Quadruplets Poised to Become New Standard in Frontline Transplant-Eligible Myeloma

Susan Bal, MD

The addition of novel monoclonal antibodies such as daratumumab (Darzalex) to standard-of-care regimens had led to deep, durable responses in transplant-eligible patients with newly diagnosed multiple myeloma, according to Susan Bal, MD; however, autologous stem cell transplant continues to retain its role in the paradigm.

“Quadruplet induction therapy is becoming the new standard of care with the incorporation of monoclonal antibodies; however, autologous stem cell transplant is still a key component of care for patients, as it continues to deepen response and improve PFS,” said Bal.

Results from the phase 3 CASSIOPEIA trial (NCT02541383) showed that the addition of daratumumab to bortezomib, thalidomide (Thalomid), and dexamethasone (VTd) before and after transplantation resulted in improved depth of response and progression-free survival in patients with newly diagnosed disease.¹

Daratumumab was also examined in combination with the standard therapeutic backbone of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) in the phase 2 GRIFFIN trial (NCT02874742). Results showed that at a median follow-up of 22.1 months, the stringent complete response (sCR) rate was 62.6% with the addition of the monoclonal antibody versus 45.4% with VRd alone.²

Additionally, the MASTER trial (NCT03224507) is the first to incorporate a minimal residual disease (MRD)­–adapted design into its examination of quadruplet therapy. Results showed that the addition of daratumumab to KRd followed by transplant, KRd consolidation, and lenalidomide maintenance led to a sCR rate of 39% after induction, 81% after transplant, and 95% after MRD-based consolidation.³

“Hopefully, as we are showing with the MASTER trial, MRD response after therapy will be the next improvement in the care of these patients; it may also help us avoid under and over treatment,” added Bal.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Multiple Myeloma, Bal, an assistant professor of hematology medical oncology at the University of Alabama at Birmingham School of Medicine, discussed key trials in the multiple myeloma space.

OncLive®: Could you briefly describe the current state of multiple myeloma treatment?

Bal: Multiple myeloma is a plasma cell disorder which is characterized by the production of abnormal immunoglobulins and end organ damage. A ton of progress has been made in the field in the past several decades and, more recently, that progress has really accelerated and we're seeing more options for our patients with newly diagnosed disease.

Transplant eligibility is a complex assessment; it's really an interplay of a person's comorbidities as well as their performance status. In the United States, chronologic age is less important and less defining for who we will take to transplant. [In the] of management of [patients with] newly diagnosed [disease], the early institution of a multi-agent induction regimen, using drugs that have a synergistic mechanism of action, [is important].

By doing that, we can rapidly debulk the disease, reduce symptom burden, and prevent or rapidly reverse any end organ damage that may have occurred. After we induce our patients, we then take them to stem cell transplant, which is typically a consolidative strategy, followed by maintenance treatment after transplant.

Could you shed light on the ENDURANCE trial along with any significant findings?

The ENDURANCE trial was a frontline study that was presented during the 2020 ASCO Virtual Scientific Program by Shaji Kumar, MD, of Mayo Clinic. This was a long awaited study that compared VRd with carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd).

[The use of] VRd has been [supported] by [results from] a large phase 3 study, which showed an improvement in overall survival (OS). KRd [has been examined in] several smaller institutional studies, which have shown much deeper responses. Both [regimens] have been cited by the National Comprehensive Cancer Network guidelines as frontline options for therapy. [As such], a head-to-head comparison [between the 2 options] was much awaited.

The authors concluded that VRd continues to be an acceptable treatment option for patients with standard-risk disease. The study does not inform about the management of high-risk patients. Also, they did notice many of cardiopulmonary adverse effects were more frequent in the elderly population. As such, this study does not inform the management of fit, young patients with high-risk disease; better therapies are still needed for that population.

Smaller studies have examined monoclonal antibodies, such as daratumumab and isatuximab (Sarclisa). These are both anti-CD38 antibodies that have really changed the treatment of patients with myeloma by providing a new therapeutic class that is very effective and efficacious.

Could you expand on the data observed with daratumumab? How has the addition of this novel agent to standard backbones improved outcomes?

Daratumumab was first assessed in the transplant-eligible setting in the CASSIOPEIA trial, which was done in Europe. In this trial, investigators evaluated the addition of daratumumab to VTd versus VTd alone. Patients on both arms received treatment for 4 cycles followed by transplant, which was then followed by consolidation with 2 additional cycles.

Results showed that the addition of daratumumab improved the depth of response when added to VTd with a higher sCR rate after transplant. Moreover, a higher rate of MRD negativity [was also observed with the quadruplet].

Overall, there was a 53% reduction in risk of progression and death between the 2 arms with a hazard ratio of 0.47. At the time of median follow-up, the OS data were not mature but they appear to favor the daratumumab arm, as well.

Thalidomide is not often used in the United States, correct?

