is often overblown. We know that the response and PFS and OS are superior in several phase 3 studies, which means that it’s generally well tolerated and risks are outweighed by the benefits. However, for really elderly patients—those with known cardiac dysfunction, uncontrolled blood pressure—there may be a role for pomalidomide. Conversely, individuals who are very cytopenic or prone to infections may be better suited for carfilzomib, based on what we saw.

It’s nice to have options, nice to have some data, and I think [when it comes to] sequencing, which is such a difficult option, we’re finally getting to see some light.

References

1. FDA approves carfilzomib and daratumumab with dexamethasone for multiple myeloma. FDA. Updated August 21, 2020. Accessed April 20, 2021. https://www.fda.gov/ drugs/drug-approvals-and-databases/fda-approves-carfilzomib-and-daratumumab-dexamethasone-multiple-myeloma
2. FDA approves isatuximab-irfc for multiple myeloma. FDA. Updated April 1, 2021. Accessed April 19, 2021. https:// www.fda.gov/drugs/drug-approvals-and-databases/ fda-approves-isatuximab-irfc-multiple-myeloma
3. Dimopoulos MA, Quach H, Mateos MA, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in relapsed or refractory multiple myeloma: updated efficacy and safety results of the phase 3 Candor study. Blood. 2020;136(suppl 1):26-27. doi:10.1182/ blood-2020-137602
4. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. Presented at: 62nd Annual American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Accessed April 19, 2021. https://ash.confex.com/ ash/2020/webprogram/Paper134573.html
5. Dimopoulos MA, Terpos E, Boccadoro M, et al. Apollo: phase 3 randomized study of subcutaneous daratumumab plus pomalidomide and dexamethasone (D-Pd) versus pomalidomide and dexamethasone (Pd) alone in patients (Pts) with relapsed/refractory multiple myeloma (RRMM). Blood. 2020;136(suppl 1):5-6. doi:10.1182/blood-2020-135874
6. Weisel K, Geils GF, Karlin K, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of the phase 3 Candor study in patients with early or late relapse. Blood. 2020;136(suppl 1):37-38. doi:10.1182/ blood-2020-133908
7. Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019;134(5):421-431. doi:10.1182/blood.2019000722