Recap: Mayo and Moffitt Face-Off in Myeloma Data Presentation

In a recent Face-Off program hosted by CancerNetwork^®, experts from Mayo Clinic, and Moffitt Cancer Center, went head-to-head to discuss recent data in multiple myeloma. The panelists discussed updated results from the recent 2022 American Society of Hematology (ASH) Annual Meeting as well as pivotal trials in the space.

From Moffitt, the clinicians included Kenneth Shain, MD, PhD, a medical oncologist specializing in malignant hematology; and Ariel Grajales-Cruz, MD, a hematologic oncologist specializing in malignant hematology. From Mayo, the clinicians were Sikander Ailawadhi, MD, a hematologist in the CAR-T Cell Therapy program; and Ricardo D. Parrondo, MD, a medical oncologist in the Bone Marrow Transplant Group and CAR T-Cell Therapy Program.

CONCEPT Trial

Results from the phase 2 GMMG-CONCEPT trial (NCT03104842) were presented at 2022 ASH.¹ This trial focused on high-risk patients with newly diagnosed multiple myeloma receiving isatuximab-irfc (Sarclisa) plus or minus carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd). The trial enrolled 153 patients who were randomly assigned to either arm A with the combination given for 6 cycles or arm B with the combination given for 8 cycles. Those in arm A then went on to receive high-dose therapy (HDT) plus autologous stem cell transplant (ASCT) consolidation for 4 cycles and maintenance for 26 cycles. Arm B followed the same strategy, but patients did not receive HDT plus ASCT.

The primary end point was to identify minimal residual disease (MRD) negativity after consolidation, with secondary end points including progression-free survival (PFS), objective response rate (ORR), overall survival, and safety. The presentation was focused on an interim analysis of the trial and comprised 99 patients in arm A who are transplant eligible and 26 patients in arm B who are transplant ineligible.

In arm A, the MRD-negativity rate was 67.7% (95% CI, 58.9%-100%; P = .004) vs 54.2% in arm B (95% CI, 35.8%-100%; P = .012). Overall, 72 patients completed consolidation, and 66 had evaluable MRD results, with 63 being MRD negative.

A stringent complete response (sCR) or a CR occurred in 72.7% of patients in arm A vs 57.7% in arm B. A very good partial response occurred in 18.2% vs 30.8% and a partial response occurred in 4.0% vs 0% in arms A and B, respectively. The ORR was 94.9% in arm A and 88.5% in arm B.

Grade 3 or higher adverse effects (AEs) occurred in 78.4% of patients in arm A and 72% in arm B. The most common hematologic AEs between arms were neutropenia (39.2% vs 28%), thrombocytopenia (26.8% vs 16%), and leukopenia (26.8% vs 16%). Additionally, nonhematologic AEs of grade 3 or higher included infection (27.8% vs 28%), hypertension (10.3% vs 8%), and gastrointestinal issues (9.3% vs 4%).

Mayo Challenges Moffitt

AILAWADHI: Can you discuss the need for a quadruplet regimen?

SHAIN: My take on that is the simple answer that more is not always better, but more doesn’t mean you shouldn’t use multi-modality therapy that targets multiple aspects of myeloma biology. If you think about CD38 myeloma biology, proteasome inhibitors, myeloma biology, image myeloma biology, and a little T-cell biology. That’s how you want to [manage] disease and then when we’re talking about the status of a newly diagnosed patient, I can’t move away from the thought that your best chance to take care of myeloma patients and give them long-term outcomes is upfront. You’re never going to get that chance again. They’re going to relapse and you’re going to get them under control but it’s not going to be as good. You need to give them your best drugs and your best combinations in a safe way in the frontline setting.

AILAWADHI: How can you determine treatment between patients who are eligible and ineligible for transplant?

SHAIN: You can’t give 4 drugs to everybody just so you can give the full dose of something to everybody. You need to ensure you’re treating the patients correctly. I don’t hold to adding [drugs] as you go. For the eligible [patients], it’s a much easier [treatment] choice. For ineligible [patients], you must use your needle and [decide], what are the right doses. No full doses for those that are sick. [You need to make sure to] use the right dosing but the right number of drugs is critical. Again, we can be more aggressive, and patients can handle more but you have to be a physician and figure out who those patients are is how I would address that question because [the treatment is affecting them].

