Callander Compares Doublet and Triplet Therapy in Early-Relapse Multiple Myeloma

Natalie S. Callander, MD

Associate Professor, Department of Medicine

Hematology/Bone Marrow Transplant

University of Wisconsin School of Medicine and Public Health

Madison, WI

CASE

• A 60-year-old White woman was diagnosed with stage II multiple myeloma.
• History: heavy smoker
• Cytogenetics: gain (1q21)
• ECOG performance status: 0
• At the time, she was treated with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induction therapy, followed by autologous stem cell transplant (ASCT).
• She achieved a complete remission and minimal residual disease (MRD) negativity with VRd and transplant.
• The patient was placed on lenalidomide maintenance therapy.

Targeted Oncology^TM: What are some high-risk and standard-risk genetic abnormalities in multiple myeloma?

CALLANDER: The [Mayo Clinic mSMART classification] lists high-risk genetic abnormalities. The top 3 genetic abnormalities are there at baseline; one either has them or they don’t, because they don’t acquire them. Deletion 17p, a TP53 mutation, or a gain of 1q, one can certainly pick up later. For standard-risk abnormalities, trisomy, translocation 11;14, and translocation 6;14 tend to be there at baseline.

I think the other thing that’s being teased out in studies is this whole phenomenon of double-hit lymphoma. But now we are talking about double-hit myeloma, when you have 2 or more of these high-risk cytogenetic features, and even triple-hit myeloma. I think now we have more and more data showing that patients who have 2 abnormalities—it often is one of the top 3, maybe with a 1q—seem to have more difficulty than a patient with [just] one of the high-risk features.¹

CASE UPDATE

• The patient had been on lenalidomide maintenance for 2 years.
• On follow-up, the patient reported severe fatigue and pain in the back and legs that was impairing her ability to work full time.
• M protein: 0.4 g/dL (rapid increase from prior bloodwork)
• λ free light chain increased from 47.5 mg/dL to 136.7 mg/dL.
• Hemoglobin: 9.8 g/dL
• White blood cell count and platelets: within normal limits
• Creatinine: 1.4 mg/dL (range: 0.59-1.04 mg/dL)
• Estimated glomerular filtration rate: 45 mL/min/1.73 m²
• PET scan showed vertebral fracture at L1 and lesions in both femurs.
• ECOG performance status: 1
• A decision to switch therapy was made.

What regimen are you most likely to recommend for this patient with early relapse while on lenalidomide maintenance after VRd induction and ASCT?

The NCCN [National Comprehensive Cancer Network] guidelines for treatment of relapsed multiple myeloma used to be a bit harder to maneuver. But now it has been divided into the preferred regimens for early relapse. Usually, preferred means these are treatments that have phase 3 data behind them. There is as well a whole list of other recommended regimens for early relapse, so I think this has become somewhat more useful.²

Most people looking at a person who is relapsing on lenalidomide are not going to use lenalidomide. Now, there are some people who might say, “can’t you just add to that drug and still capture a response?” That’s a question that I think we don’t know the answer to, and it’s something that people are very interested in. But, suffice it to say, most people would try to go to a different class. So, at the top of the list we have the proteasome inhibitor plus carfilzomib [Kyprolis] plus a monoclonal antibody.

What data support the preferred triplet therapy recommendations in the NCCN guidelines?

The IKEMA study [NCT03275285] had patients with a median of 2 lines of prior therapy [receiving an isatuximab (Sarclisa) combination in the experimental arm]. The CANDOR study [NCT03158688] was done with intravenous [IV] daratumumab [Darzalex]. Both studies had twice-a-week carfilzomib, probably something that most people are not doing [and dexamethasone]. Now, one of the things to take away from all of this is that for these triplets vs doublets, patients couldn’t have been exposed to what is in the doublet.

The only exception to this is the CASTOR study [NCT02136134], where some patients had previous bortezomib. But they can’t be refractory to those regimens because it wouldn’t be ethical to run the study. The CANDOR study, which had IV daratumumab, had a progression-free survival [PFS] of 28.6 months for the triplet arm vs 15.2 months for the doublet [HR, 0.59], and high rates of MRD.^3-6

The CASTOR study had patients who were by and large all refractory to lenalidomide. Some of them did have previous bortezomib. The overall group had a PFS of 16.7 months for the triplet vs 7.1 months for the doublet. If one breaks it down to the group of people who got DVd [daratumumab, bortezomib, dexamethasone] as their first relapse treatment, they do quite a bit better than this.⁴

There are the studies that include pomalidomide [Pomalyst], like the ICARIA-MM study [NCT02990338] with isatuximab/pomalidomide/dexamethasone vs pomalidomide/dexamethasone. The PFS was 11.1 months for the triplet vs 5.9 months for the doublet. The APOLLO trial [NCT03180736] had subcutaneous daratumumab and pomalidomide. These 2 trials had a little bit more refractory populations, a higher percentage of people who had previous ASCT.^7,8 But in this case, I think one could probably argue that these would all be reasonable.