Yes, we tend to use lenalidomide. The GRIFFIN study was a randomized phase 2 study that examined daratumumab plus VRd, which is the standard backbone of therapy for patients with newly diagnosed disease. The question was whether the addition of daratumumab to this combination would improve PFS.

This study was performed at about 35 sites in the United States through 2016 to 2018. Again, it took induction VRd versus daratumumab/VRd, followed by transplant, and followed by 2 additional cycles of consolidation. Thereafter, maintenance was performed with daratumumab and lenalidomide versus lenalidomide alone.

Results showed that depth of response and MRD was much higher in the daratumumab-containing arm and responses deepened over time. Median PFS and OS were not reached in either arm at the time of the 22-month follow-up. However, it will be interesting to see more. The curves are starting to separate so [those data will] be quite interesting. The 24-month PFS rate was approximately 96% versus 90% for the daratumumab/VRd arm versus VRd-alone arm.

Daratumumab was also examined in combination with KRd. Could you discuss the MASTER trial? What did this research reveal about MRD?

The multicenter, investigator-initiated MASTER trial was spearheaded by Luciano J. Costa, MD, PhD, of University of Alabama at Birmingham School of Medicine. In this study, KRd served as the base and then daratumumab was added. Patients started off with 4 cycles of induction with daratumumab/KRd; this was followed by autologous stem cell transplant.

Notably, a MRD assessment was done after each block of therapy. Once patients attain 2 consecutive [tests showing] MRD negativity with a sensitivity of 10-5 using the next-generation sequencing platform, they could actually come off therapy and go into a treatment-free observation with MRD surveillance, which was performed at multiple time points.

What's really interesting is that this gives us the approach to not only use MRD as a prognostic tool, but also to use it to help guide and adapt therapy to avoid over and under treatment of patients who do exceptionally well or not as well and need intensification of therapy.

In the study, similar to the CASSIOPEIA and GRIFFIN trials, each phase of therapy resulted in deepening of responses [on the daratumumab arm]. Although there was no comparator arm in this trial, responses [deepened] over time with each phase of therapy and the stringent CR rate was 95% at the completion of MRD-based consolidation. I believe this is very exciting and great news for our patients. Additionally, 82% patients had MRD less than 10-5 at the end of MRD-adapted consolidation.

Did efficacy with the combination differ with regard to risk?

All patients benefitted from [this approach], standard-risk and high-risk alike. Patients with standard risk did benefit more, but those who were high risk also derived significant benefit with this combination.

During the 2020 ASCO Virtual Scientific Program, Smith Giri, MD, MHS, of University of Alabama at Birmingham School of Medicine, presented an abstract that demonstrated the benefit of daratumumab within the high-risk patient population. This has been a matter of debate up until now. Using meta analyses, they showed that all patients who received daratumumab, whether they have standard-risk or high-risk, newly diagnosed or relapsed [disease], will derive benefit.

This is a novel observation because there had been a question regarding the benefit of daratumumab in patients with high risk. Although the magnitude of benefit [in this subgroup] is lower than the benefit [observed] in [those who are] standard risk, they do appear to benefit [from this approach]. Thus, this should be a part of their [treatment], as well.

Given all of these novel combinations, has the role of stem cell transplant shifted?

The role of early versus delayed stem cell transplant approach [is a very interesting topic of discussion]. Several meta analyses have shown that early autologous stem cell transplant and high-dose therapy does improve PFS in patients with newly diagnosed myeloma who are eligible for this procedure.

As such, we wanted to leverage the MRD data yielded from the MASTER study to see whether autologous stem cell transplant adds benefit in the setting where some of the most potent and efficacious agents that we have are being used. The MASTER study used some of the best agents that we have available and the question was: Does an autologous stem cell transplant still add benefit when we use these agents up front for induction and consolidation?

We showed that, even with this extremely efficacious quadruplet regimen, stem cell transplant was able to deepen the MRD response in about 86% of patients. In fact, the incremental depth of response with transplant with MRD sensitivity of 10-5 was actually 41% after induction. This then increased to 73% [after] autologous stem cell transplant. It was really interesting to show this benefit [with transplant], even in the context of excellent novel agents.

In our study, we showed that transplant added a median of 1 log reduction of about 0.9 in the burden of MRD with transplant. Although our data are not mature enough yet to show the difference in PFS and OS, previous studies from other groups have demonstrated that each log reduction in MRD resulted in a substantial improvement in survival. I believe that, with more follow up, we will see differences in survival outcomes, as well.

References

1. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192:29-38. doi:10.1016/S0140-6736(19)31240-1
2. Voorhees PM, Kaufman JL, Laubach, JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update. Blood. 2019;134(suppl 1):691. doi:10.1182/blood-2019-123456
3. Costa LJ, Chhabra S, Godby KN, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (dara-KRd) induction, autologous transplantation and post-transplant, response-adapted, measurable residual disease (MRD)-based dara-Krd consolidation in patients with newly diagnosed multiple myeloma (NDMM). Blood. 2019;134(suppl 1):860. doi:10.1182/blood-2019-123170