Grajales-Cruz Interprets Data for Earlier- Line CAR T-Cell Therapy in R/R MM

Ariel F. Grajales-Cruz, MD

Assistant Member, Multiple Myeloma Section

Department of Malignant Hematology

Moffitt Cancer Center

Tampa, FL

CASE SUMMARY

• A 60-year-old woman was diagnosed with Revised International Staging System (R-ISS) stage 2/R2-ISS stage 3 IgG-κ multiple myeloma.
• Medical history: acute onset of renal insufficiency and hypercalcemia
• Cytogenetics: 1q21+ amplification; t(14:16); high risk
• ECOG performance status: 0
• Patient declined autologous stem cell transplant.
• She received daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, followed by lenalidomide maintenance.
• Best response:
  • Very good partial response (VGPR)

Two Years Later

• Patient experienced her first relapse.
• Patient continued lenalidomide maintenance therapy.
• On routine follow-up, she reported having mild fatigue but continued to work full time.
  • Bone marrow plasma cells, light chains, and M protein levels rising
  • Kidney function worsening: estimated glomerular filtration rate: 22
  • — Now stage IV chronic kidney disease
• Following second relapse, the patient was initiated on daratumumab, carfilzomib (Kyprolis), and dexamethasone with a best response of VGPR.
  

Six Months Later

• After 2 prior lines of therapy, the patient presents to her oncologist with complaints of increased fatigue and persistent bone pain in her lower back exacerbated by minimal movement.
• She expresses interest in chimeric antigen receptor (CAR) T-cell therapy with her clinical team.
• She also states that she wants to travel out of the country for her daughter’s wedding in 3 months.

PEERS & PERSPECTIVES IN ONCOLOGY: What was the significance of the KarMMa-3 trial (NCT03651128) in the setting of relapsed/refractory multiple myeloma?

GRAJALES-CRUZ: KarMMa-3 is a phase 3 clinical trial that compares idecabtagene vicleucel (ide-cel; Abecma] vs standard of care [SOC], being DPd [daratumumab, pomalidomide (Pomalyst), dexamethasone], DVd [daratumumab, bortezomib, dexamethasone], IRd [isatuximab (Sarclisa), lenalidomide, dexamethasone], Kd [carfilzomib plus dexamethasone], or EPd [elotuzumab (Empliciti), pomalidomide, and dexamethasone]. These were patients who had received 2 to 4 prior lines of therapy. This study led the FDA to make the change; based on the data from the study, now we can consider one of the CAR T-cell products in patients who have received at least 2 prior lines of therapy and are triple-class exposed.¹

The first disclaimer that I want to make: ide-cel and ciltacabtagene autoleucel [cilta-cel; Carvykti] are the 2 CAR T-cell products, and we don’t have a head-to-head comparison. Doing cross-trial comparison is difficult, if not unfair, so when saying one is better than the other, you have to take that with a grain of salt and take into consideration that there are nuances in the products. You can always say that [either] is a phenomenal option for the patient. This was a significant change in our treatment algorithm because…instead of 4 prior lines of therapy, we’re going to just 2, so the patient is not as exposed.

The baseline characteristics are very balanced altogether in terms of what [patients] haven’t been exposed to, including the CD38 [antibody].² Everyone in our practice will get daratumumab or isatuximab in the first 2 lines of therapies. Nowadays if somebody has not seen a CD38 [antibody], we have to question why, because that is going to be the better tolerated drug altogether.

But all these patients were triple-class exposed, and a very significant portion of these patients were refractory to daratumumab. These patients had heavily treated disease altogether.

What is your impression of the final progression-free survival (PFS) analysis of KarMMa-3?