How would you re-evaluate a patient with early relapse multiple myeloma?

With these relapsed patients, obviously, one is going to do the typical myeloma studies, but I think there are a couple of other things that one wants to think about. Sometimes I am very interested in seeing if people have proteinuria. Occasionally, we will pick up somebody who’s got secondary amyloidosis, for example, and if they have a lot of albuminuria, that can tip you off. There are people who have almost lymphoma-like relapses, where they are having lots of EMD [extramedullary disease]. In those patients, lactate dehydrogenase is often not only a great marker for relapse, but also a marker of how the patient is doing. So, if they are improving, it should go down. This patient had a PET scan. But I think we would all agree that we might as well skip the bone survey and go straight to some sort of advanced imaging that’s going to help you either look for marrow disease, or else look for that EMD.

Particularly in patients who have poor blood counts, I think a bone marrow biopsy and aspirate are mandatory to figure out if it is overwhelming disease [burden], or if it is myelodysplastic syndrome. The other thing is that patients don’t have to relapse the way they presented. Most physicians have seen the patient who relapsed with very little protein, so almost no elevation of their M protein, even if they had a lot, but they end up having a very big relapse. Some of those patients you end up having to follow even with things like a β2-microglobulin because they are not making a lot of protein.

The other thing that I think is becoming more common for all of us is now we have patients who have multiple cancers that we are treating. I have a whole bunch of patients who have myeloma plus breast cancer, myeloma plus prostate cancer, and a couple of patients with myeloma plus lung cancer. They come in with a new mass and one must figure out what that is. Recently, we had a patient who came in with abdominal lymphadenopathy and a big relapse of myeloma. Then you want to see how their organ function is doing because that all influences choices.

How would you review the history of a patient with early relapse multiple myeloma?

This patient is on 1 agent, but if you have people who are on, say, double maintenance with lenalidomide and bortezomib, that’s going to influence your relapse choice. I don’t see how you are not going to use a triplet in those kinds of patients. As people are getting older, we have a lot of people now who have neuropathy and some people have [congestive heart] failure.

A big thing for me is talking about oral pomalidomide; in some of my Medicare patients, we can’t get coverage for an oral agent, and so that means that we are falling back on what we can give in clinic. Certainly, we would want to put a patient on a trial if we’ve got it. You must consider if the person, maybe it was 5 years since their relapse, is frailer. We are in the Midwest. We live in rural areas. Can you get that person to the clinic?

They may not be able to have a once-a-week regimen when it comes [down] to it. I think that influences choices a lot. If it’s something more complicated, do these patients have a caregiver who can help manage symptoms if they have it at home? I believe that ASCT is still here to stay. If a patient has stem cells stored, I will think about a salvage ASCT as an intervention, and then consider if they have other comorbidities.

CASE UPDATE

• PET/CT scan demonstrated new lytic lesions.
• The patient was started on isatuximab/ carfilzomib/dexamethasone (Isa-Kd) and achieved a very good partial response (VGPR).

How was the IKEMA trial in relapsed multiple myeloma designed?

The phase 3 IKEMA data were from relapsed patients who had 1 to 3 lines of therapy. They were receiving weekly IV isatuximab 10 mg/kg for about 90 minutes for the first month, and then you go to every other week for the following months. In this study, the carfilzomib is given twice per week, and dexamethasone. In the doublet arm, carfilzomib [is given] at the same doses up to 56 mg/m², and then, again, dexamethasone.

The primary end point determined by independent review committee was PFS, and the key secondary end points were ORR [overall response rate], the rate of VGPR or better, MRD negativity, CR [complete response] rate, and OS [overall survival] rate. The estimate, which I think was fair, is that the carfilzomib/dexamethasone arm would have a median PFS of about 19 months. There was a prespecified interim analysis when 65% of the PFS events had happened.³

The population was typical of a first relapse study, with 65 years as the median age in the Isa-Kd arm. About 10% of patients were older than 75, and some of these patients, about a quarter of them in the Isa-Kd arm, had a creatinine clearance of less than 60 mL/min. The International Staging System scores at baseline were the usual distribution. About a quarter of the patients had high-risk cytogenetics, about 40% had a 1q amplification or gain, and the median lines of therapy was 2. Most of these patients were refractory to proteasome inhibitors, immunomodulatory drugs, and their last line of therapy.³

What was the efficacy seen with Isa-Kd vs Kd?