MonumenTAL-1 Trial

Updated results from the phase 1/2 MonumenTAL-1 trial (NCT03399799/ NCT0463455) assessed the use of talquetamab in patients with relapsed/ refractory multiple myeloma.² There were 3 treatment arms in which patients received 0.4 mg/kg each week of talquetamab subcutaneously delivered, 0.8 mg/kg every 2 weeks given subcutaneously, or a combination of the 2 previous arms.

The ORR for patients receiving treatment every week was 74.1% compared with 73.1% in those treated every 2 weeks. Additionally, triple-class refractory disease was observed in 72.6% vs 71.0%, respectively and penta-drug refractory disease was observed in 71.4% vs 70.6% in patients receiving treatment every week vs every 2 weeks. The median time to first response in the every-week treatment arm was 1.2 months (95% CI, 0.2-10.9) with a median time to best response of 2.2 months (95% CI, 0.8-12.7). In the every-2-weeks-arm, the median time to response was 1.3 months (95% CI, 0.2- 9.2) with a median time to best response of 2.7 months (95% CI, 0.3-12.5).

The median duration of response (DOR) in all responders was not evaluable (NE; 95% CI, 20.2-NE) vs 9.3 months (95% CI, 6.6-12.7) in those who had a CR or better in the every-week treatment arm. In the every-2-weeks treatment arm, the median DOR was NE (95% CI, 10.6-NE) in those with a CR or better, and 13.0 months (95% CI, 10.6-NE) in all responders.

The median PFS in the once-weekly treatment arm was 7.5 months (95% CI, 5.7-9.4) vs 11.9 months (95% CI, 8.4- NE) in the every two-weeks arm.

Grade 3/4 AEs included anemia (31.5% vs 24.8%), neutropenia (30.8% vs 22.1%), lymphopenia (25.9% vs 25.5%), and thrombocytopenia (20.3% vs 16.6%) between the every-week and every-2-weeks-arms, respectively. Infections were also observed, with 16.8% vs 11.7% being grade 3/4 in the every-week and every-2-weeks treatment arms, respectively. During treatment, 2 patients died from COVID-19. Of note, there were lower rates of nonhematologic AEs observed in this trial.

Cytokine release syndrome (CRS) was also prevalent during the trial. In the every-week treatment arm, grade 1 CRS was observed in 62.2% of patients, 14.7% had grade 2, and 2.1% had grade 3. In the every-2-weeks treatment arm, 54.1% had grade 1 CRS, 17.2% had grade 2, and 0.7% had grade 3. Most CRS events were confined to step-up dosing and the first full dose.

Immune effector cell-associated neurotoxicity syndrome occurred in a small number of patients. Most included grade 1/2, affecting between 10% to 11% of patients in both arms while 7% to 8% received supportive care measures.

Moffitt Questions Mayo on Trial Presentation

SHAIN: How will talquetamab fit into our treatment armamentarium for this patient population?

AILAWADHI: The holy grail of trying to figure out how to sequence all these drugs or regimens that we suddenly have or have even now [is still in the works]. A couple of things to keep in mind is that BCMA is something that the myeloma cell is dependent on forever. BCMA does not go away. GPRC5, on the other hand, can be lost as a target. If I were to have all these drugs available, the way I think about it is there are some data emerging that after bispecific [treatment is given], T-cell apheresis becomes difficult. These are drugs that are targeting or T-cell engaging so T-cell apheresis becomes difficult.

There are a little bit of data showing that GPRC5 is effective post BCMA. We don’t know vice versa yet. If I were to have all the drugs with enough slots for CAR T manufacturing available, I would prefer to go first with CAR T-cell therapy. Sometimes after that, when the disease comes back with a GPRC5 and then after that, down the road, we can potentially go back to a BCMA targeting agent [that may be] BCMA bispecific. That is everything else equal in having access, in my mind, that is the right sequence based on the data we have available to date.

SHAIN: How can we begin to address the unequal access to therapies?

AILWADHI: If all the CAR T centers got all the slots that we are promised or we are expected to get for [those approved] CAR Ts, in the ideal case scenario, the maximum number of CAR T treatments we can give in a year is 5500. We have 35,000 [patients] diagnosed with myeloma each year. You’re right, access is just horrible, and then when we talk about logistics, both the BCMA bispecific, whether it’s teclistamab [Tecvayli] that is FDA approved or elranatamab, which will hopefully get approved, the patients need to be hospitalized. I don’t know how your situation is, but we have no beds and nothing available in the hospital to put a patient into. If we talk about step-up dosing and CRS that can occur anytime you’re looking at teclistamab, [there can be] potentially a 9-day hospitalization. With elranatamab, it is maybe a 4- or 5-day hospitalization.

