Role of Monoclonal Antibodies in Up-front Therapy for Multiple Myeloma

EP: 1.Case Overview: Multiple Myeloma

EP: 2.Initial Impressions: Goals and Challenges

EP: 3.Considerations for Selecting First-Line Therapy in Newly Diagnosed Multiple Myeloma

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EP: 4.Role of Monoclonal Antibodies in Up-front Therapy for Multiple Myeloma

EP: 5.Phase 3 MAIA Trial Review

Rafael Fonseca, MD: In 2020, without question, 3 drugs were the standard of care for the frontline treatment of patients with multiple myeloma. Because of the clinical trials published, including those presented by SWOG, the IFM [Intergroupe Francophone du Myélome], and others, it had become clear that the use of 2 drugs was no longer appropriate for the induction therapy of patients with multiple myeloma. That is the case for going through with the transplant as well as patients who are not transplant candidates. In particular, the SWOG trial was designed for patients who didn’t have the initial intent of moving forward to stem cell transplant, and it showed superiority, both for PFS [progression-free survival] as well as overall survival for RVd [lenalidomide, bortezomib, dexamethasone].

I said 2020 on purpose, because at the end of that year, at ASH [American Society of Hematology Annual Meeting], we saw very meaningful updates for quad regimens. We saw glimpses of this in past presentations at ASCO [American Society of Clinical Oncology] and ASH. But the real question is: If 3 drugs are better than 2, why not 4? The reality is that we don’t have the long-term outcomes to make definitive statements, but the early readings are very clear. Deeper levels of response have resulted from the addition of monoclonal antibodies and, in particular, we’ve seen more of monoclonal antibodies in the form of daratumumab [Darzalex] added to the triplets. That is measured both by traditional standards, as well as by the addition of this MRD [minimal residual disease] determination.

There are 2 key studies. The first was the GRIFFIN study, which has been previously presented and published by Dr [Peter] Voorhees and updated at the American Society of Hematology by Dr Jonathan Kaufman, who showed that you can achieve MRD negativity 10-5 in about 60% of patients. This particular study is a randomized phase 2 study that includes the 4 drugs versus the 3 drugs, with the omission of the monoclonal antibody, transplant, and then further therapy post-transplant. The best response is when you get that 60%, 10-5 MRD negative. The study is remarkable in that those results have never been published in other series showing such a depth of response. The question is out there: Can we extrapolate that depth of response into longer duration of disease control? The answer is that only time will tell. But from what we know, every study that shows an improvement in depth of response in MRD negativity seems, in time, to show the improvements in PFS and overall survival.

The other study that was presented at ASH last year was the MASTER trial. The trial was recently updated and observes the addition of daratumumab [Darzalex] to the combination of KRd [carfilzomib, lenalidomide, dexamethasone]. So they’re very similar, except the backbone, which is KRd [carfilzomib, lenalidomide, dexamethasone] instead of VRd [bortezomib, lenalidomide, dexamethasone]. What we’re seeing with that regimen is that you get even deeper responses. Dr Luciano Jose Costa has presented the data: 10-5, 80% at the time of best response; 10-6, which will soon become the standard for measurement of depth of response, is 60%. That is unprecedented. There’s another study, which adds a monoclonal antibody to the frontline therapy as well, that was presented by Dr Ola Landgren.

With those updates, the myeloma community is trying to decide what to do going forward. Is a patient with multiple myeloma who gets only 3 drugs up front not getting the full benefit of what we’re seeing with 4 drugs? This is a moment of transition in which more people will start doing 4 drugs as opposed to the 3. From what we continue to hear, those combinations can be administered in a very safe manner for patients. In many ways, if people are more on the conservative stance, they will say, “I want to have more follow-up. I want to know what happens long term.” That is correct, and it’s accurate. On the other hand, it’s as if you’re in the fourth quarter of a game, and you’re way ahead. You haven’t won yet, but you know you’re way ahead, so there’s a high likelihood you will win. That’s what we’re seeing with these early results and with the early readout.

Another study that was presented at ASH was an update on the FORTE clinical trial by Dr Francesca Gay from Italy. She has presented this study before, but here, they presented the follow-up after a second randomization, which included, in the back end, maintenance with KR [carfilzomib, lenalidomide] versus R [lenalidomide]. That’s not the sole purpose of this conversation. But what she was able to show is that treatment with better maintenance, with more drugs, results in better outcomes. The concept is agnostic to drugs. I’m making reference to the fact that we’re adding monoclonal antibodies up front, and we’re seeing that even in the next step, adding another drug seems beneficial. I’m very excited with what I’m seeing, and I’m going to venture to say that we’re at the point where we would have to start considering the treatment of all patients up front with the quad regimens.

Transcript edited for clarity.

Case: A 77-Year-Old Woman with Multiple Myeloma

Initial Presentation

• A 77-year-old woman presents with decreased appetites, fatigue, and back pain
• PMH: unremarkable
• PE: pain during ambulation, point tenderness on palpation of the mid-back
• ECOG 1

Clinical Workup

• Hb 9.2 g/dL, corrected calcium 11.8 mg/dL, LDH 285 U/L, creatinine 2.1 mg/dL, albumin 3.8 g/dL, CrCl 45 mL/min
• Peripheral blood smear showed rouleaux formation
• Beta-2 microgloblulin 4.2 mcg/mL, M-protein 2.5 g/dL
• Lambda free light chains: 0.7 mg/dL, kappa free light chains: 13.3 mg/dL
• FISH: hyperdiploid
• UPEP: M-spike of 410 mg of lambda light chains in 24 hours
• PET/CT revealed lytic bone lesions in at L2/L3
• Bone marrow biopsy shows 60% plasma cells IgG k
• Diagnosis: R-ISS stage II MM

Treatment

• Patient is ineligible for ASCT due to comorbidities
• Initiated treatment with daratumumab + bortezomib + lenalidomide + dexamethasone