Quadruplet Therapy Shows Benefit for Newly Diagnosed Multiple Myeloma

Thomas G. Martin, MD, discussed the advantages of quadruplet therapy for multiple myeloma in light of an FDA approval for Isa-VRd in this indication.

CancerNetwork® spoke with Thomas G. Martin, MD, a clinical professor of medicine at the Adult Leukemia and Bone Marrow Transplantation Program, and associate director of the Myeloma Program at the University of California San Francisco (UCSF); and co-leader of the Cancer Immunology & Immunotherapy Program at the Helen Diller Family Comprehensive Cancer Center. The conversation was preceded by a recent FDA approval of isatuximab-irfc (Sarclisa) in combination with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (Isa-VRd) in patients with transplant ineligible newly diagnosed multiple myeloma (NDMM).¹

Martin briefly outlined results from the phase 3 IMROZ trial (NCT03319687), which portrayed enhanced efficacy and similar safety for VRd therapy with isatuximab vs VRd alone.^2,3 He emphasized the quadruplet therapy’s higher minimal residual disease (MRD) negativity rate, significantly improved 60-month progression-free survival (PFS) rate, and showed promising interim overall survival (OS) data, indicating a benefit for patients with transplant-ineligible NDMM.

Martin additionally stressed that infection rates, adverse effects, and toxicity incidences, were similar across treatment groups, particularly when accounting for treatment duration. He concluded by disclosing other multiple myeloma developments that he believes may impact clinical practice, including an additional trial evaluating quadruplet vs triplet therapy with bortezomib as the investigational agent, and recent approvals for the use of BCMA bispecific antibodies in earlier lines of therapy.

Q: What does the FDA approval of Isa-VRd in patients with newly diagnosed multiple myeloma mean for this population?

Martin: The recent FDA approval based on the IMROZ trial is in a patient population who do not intend to go to bone marrow transplant. These patients receive induction therapy, and then it evolves into consolidation therapy, and this is a big advantage for them now to be able to get a 4-drug induction therapy. This combination of Isa-VRd, provides deep and durable responses in this patient population, and we know that it increases the PFS vs the VRd triplet. It likely will improve the OS, and it certainly improves the ability for patients to achieve what is considered MRD negativity, which is our gold standard these days, for a complete response in multiple myeloma. This is a great regimen and a nice win for patients who have NDMM who are transplant ineligible.

Q: The supporting data for the approval in this indication came from the phase 3 IMROZ trial. What is your impression of the findings?

Martin: The phase 3 IMROZ trial (NCT03319667) did compare the quadruplet of Isa-VRd to VRd. Patients were randomly assigned to 4 drug induction vs 3 drug [induction] and then they received that essentially for 8 to 9 months worth of therapy. Then [patients] continued on maintenance-based therapy, [including] isatuximab, lenalidomide, and dexamethasone vs what is standard, which is lenalidomide and dexamethasone. It is continuous therapy, and these patients tolerated the therapy quite well.

In fact, there was not a significant safety signal [found with] 4 drugs vs 3 drugs. The quadruplet is quite safe, and it is easy to add isatuximab to what we consider a VRd backbone. The patient population was quite large, over 250 patients received Isa-VRd and 180 patients received VRD. The median age for this group…was 72 years of age. Approximately 10% of them had high-risk disease, and that is what is typical for this older patient population.

When patients were followed for the events of PFS, there was a marked advantage in the quadruplet vs the triplet [arm], where the 60-month PFS in the isatuximab arm was 63%, the 60 month PFS in the VRD arm was 45%, a marked difference. That 63% at 60 months is the longest PFS that we have seen–– the longest remission duration of an upfront newly diagnosed multiple myeloma trial in this transplant-ineligible patient population that has ever been published or presented.

