Khouri Analyzes How Daratumumab-Based Quadruplet Therapy Achieves MRD States in Multiple Myeloma

Jack Khouri, MD

Assistant Professor, Department of Medicine

Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Taussig Cancer Center

Cleveland Clinic

Cleveland, OH

CASE SUMMARY

• A woman aged 54 years presented to her physician with complaints of back pain, fatigue, and occasional but recurring dizziness.

Lab results:

• Hemoglobin, 7.0 g/dL; β₂-microglobulin, 6 mg/L; albumin, 3.2 g/dL
• Calcium, 11.3 mg/dL
• Lactate dehydrogenase, 200 U/L (within normal limits)
• Creatinine, 1.5 mg/dL
• Bone marrow: 22% monoclonal plasma cells
• Serum free light chain κ: 240.0 mg/L
• Serum monoclonal protein: 5 g/dL
• Serum immunofixation electrophoresis: IgG-κ present
• Cytogenetic (fluorescence in situ hybridization and karyotyping) abnormalities: hyperdiploidy (gain 9 and 11)
• ECOG performance score: 1
• PET-CT: Multiple bone lesions in vertebrae without extramedullary disease
• Diagnosed with Revised International Staging System (R-ISS) stage 2/R2-ISS stage 3 IgG-κ myeloma; identified as being transplant eligible

PEERS & PERSPECTIVES IN ONCOLOGY: What did the final analysis of the phase 2 GRIFFIN study (NCT02874742) show for the long-term use of D-VRd (daratumumab [Darzalex], bortezomib [Velcade], lenalidomide [Revlimid], dexamethasone)?

KHOURI: There was a trend toward better PFS [progression-free survival] with [the addition of] daratumumab.¹ At 4 years, the PFS rate was 87.2% [for those patients given daratumumab] compared with 70% in the VRd arm, which was also significant [HR, 0.45; 95% CI, 0.21-0.95; P = .032]. However, overall survival [OS] was still not significantly different at the 3-year and 4-year landmark analyses. [Similar to the PFS results], the response rate was better with D-VRd, and we also see more complete responses with the addition of daratumumab [to triplet therapy]. In the final analysis [of the GRIFFIN study], a CR [complete response] or better was seen in 83% of the patients [in the quadruplet arm] vs 60% with VRd [Figure¹]. In summary, there’s a better potential PFS [with the addition of daratumumab], CR rates were better, but there was no difference in OS, although this was a phase 2 study so there were smaller numbers of patients.¹

How did minimal residual disease (MRD) negativity rates change with the addition of daratumumab?

Looking at MRD-negative rates, more MRD negativity was seen with the addition of daratumumab.¹ The rate of MRD deepened over time, so we did see more patients getting into an MRD-negative state as time went on, which is something that we [would hope to see]. If you check the MRD negativity rates with your patients, with time and maintenance therapy, even if they’re MRD positive, a lot of them will have less of an MRD burden as time goes on. So, if the patient starts with 60 clones per million after transplant, you’ll see that clone getting smaller and smaller down to 10, and then maybe to 5, and then to an MRD-negative state as time goes on. We do see deepening of responses from transplant and beyond with maintenance therapy, and this rate was better in the daratumumab arm.¹

Please describe the design of the phase 3 PERSEUS trial (NCT03710603).

This study is similar to the GRIFFIN study, but it is a larger phase 3 study, which means more patients were observed, [but still focused on] D-VRd vs VRd and included all transplant-eligible patients.² A few things different about the design [of PERSEUS were] that the patients all got subcutaneous daratumumab, which a lot of us are doing in clinic already. Rarely are people giving daratumumab intravenously, so that’s something that’s similar to the real-world setting. Something else that was interesting was the way they gave bortezomib…where they gave it biweekly, so on days 1, 4, 8, and 11, which is different from what we do in real life, but the use of lenalidomide was similar to the real-world setting. The way they gave dexamethasone in the study is also a little bit different [to the way it’s given in the clinic], which is a common problem in our studies [of treatments for patients with multiple myeloma].² There [are] always a lot of steroids given [in a trial], which is different from what we do [in the clinic]. They gave two 4-day pulses of 40 mg [of dexamethasone], which…is a lot of dexamethasone, and a lot of patients would have heavy adverse events from that.²

What were the methods for consolidation and maintenance therapy in this trial?

After transplant, they gave patients 2 cycles of consolidation with intensive therapy, which a lot of us [in clinic] do not do…. In general, once patients are out of transplant, we move on to maintenance therapy right away. So, these are…little caveats to the PERSEUS study design [compared with the real-world setting]. Another thing is there was no second randomization for maintenance therapy, so patients were not [randomly assigned] after consolidation in terms of maintenance therapy.² They either got daratumumab with lenalidomide if they had daratumumab in the front line or they had lenalidomide if there was no daratumumab in the front line. The maintenance strategy that they implemented in this study was that after 2 years of daratumumab and lenalidomide maintenance in the daratumumab arm, patients were able to [discontinue] daratumumab if they had sustained MRD negativity for at least a year…and just continue lenalidomide.²

What were the main efficacy results from this study?

