Data for Quadruplet Therapies Could Alter Frontline SOC for Transplant-Ineligible Multiple Myeloma

Muhamed Baljevic, MD, FACP, a hematologist and medical oncologist, and an associate professor of medicine in the Division of Hematology Oncology at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, discussed recent advancements and ongoing research in the frontline treatment of multiple myeloma, particularly focusing on high-risk patients; the role of quadruplet regimens and autologous stem cell transplant (ASCT); and the impact of minimal residual disease (MRD) status.

“I would argue that we can impact disease [earlier] than later in the treatment course. I would also argue that the MRD-guided era is increasingly maturing. Within a few years, it may be ready for primetime and [we] may be better informed on how to use [MRD] in terms of modulation of therapy; when to start and stop [therapy]; and [when to] de-escalate therapy,” he explained.

Baljevic, who is also the director of Plasma Cell Disorders Research, director of the Vanderbilt Amyloidosis Multidisciplinary Program at Vanderbilt-Ingram Cancer Center, and co-chair of the Vanderbilt-Ingram Cancer Center Protocol Review and Monitoring System, discussed additional takeaways for the investigation of quadruplet therapies in the frontline treatment of multiple myeloma in another interview with OncLive^® following the Vanderbilt Stem Cell Transplant and Cellular Therapy Symposium.

OncLive: What role could quadruplet combination play for patients with high-risk cytogenetics?

Baljevic: Daratumumab [Darzalex] plus carfilzomib [Kyprolis], lenalidomide [Revlimid], and dexamethasone [dara-KRd] is an excellent quadruplet. An example of this regimen was seen in the phase 2 MANHATTAN study [NCT03290950] that was a single-arm and nonrandomized trial where MRD negativity rate was also a primary end point after 8 cycles of therapy. [In these patients] with high-risk genetics, there was a 100% overall response rate [ORR] and [71%] MRD negativity rate.¹

A general point is the impact of ASCT on next-generation sequencing–defined MRD burden after quadruplet induction therapy. [Investigators] showed the presence of high-risk genetics was another factor that was associated with MRD disease burden. This highlights the importance of ASCT, particularly in these high- or ultra high–risk subgroups, where patients have multiple high-risk features.

How do you see the role of CAR T-cell therapy fitting into treatment with quadruplet therapy?

There are a lot of questions that come to us about the role of ASCT and if transplant will be replaced by CAR T-cell therapy. At this point, transplant still has a defined role, in my opinion, particularly in high-risk patients. We saw the results of the phase 2 MASTER trial [NCT03224507] with dara-KRd plus transplant.

[The phase 2] MASTER-2 trial [NCT05231629] will look at daratumumab, bortezomib [Velcade], lenalidomide, and dexamethasone [D-VRd] for 6 cycles before using MRD-stratified approaches. Patients in the MRD-negative group will be able to proceed to either D-VRd consolidation and daratumumab/lenalidomide maintenance, or undergo ASCT and receive daratumumab/lenalidomide maintenance. For patients who are MRD-positive, both groups will get transplant; however, some will be treated with teclistamab-cqyv [Tecvayli] plus daratumumab for 3 cycles [as consolidation therapy] and then teclistamab plus daratumumab as maintenance, whereas the other group will get additional daratumumab/lenalidomide during consolidation and maintenance. MRD will be checked at different points to measure the impact of this therapy and the depth of response. This is an innovative trial design, and our center will participate in [the study].

What questions remain in the treatment of patients with relapsed/refractory multiple myeloma?

What can we do better for high-risk patients who are relapsing for the first time? [A trial we are planning] will include patients with high-risk features at diagnosis at their first relapse. [The study will also include] patients who don't necessarily have routine high-risk cytogenetic features if they progressed within 2 years of induction, [irrespective of] transplant eligibility.

[With] some of the progression-free survival [(PFS) data we have] with quadruplet therapy, any patient who is progressing within 2 years is high-risk in general. [However], in this trial, it will be important that patients are either daratumumab naive or have not had daratumumab for the past year. Patients will be randomly assigned 1:1 to receive either daratumumab plus teclistamab, or physician’s choice of therapy. The primary end point will be 6-month MRD-negative rate; we'll also have some secondary end points including the 12-month MRD-negative rates, toxicity, PFS, overall survival, and ORR.

This is an important trial because we’re evaluating whether early incorporation of immune-based therapies via a bispecific antibody can give us better results in this population with high-risk disease vs some of the other standard-of-care options that we're using currently.

What could quadruplets potentially mean for the frontline treatment of patients who are ineligible for ASCT?

In the transplant-ineligible space, the [phase 3] IMROZ trial [NCT03319667] has reported positive results for isatuximab [Sarclisa] plus VRd vs VRd alone for 4 cycles, followed by isatuximab plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone in 4-week cycles until progression. The PFS was positive, and we'll see the data [at the 2024 ASCO Annual Meeting and the 2024 EHA Congress].²

This is going to be important because this is in the transplant-ineligible space with a quadruplet vs a triplet. We are curious to see how the community and practitioners [interpret] this data and whether this will meaningfully change their practice patterns when it comes to the standards in the transplant-ineligible space, where VRd or daratumumab plus dexamethasone is the standard choice.

Additionally, the phase 3 CEPHEUS trial [NCT03652064] will also look at the D-RVd vs RVd for 8, 3-week cycles, followed by DRd vs Rd in 4-week cycles indefinitely. This trial is also in transplant-ineligible space.

[Data] for quadruplets are coming in the transplant-ineligible area, and it certainly seems like we may be at the point where one could make an argument that quadruplets are potentially beneficial [in the frontline setting, irrespective of transplant eligibility].

References

1. Landgren O, Hultcrantz M, Diamond B, et al. Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma: the MANHATTAN nonrandomized clinical trial. JAMA Oncol. 2021;7(6):862-868. doi:10.1001/jamaoncol.2021.0611
2. Sarclisa (isatuximab) phase 3 trial met primary endpoint of progression free survival in patients with newly diagnosed multiple myeloma not eligible for transplant. News release. Sanofi. December 7, 2023. Accessed May 28, 2024. https://www.sanofi.com/en/media-room/press-releases/2023/2023-12-07-06-35-00-2792221