The PFS determined by an independent review committee with FDA censoring rules yielded a PFS of 41.7 months with Isa-Kd and 20.8 months with Kd [HR, 0.59; 95.4% CI, 0.42-0.83], coming in close to what was expected in the control arm.

If one does the analysis without the censoring, it goes a little bit lower, 36 months for Isa-Kd and 19 months for the control arm [HR, 0.58; 95% CI, 0.42-0.79]. The 42-month OS rate for the Isa-Kd arm was 66.3% vs 54.5% for the Kd arm.⁴ I don’t know how many people were aware of these data, which are pretty good. I think it ends up being one of the best regimens in terms of PFS.

For the subgroup analysis, I think one of the reasons we are having the discussion about 1q is that Isa-Kd performed particularly well in this group, whereas some of the other regimens out there have not done nearly as well. In patients who are older than 65, this regimen performed very well. Having more than 1 prior line of therapy didn’t seem to make a difference. High-risk cytogenetics didn’t do quite as well, but still [resulted in] a respectable hazard ratio of 0.72. This all was with a median follow-up of 44 months.

MRD was very good. Patients with MRD negativity were 33% for the Isa-Kd arm vs 15.4% for the Kd arm with a next-generation sequencing of 10^-5. For the combined patients who had a CR and MRD, it was 26.3% in the Isa-Kd arm vs 12.2% in the Kd arm. The overall CR rate was 44.1% vs 28.67% [odds ratio, 2.09; 95% CI, 1.26-3.48]. These are outstanding responses for a relapsed/refractory trial like this, and I think that is part of why we are looking at it. There aren’t many other trials that have MRD rates comparable with these in the relapse setting.

Of course, most patients did experience at least 1 adverse event [AE], as you might expect. Most of these tended to be hematologic. AEs that led to discontinuation were a little bit less in the Isa-Kd arm. For the rate of cardiac failure greater than grade 3, isatuximab didn’t seem to change that risk at all.

Most patients with these kinds of regimens do experience hematologic toxicity. The other thing that tends to happen with carfilzomib, particularly this biweekly schedule, is hypertension, which, if you’ve used carfilzomib, you are aware that you should aggressively manage that. The bottom line for me, and I think what most people would probably do, is use carfilzomib once a week. In general, that tends to cut down on both the cytopenia and certainly on the hypertension and any other cardiac symptoms.

How do the IKEMA data compare with those of other standard triplet regimens used in this setting?

The CANDOR trial was a very comparable population. The median PFS was very respectable for the daratumumab/ carfilzomib/dexamethasone arm at 28.6 months and the Kd arm at 15.2 months [HR, 0.59]. They had very similar AEs in terms of that hematologic toxicity. Again, this was twice-a-week carfilzomib with IV daratumumab.

There were a bit more fatalities and a higher rate of treatment discontinuation.⁵ But this is certainly an active regimen, and I think the difference is in that 1q subgroup. I think that is probably something that we are going to be seeing more investigation into in the future.

Another proteasome inhibitor-based trial, the CASTOR trial, is a bit different than what we just looked at in the sense that everybody on this trial essentially was lenalidomide refractory. A lot of these patients had transplants.

For the overall population, the median PFS was 16.7 months in the daratumumab/bortezomib/dexamethasone arm vs 7.1 months in the bortezomib/ dexamethasone arm [HR, 0.31; 95% CI, 0.24-0.39; P < .0001].

Patients who had only 1 line of therapy do better than this usually. But the median PFS was around [17] months.⁶ So, I think that this is also a reasonable regimen. CASTOR was written with twice-a-week bortezomib and daratumumab every 3 weeks. I think most people would probably modify this in practice, and change this to once a week for both drugs.

_REFERENCES

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_{2. NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2022. Accessed November 09, 2022. https://bit.ly/3UYip0f}

_{3. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi:10.1016/S0140-6736(21)00592-4}

_{4. Moreau P, Dimopoulos MA, Mikhael J, et al. VP5-2022: Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Ann Oncol. 2022;33(6):P664-665. doi:10.1016/j.annonc.2022.04.013}

_{5. Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197. doi:10.1016/S0140-6736(20)30734-0}

_{6. Spencer A, Lentzsch S, Weisel K, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103(12):2079-2087. doi:10.3324/haematol.2018.194118}

_{7. Richardson PG, Perrot A, San-Miguel J, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022;23(3):416-427. doi:10.1016/S1470-2045(22)00019-5}

_{8. Dimopoulos MA, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-812. doi:10.1016/ S1470-2045(21)00128-5}