This means that patients are going to go more than, on average, 5 years–– perhaps it will end up being 6 or 7 years–– of remission duration or longer with this combination. That is a huge advantage of this quadruplet vs what we were doing in the past, which was a triplet. It typically was a CD38 plus lenalidomide as a triplet in the past as our standard. This, in my mind, is the new standard based on this high PFS rate.

The investigators of the study did multiple subgroup analyses looking at age and ECOG performance status and whether they had extramedullary disease at the start, or what their revised [International Staging System (ISS)] stage was, or their cytogenetics. In fact, every subgroup that received this therapy benefited from receiving the quadruplet vs receiving the triplet. It is [intended] for all patients who can tolerate a 4-drug regimen that has transplant-ineligible multiple myeloma.

The MRD rates were [55%] MRD negative in the quadruplet vs 44% in the VRd arm, a statistically significant advantage. Then the sustained MRD advantage of more than 12 months was 47% vs 24%. [Isatuximab] doubled the sustained MRD results, demonstrating the potency of this quadruplet regimen. Although the OS data are premature, there seems to be, right around the 5-year mark, a separation of the curves. I suspect there will be a survival advantage. It just bodes to the fact that we should be using powerful combinations like this quadruplet in the frontline for patients who have transplant-ineligible NDMM.

Q: What unmet need does this approval help to reduce?

Martin: It is great because in the present, with multiple myeloma, we have so many new drugs and so many novel combinations, but the true unmet need is getting smaller and smaller. One of the unmet needs is the patients that have an early progression from frontline therapy. Because this quadruplet is so potent, we are seeing fewer patients who have early relapse or early progression. It is capturing patients and inducing deep and durable remissions right from the beginning.

The previous combination, of the CD38 [antibody plus] lenalidomide and dexamethasone, that triplet was our standard triplet prior to these data on the quadruplet, and that triplet did quite a good job. It had a median PFS of about 60 months. [The quadruplet] is going to eclipse that. Some of the people who would have relapsed even on our most powerful previous triplet, will still be in remission on this quadruplet therapy.

The unmet need in the front line is to try to keep people in remission for longer and to induce a deeper and more durable remission. This also enhances the level of patients achieving MRD negativity. In terms of the unmet need for frontline, it is deeper and more durable remissions. This checks both those boxes.

Q: How might you see the combination therapy being implemented into clinical practice?

Martin: These data stand out and speak for themselves, especially the safety component of the data. The addition of isatuximab to VRD does not add a significant amount of toxicity, which is great. That means that adding this CD38 antibody to what many people use as their induction regimen for transplant-ineligible VRD is easy, in my mind. It is very well tolerated. It is not going to enhance significant cytopenia or other [adverse] effects that need to be mitigated. What it is going to do is provide a more beneficial anti-myeloma effect.

People will see the safety data as well as the response data and say there is no reason why I should not give this particular patient a quadruplet over a triplet. We just had a myeloma meeting in Brazil, and there was much to do about that discussion of who can tolerate a triplet [vs] a quadruplet. Many multiple myeloma physicians like myself support the fact that these quadruplet regiments are so well tolerated that, essentially, there are few patients who are frail that we would start with perhaps a doublet or a triplet and try to get to the quadruplet. For most patients–– and this involved patients up to age 80 certainly can tolerate this. In my practice, I use it in patients who are over the age over the age 80, especially if they are in good shape.

Q: Are there any toxicities or AEs associated with the combination therapy that stands out to you?

Martin: In general, if we look at grade 3 treatment-related adverse events [TRAEs], they were very similar in both arms. If we specifically look at the grade 3 events, there was slightly higher grade 3 neutropenia, which we know when [a CD38 antibody] combines with [immunomodulatory drugs (IMiD)], we do see a slightly higher rate of that, but there was not an increased risk of febrile neutropenia.