INSURE Study

A pooled analysis of patients with relapsed/refractory multiple myeloma was used in the INSURE study.³ INSURE was a pooled analysis comprised of INSIGHT MM (NCT02761187), UVEA-IXA, and REMIX, with a total of 564 patients.^4-6 Patients were given ixazomib (Ninlaro), lenalidomide, and dexamethasone (IRd) as a second or later line of therapy.³

In the trial, the median time to the next treatment (TTNT) was 18.4 months (95% CI, 15.3-20.8). However, it was noted that for those who received ixazomib as second-line therapy, the median TTNT was 20.7 months (95% CI, 17.0-27.5). In the overall population, the median PFS was 19.9 months (95% CI, 16.6-23.6), and it was 21.7 months (95% CI, 18.6-35.2) for those receiving ixazomib in the second line.

The median time to best response was 4.0 months, and the ORR was 65%. Of those who received ixazomib in the second line, the median time to best response was 3.9 months and the ORR was 70%. When patients were analyzed by frailty status, the median time to best response was 4.7 months with an ORR of 67% in the nonfrail group vs 3.2 months and 59%, respectively, in the frail group.

Moffitt Receives Line of Questioning from Mayo

PARRONDO: In the real world with high-risk patients receiving lenalidomide: If they are put on a dual agent maintenance, what is the utility of this regimen?

GRAJALES: In this day and age, we have this triple induction therapy or quadruplet regimen for the vast majority of patients, followed by lenalidomide maintenance, which is the most commonly studied agent in terms of maintenance. There are some patients, however, who do benefit from the larger combination with lenalidomide, especially those certain [cases] where patients were off therapy, because not everybody is going to be refractory to lenalidomide. There are some patients who decide to stop maintenance or who simply choose not to pursue maintenance after transplant; it’s a patient’s choice. Just like transplant is an elective procedure for these patients, so is maintenance. There are some who believe that they already went through this and want to take their chances to see. I think that is the type of population that would benefit from revisiting lenalidomide, in all fairness. If you’re refractory to lenalidomide, trying something else [is] not necessarily going to be the most exciting approach because you’re going to end up doing basically an ixazomib single-agent approach. That would be the [ideal] patient who will benefit from [treatment].

AILAWADHI: Can we depend on these data? Were these patients extremely preselected?

GRAJALES: In myeloma, we do overtreat patients. In this study, did everybody need more than 20 months of treatment rather than 15 months, or could we just stop a little bit earlier? That PFS was going to be seen no matter what…the overtreatment in myeloma, we know that happens. We simply don’t know what patients need for drugs, how patients will respond for 10 years with 1 agent. In maintenance lenalidomide, you get a phenomenal run for your money. That behavior with the biology of the disease makes it unpredictable to some extent, and I think that has something to do with it.

Presentation of a Triplet Regimen

This trial evaluated the use of bortezomib (Velcade), carfilzomib, daratumumab (Darzalex), or ixazomib and was combined with either lenalidomide or pomalidomide (Pomalyst) for patients with relapsed/ refractory multiple myeloma.⁷ This trial included 741 patients with first-line therapy and 820 patients who had 2 or more lines with a lenalidomide and dexamethasone (Rd) backbone. The treatment combinations included bortezomib plus Rd (VRd), KRd, daratumumab plus Rd (DRd), and IRd.

Additionally, the trial included another 348 patients with 392 having 2 or more lines of therapy with a pomalidomide plus dexamethasone (Pd) backbone. These combinations included bortezomib plus Pd (VPd), carfilzomib plus Pd (KPd), daratumumab plus Pd (DPd), and ixazomib plus Pd (IPd).

The median follow-up for those with the Rd backbone was 13.0 months, and it was 9.5 months for the Pd backbone. Duration of therapy (DOT) for those receiving 2 or more lines of therapy with the Rd backbone included VRd at 10.7 months, IRd at 8.5 months, and KRd at 7.0 months (P = .0034). However, those treated with DRd were not estimable for more follow-up. In those with a Pd backbone, the median DOT was 9.7 months for VPd, 8.8 months for IPd, 6.7 months for KPd, and 6.0 months for DPd (P = .4784).