I looked at the separation of the [Kaplan-Meier] curves. When you see these graphs, some of us will be impressed; some of us will be disappointed because [of] the numbers. There is clear separation…[and] a significant difference. The median PFS is rounded up to 14 months [with ide-cel].³ If you remember the original KarMMa study [NCT03361748], the median PFS was 8.8 months.⁴

We expected that gap to be bigger, but we also have to take into consideration… the comparator. Is [a median PFS] of 4.4 months what would we get from these [regimens in the second line]? DPd on the APOLLO trial [NCT03180736] was 11 months.⁵ DVd was 12 months from CASTOR [NCT02136134].⁶ Even EPd was 11 months.⁷ These numbers have been the comparators…because of the historical data, but…that is why cross-trial comparison is very tricky. There’s an undeniable difference…with the HR [of 0.49; 95% CI, 0.38-0.63] for ide-cel vs SOC.³

What other data from this trial support the earlier use of ide-cel?

When you look at the quality of responses, you clearly see a difference. You see the rates of complete response [CR] or better of those patients [of 44% with ide-cel vs 5% with SOC]. That was proposed by the first KarMMa study. The median PFS might have been 8.8 months, but the duration of response for those patients who had achieved a CR, which was approximately 40%, was over 2 years.⁸ You cannot neglect the fact that the patients who respond to CAR T-cell therapy respond durably. For [the case patient’s daughter’s] wedding in 3 months, she can book her ticket and be there.

With a minimal residual disease negativity rate of 35% [vs 2% with SOC], the depth of response was undeniable.3 These patients simply did great altogether compared with SOC.

When they did the subgroup analysis on the patients who were receiving the bridging therapy, the PFS was better in the patients who had a decrease in the disease.⁹ Burden of disease is a bad predictor altogether, in terms of how the patient is going to do and what type of response they can get. But it also comes with common sense. If your patient is not responding to anything, they’re not going to respond to [CAR T-cell therapy]. I had a patient [who died] 8 months from being newly diagnosed. He received 9 lines of therapy. He would progress in 3 weeks, always with extramedullary disease, and we all have patients like that.

It was the same with the overall response rate. Those patients who had a decrease in the burden of disease had a better overall response rate and had a better duration of response and soluble B-cell maturation antigen [BCMA] level. Soluble BCMA is definitely something that we expected to be a part of our algorithms in terms of what we do, especially because…BCMA expression in immunohistochemistry is absolutely unreliable.

What takeaways are there from the adverse event (AE) profile of ide-cel in this trial?

By now we’re all very familiar with the AEs from CAR T-cell therapy. We all know there are delayed cytopenias that can happen with ide-cel.² We all know about cytokine release syndrome [CRS], we all know about ICANS [immune effector cell–associated neurotoxicity syndrome]. We know that CAR T-cell therapy in the myeloma world is nothing comparable to what we see in the lymphoma world in terms of how severe the CRS can be. Here, many of the patients got CRS, but when you see single-digit rates of grade 3 or 4, I can live with that. I always tell my patients you have to be aware of the AEs but you cannot be afraid of them. Be afraid of myeloma because if you have an incurable disease, that is what is going to be the driver of the complications. When you see this AE profile, it’s OK, and we also have to remember that you can encounter CRS and neurotoxicity with any of the CAR T-cell therapy products but also the bispecific products.

Infections are a big driver of [the grade 5] toxicity. You cannot compare the immunosuppression from CAR T-cell therapy with carfilzomib/dexamethasone.

What is the significance of the health-related quality of life (QOL) outcomes for KarMMa-3?

QOL was far better when you took ide-cel vs SOC.¹⁰ It got to a better QOL faster. The fact that we’re looking at QOL as an outcome is phenomenal. The limitation in my view is that QOL is very subjective. But in their analysis, everybody had a better QOL after ide-cel, and in clinical practice, that’s what we see. The patient will tell you, “These are the best years of my life since I was diagnosed.” They’re not seeing [their oncologist]; there is no treatment.… Even [with] low-dose lenalidomide and daratumumab/carfilzomib/ dexamethasone—how many times does your patient tell you, “I feel great, but I’m very fatigued”? It’s just not the same [as being treatment free].

That’s a very important factor for us when we take into consideration what we do next because now we have options. It [is a challenge] physically and emotionally because you’re actively remembering that you have a disease that needs treatment. QOL is undeniable, and it’s a very important topic with our patients.

How did the real-world outcomes with CAR T-cell therapy compare with KarMMa-3?