The primary end point was PFS, as many of the trials [for patients with] multiple myeloma have. There was a clear PFS benefit through the addition of daratumumab in the front line, [with a 4-year PFS rate of] 84.3% vs 67.7% [in the triplet arm], which is pretty good, in my opinion.² Looking at subgroup analyses, almost everybody benefitted from the addition of daratumumab, and the rates of CR or better were also better with D-VRd [than those on just VRd] at 87.9% vs 70.1%, respectively. Of note, patients who were older than 65 years did not seem to derive benefit from the addition of daratumumab, which is hard to interpret as the numbers [in this group] were small in both arms. By looking at the study more carefully, there were more patients with high-risk disease who were older than 65 [years], so this may have skewed the results a little bit. I’m still going to consider daratumumab for everybody regardless of age [based on these overall results]. But, hopefully, with more follow-up we can learn more about this. One more thing to note is that OS is not mature here, but there was potentially a trend toward a better OS with daratumumab.²

Did the MRD negativity rates still improve with the addition of daratumumab?

Looking at MRD, again, there are more MRD-negative [10^–5] patients with the addition of daratumumab [compared with the triplet], so 75.2% vs 47.5%—almost double the MRD-negative rates [OR, 3.40; 95% CI, 2.47-4.69; P < .0001].² Patients were also able to sustain their MRD-negative status at 10^–5 [ for 12 months or more] if they had daratumumab [compared with those without] at 64.8% vs 29.7%. Overall, the data speak favorably to the addition of daratumumab.²

Please describe the phase 2 MASTER study (NCT03224507).

[This single-arm study looked at] another quadruplet therapy, D-KRd [daratumumab, carfilzomib (Kyprolis), lenalidomide, and dexamethasone], in this setting.³ The way this was done was for all transplant-eligible patients, again, but the way they confirmed that was they checked MRD at different time points here. So, MRD was checked after induction and then again after transplant. They also did consolidation therapy and again checked MRD, and really, they based how much treatment they gave on the patient’s MRD status. So, if any patient were MRD negative 2 times— so let’s say they’re MRD negative after induction and then after transplant—they could stop treatment and be observed, which these patients were called MRD-SURE. If the patient is still MRD positive, they would undergo more treatment with consolidation, so treatment intensification based on MRD…. There [weren’t many] high-risk cytogenetic patients in this study, which was good because those are the patients we struggle with the most. Again, this was a single-arm study, and the primary end point was MRD negativity at 10^–5.³

What did the survival data look like on this study?

Looking at PFS and OS data…patients who did not have high-risk cytogenetics or patients who had 1 high-risk cytogenetic feature did much better than patients who had 2 or more high-risk cytogenetics in both categories.⁴ So, even patients who had 2 or more high-risk cytogenetic features still did not do well [with this intensive treatment]. And these are the patients that I’m sure many…physicians see in clinic, and these are what we call the ultra–high risk or double-hit patients with multiple myeloma…. So, these are the patients who don’t benefit from this intensive kind of therapy from the get-go. But patients who have 1 high-risk feature, they do as well as patients who are standard risk and have no high-risk cytogenetics.⁴ This gives us more insight into this population of patients that needs a lot of work still [to find a suitable therapy].

Was there a correlation between survival data and the patient’s MRD status?

They looked at the PFS and OS for patients who were MRD positive or MRD negative at the end of induction.⁴ What they found was…that PFS was essentially the same for MRD-negative and MRD-positive patients, which is a little bit counterintuitive. But then if you think about it, in this study, patients who were MRD positive underwent more treatment, so they [had a higher] intensification of therapy. Over time, they did become MRD negative, potentially, and they got more treatment, which may have led to this overlap of the PFS curves. [The same was seen for] OS data,⁴ and again, it speaks to the importance of MRD negativity and getting patients to an MRD-negative state.

Did the MRD negativity status change at all post transplant?

The same thing was seen post transplant, as well.4 When you check their MRD status post transplant, MRD-negative or [MRD-] positive patients had a similar PFS, likely due to the treatment intensification in patients who had MRD positivity after a transplant. Now, looking at PFS by MRD status in all patients, PFS was better in patients…who could sustain MRD negativity at 10^–5 [HR, 0.52; 95% CI, 0.22-1.19; P = .12]. And whether you look at 10^–5 or 10^–6 on MRD the results were the same [HR, 0.28; 95% CI, 0.11-0.68; P = .0025].⁴ So, again, it’s a recurring theme where the MRD status is important. Now, the main question is how to use MRD [in the real-world setting]. Do we know how to use MRD? And the answer is, we still need more data on how to use MRD.

_REFERENCES

_{1. Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837. doi:10.1016/S2352-3026(23)00217-X}

_{2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al; PERSEUS Trial Investigators. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301- 313. doi:10.1056/NEJMoa2312054}

_{3. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(25):2901- 2912. doi:10.1200/JCO.21.01935}

_{4. Costa LJ, Chhabra S, Medvedova E, et al. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol. 2023;10(11):e890-e901. doi:10.1016/ S2352-3026(23)00236-3}