For patients who received 2 or more lines of therapy, the TTNT was 13.9 months for VRd, 11.4 months for IRd, and 8.7 months for KRd, with DRd being NE. In those with a Pd backbone, the median TTNT was 12.0 months for VPd, 9.5 months for IPd, 6.7 months for KPd, and NE for DPd (P = .0946).

Mayo Holds their Position as Moffitt Questions

GRAJALES: How do you determine treatment after the first relapse?

PARRONDO: If someone received VRd transplant and lenalidomide maintenance, and they’re progressing on lenalidomide maintenance, I consider them lenalidomide refractory. There were data presented [at ASH] showing it doesn’t matter whether it’s 10 mg or 25 mg, so I will tend to switch classes. My second line will be a CD38 monoclonal antibody plus proteasome inhibitor. I don’t tend to give them pomalidomide in the second line if they were just refractory to an immunomodulatory drug, so I tend to switch the class that they were previously on. That’s how I use the subsequent treatment.

AILAWADHI: Another thing to quickly add to, which somebody had mentioned, is that in the US we can maybe give 3 legitimate lines of therapy without a BCMA drug to every patient. We are scraping the bottom of the barrel when it comes to the fourth line. We don’t have a legitimate fourth line anyway, so that’s what the struggle becomes [because] the BCMAs are approved after 4 prior lines of therapy. In this study, you’re highlighting the tendency of us as physicians [to treat] our patients with the right drugs. What does this tell you about real-world data vs clinical trial data, and how do you rectify those 2 things because you need them both to figure it out?

PARRONDO: That’s where the struggle comes. When idecabtagene vicleucel [ide-cel; Abecma] comes in clinical trials, it has a 12-month median PFS, and when it comes to the real world, it’s 8 to 9 months PFS. When daratumumab is given in a clinical trial, the median DOT in the front line is 4 or 5 years. In the real world, in the US, market data show that daratumumab is given on an average for 8 months, and then it is dropped or stopped. With carfilzomib, on average the median duration given in the US is about 7 or 8 months and the biggest fallacy with this is real-world data. Now going forward, things will probably change. We’re talking about these potentially homeopathic doses of bispecific antibodies that can keep the disease quiet for a long period of time.

Stay tuned for our next installment of Face-Off, where clinicians from Moffitt and Mayo will debate chronic myeloid leukemia and the winner will be determined.

Editor's Note: This article was updated on 2/27/2023 to correct an error in which a mention of teclistamab was inaccurately transcribed as talquetamab in reference to an FDA approval.

References

1. Weisel K, Besemer B, Haenel M, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in patients with high-risk newly diagnosed multiple myeloma: planned interim analysis of the GMMG-Concept trial. Blood. 2022;140(suppl 1):1836- 1838. doi:10.1182/blood-2022-156309
2. Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D x CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from MonumenTAL-1. Blood. 2022;140(suppl 1):384-387. doi:10.1182/blood-2022-159707
3. Leleu X, Boccadoro M, Lee HC, et al. The INSUREstudy (INSIGHT MM, UVEA-IXA, REMIX): a pooled analysis of relapsed/refractory multiple myeloma (RRMM) patients (pts) treated with ixazomib-lenalidomide-dexamethasone (IRd) in routine clinical practice. Blood. 2021;138(suppl 1):2701. doi:10.1182/blood-2021-150150
4. Costello C, Davies FE, Cook G, et al. INSIGHT MM: a large, global, prospective, non-interventional, real-world study of patients with multiple myeloma. Future Oncol. 2019;15(13):1411-1428. doi:10.2217/fon-2019-0013
5. Ludwig H, Terpos E, Mateos M-V, et al. Effectiveness and safety of ixazomib-based therapy in relapsed/refractory multiple myeloma (RRMM) patients (pts) treated outside the clinical trial setting via an early access program (EAP) in Europe: second interim analysis of the ‘Use Via Early Access to Ixazomib’ (UVEA-IXA) study. Blood. 2020;136(suppl 1):42-44. doi:10.1182/blood-2020-136519
6. Clement-Filliatre L, Benboubker L, Stoppa AM, et al. Real-life-setting effectiveness of ixazomib in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: the Remix study. Blood. 2020;136(suppl 1):25-26. doi:10.1182/ blood-2020-133807
7. Davies F, Rifkin R, Costello C, et al. Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/ refractory multiple myeloma (RRMM) in the US. Ann Hematol. 2021;100(9):2325-2337. doi:10.1007/s00277-021-04534-8