If we look at overall infections, rates were similar between the 2 arms. If we look specifically at pneumonia, there was a slightly higher risk of grade 3 pneumonia in the Isa-VRd arm vs the VRd arm. Other AEs–– neuropathy, and gastrointestinal adverse effects––are all similar. There was no change in the incidence of secondary malignancies. If you look at events like infection per patient-year–– because patients that are on the quadruplet are on therapy longer than the triplet–– if you look at infections, and you do it over time, the infection rate in both arms is exactly similar.

There were [slightly] more infections in the quadruplet arm, but patients were on therapy for longer, and the infections can happen any time, while they are on therapy. If you look at over time, how many infections per week or month, etc, [both arms were] similar. There is no toxicity say to me that limits the use of these drugs in this population. There are none. It is great, that is the nice signal here.

Q: Beyond this approval, what other developments in multiple myeloma have the potential to change clinical practice?

Martin: That is a big question. I will start with a few. One of the developments is in another isatuximab-based trial. It was called the phase 3 BENEFIT trial (NCT04751877), and the trial [compared] Isa-VRd vs isatuximab lenalidomide and dexamethasone (Isa-Rd).⁴

This [trial] was the first time we had quadruplet vs triplet [regimens], where the only drug that changed was bortezomib–– whether to leave bortezomib out, not leave CD38 out, like all the [other trials evaluating] quadruplets vs triplets. The other advantage was that bortezomib was given in a weekly administration. It was given [subcutaneously week 3] out of 4 weeks for the first 12 cycles, and then it was every other week for the next the next 6 cycles. Bortezomib continued for 18 months.

This is also the first trial where bortezomib continued for this long as induction-based therapy. Usually, bortezomib is completed by the first 8 to 10 months, mostly because of neuropathy. This was to do it weekly to see better. I was anticipating that there would not be much difference between these 2, the quadruplet vs the triplet, but that is why we do the trials. The surprising result was that the quadruplet of Isa-VRd vs Isa-Rd showed a significant advantage for the primary end point [which] was MRD negativity. There was a deeper and more durable response based on MRD negativity in the Isa-VRd arm vs the Isa-Rd arm.

The bortezomib, maybe even at weekly dosing, 3 out of 4 weeks for the first 12 months showed a significant advantage and that trial only has 24 months of follow-up. We are not close to the medium PFS just yet. The medium PFS, with these regimens, looks like it is going to be over 60 months, which is amazing. We are going to need 2 or 3 more years of follow-up to see what the difference in the PFS is in those 2 arms. That changed my practice because now I use [a CD38 antibody] plus bortezomib weekly, 3 out of 4 weeks, plus lenalidomide and dexamethasone.

Q: Is there anything else related to the FDA approval or the IMROZ trial that you would like to highlight?

Martin: For people who are practicing out there, and they are going to choose their next regimen, a quadruplet regimen is tolerable for the far majority of patients with multiple myeloma, whether they are transplant eligible or ineligible. The combination of Isa-VRd, especially with bortezomib given on the weekly 3 out of 4-week dosing regimen, is well tolerated and has the ability to produce deep and durable remissions.

There [are not] many exclusionary comorbidities that prevent patients from getting these therapies. Potentially, they have diabetes, they have bad baseline neuropathy, or they have a bad cardiopulmonary reserve, those patients you might want to start on a doublet or a triplet and add in a medicine, and as they are tolerating it. Again, for the far majority, the data from trials like IMROZ prove that quadruplets are the way to go.

References

1. FDA approves istauximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. FDA. News release. September 20, 2024. Accessed October 2, 2024. https://shorturl.at/B8d3c
2. Facon T, Dimopoulos MA, Leleu XP, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). J Clin Oncol. 2024;42(suppl 16):7500. doi:10.1200/JCO.2024.42.16_suppl.7500.
3. Facon T, Dimopoulos M-A, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. Published online June 3, 2024. doi:10.1056/NEJMoa2400712
4. Leleu X, Hulin C, Lambert J, et al. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nat Med. 2024;30:2235-2241. doi:10.1038/s41591-024-03050-2