At Moffitt Cancer Center, we have had the honor of having Doris K. Hansen, MD, doing this real-world experience with a huge consortium that has been publishing data that have validated what we do with ide-cel and also with cilta-cel. The representation of ide-cel was pretty close to what we have.¹¹

How did ide-cel perform in patients who received prior BCMA-targeted therapy?

This is a very important topic because it starts touching the unanswered question of sequencing. Based on the experience that we’ve had already, we know that these patients who get prior BCMA-targeted therapy…when they get to CAR T-cell therapy, they won’t do as [well] as they would have if they hadn’t had it.¹² That’s why we’re doing a lot of talquetamab [Talvey] bridging. It’s a different target.

That’s why you see us for the most part saying, “Don’t start a bispecific that targets BCMA if you’re going to think about CAR T-cell therapy.” We know that those patients don’t do as well [Figure¹²]. If we’re thinking about BCMA-targeted therapy, we always favor CAR T-cell therapy first. If the patient cannot get to a CAR T-cell therapy, then we can think about a BCMA-targeted…bispecific, and we have 2 good ones.

The other way around, we have good data for those patients who get a bispecific after CAR T-cell therapy. We have responses after that.^13,14 But an important topic revolves around what we already discussed: QOL. Do I want to hinder the response of the product that will give them the longer run without treatment? No, I can always catch up with my bispecific anytime and get some response. One of the key messages is CAR T-cell therapy always comes first.

REFERENCES:

1. U.S. FDA approves Bristol Myers Squibb and 2seventy bio’s Abecma for triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy. News release. Bristol Myers Squibb. April 5, 2024. Accessed May 13, 2024. https://bit.ly/3WDCEnF

2. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614

3. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Idecabtagene vicleucel (ide-cel) versus standard (std) regimens in patients (pts) with triple-class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM): updated analysis from KarMMa-3. Blood. 2023;142(suppl 1):1028. doi:10.1182/blood-2023-178933

4. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850

5. 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

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. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379(19):1811-1822. doi:10.1056/NEJMoa1805762

8. Anderson LD Jr, Shah N, Jagannath S, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, for the treatment of patients with relapsed and refractory multiple myeloma (RRMM): updated results from KarMMa. Clin Lymphoma Myeloma Leuk. 2021;21(suppl 2):S17-S18. doi:10.1016/S2152-2650(21)02101-7

9. Einsele H, Rodriguez-Otero P, Arnulf B, et al. Idecabtagene vicleucel (ide-cel) versus standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: KarMMa-3 subgroup analysis in patients receiving bridging therapy. Presented at: 2023 International Myeloma Society Annual Meeting; September 27-30, 2023; Athens, Greece. Abstract P-0008.

10. Delforge M, Patel K, Eliason L, et al. Effects of idecabtagene vicleucel (ide-cel) versus standard regimens on health-related quality of life (HRQoL) in patients with relapsed/refractory multiple myeloma (RRMM) who had received 2-4 prior regimens: updated results from the phase 3 KarMMa-3 trial. Blood. 2023;142(suppl 1):96. doi:10.1182/blood-2023-179152

11. Sidana S, Ahmed N, Akhtar OS, et al. Real world outcomes with idecabtagene vicleucel (ide-cel) CAR-T cell therapy for relapsed/refractory multiple myeloma. Blood. 2023;142(suppl 1):1027. doi:10.1182/blood-2023-181762

12. Ferreri CJ, Hildebrandt MAT, Hashmi H, et al. Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy. Blood Cancer J. 2023;13(1):117. doi:10.1038/s41408-023-00886-8

13. Touzeau C, Krishnan AY, Moreau P, et al. Efficacy and safety of teclistamab (tec), a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients (pts) with relapsed/refractory multiple myeloma (RRMM) after exposure to other BCMA-targeted agents. J Clin Oncol. 2022;40(suppl 16):8013. doi:10.1200/ JCO.2022.40.16_suppl.8013

14. Bahlis NJ, Costello CL, Raje NS, et al. Elranatamab in relapsed or refractory multiple myeloma: the MagnetisMM-1 phase 1 trial. Nat Med. 2023;29(10):2570-2576. doi:10.1038/s41591-023-02589-w