Updated GRIFFIN Data Show Safety, Efficacy of Adding Daratumumab in NDMM Maintenance

Can daratumumab be taken safely as a maintenance therapy? Will quadruplet therapy become more common in the treatment of newly diagnosed multiple myeloma (NDMM)?

The answer to both questions is yes, based in part on updated results from the phase 2 GRIFFIN trial (NCT02874742), says Jacob Laubach, MD, MPP, senior physician and clinical director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston, Massachusetts.

Laubach presented the GRIFFIN data during the 2021 American Society of Hematology Meeting & Exposition in December.¹ Primary results from GRIFFIN had shown that in autologous stem cell transplant (ASCT)-eligible, newly diagnosed patients, daratumumab (Darzalex) plus lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (D-RVd) improved the rate of stringent complete response (sCR) compared with RVd alone (42.4% vs 32.0%).²

New data show that patients who took daratumumab with lenalidomide for 24 months after receiving the quadruplet therapy and an ASCT had better outcomes than those who received the triplet (RVd) and maintenance with lenalidomide alone. The rate of sCR favored the D-RVd arm vs the RVd arm (66.0% vs 47.4%, 2-sided P=.0096%). Minimal residual disease (MRD) negativity rates were higher for those taking daratumumab (64.4% vs 30.1%), as well as among patients who achieved a CR or better (78.0% vs 47.5%, P=.0003).

Although the study was not powered for progression-free survival (PFS), the estimated 36-month PFS was 88.9% for those taking the daratumumab quadruplet vs 81.2% for the triplet. No new safety concerns were seen with the extended follow-up.¹

Laubach discussed the updated results from GRIFFIN with Evidence-Based Oncology™ (EBO):

EBO: You now have an extended period of follow-up for the phase 2 patients from GRIFFIN. What are the most important takeaways thus far?

Laubach: This analysis took place after patients had received approximately 2 years of maintenance therapy. So it really gave us an opportunity to see how patients were doing with extended follow-up, and they continued to show improvement. All the major outcomes of the study, including stringent complete response, MRD at a sensitivity of 10-5, and MRD at a sensitivity of 10-6. It also demonstrated sustained MRD negativity in a significantly higher percentage of patients who were receiving daratumumab as a component of induction consolidation, and posttransplant maintenance. And finally, the results showed a strong trend toward improvement in progression free survival after approximately 3 years of treatment overall and 2 years of maintenance therapy.

EBO: The study was not powered for PFS, but the trend favors the daratumumab arm. Can you discuss this finding?

Laubach: I think extended follow-up is key here. If you look at the progression-free survival curve, you see that the curves are essentially superimposed until approximately the 22 months’ time point, which is after essentially 1 year of maintenance. And with the longer period of posttransplant maintenance therapy with daratumumab as well as lenalidomide in the daratumumab-treated patients, you’re seeing further separation of the curves. So the confidence interval still crosses 1 at this point in time. It’s 89% versus 81% progression free survival rates. The curves appear to continue to diverge. With longer follow-up, it’s quite possible that this will reach a level of statistical significance.

EBO: How was MRD measured in GRIFFIN? Is there a consensus on the best way to measure MRD in multiple myeloma?

Laubach: MRD can be assessed both by multiparameter flow cytometry to a sensitivity of 10-5 or via next-generation sequencing to 10-6. I think that there is some variation institutionally and also geographically in terms of what’s available at our sites. We tend to prefer the next-generation sequencing approach with a higher level of sensitivity. But if that’s not available and multiparameter flow cytometry is, that’s certainly a very valuable tool. It allows us to assess depth of response in a way that’s using either technique, more sensitive than traditional measures, utilizing a serum free light chain, serum protein, electrophoresis, and bone marrow analysis. I think either technique is quite good.

We were very excited to see with this study that with longer follow-up we’re continuing to see the improvement in MRD negativity rates. And you could say, almost surprisingly, that at the highest level of sensitivity at 10-6, between year 1 and year 2 of maintenance therapy, there was a significant improvement in MRD negativity rates, suggesting that that longer duration of exposure to drug maintenance with daratumumab and lenalidomide is really making a difference. To piggyback on that point, across the study, whether a patient was in the RVD arm or Dara-RVD, if patients had sustained MRD negativity extending beyond 12 months, nobody progressed. It’s an important clinical measure that, as I think we are well aware from prior studies, correlates well with progression free survival.

EBO: Can you discuss the safety results?

Laubach: The safety data were quite consistent with prior reports on the Dara-RVd regimen. There were higher rates of hematologic toxicity, including a higher rate of grade 3 hematologic toxicity. But within the field of myeloma, recognizing some of the challenges that we face with managing hematologic toxicity in general is something that we can readily manage in the clinic by holding doses, reducing doses, and giving appropriate supportive care.

I think the important finding was that for nonhematologic toxicities, [although] there was an increased rate of some nonhematologic toxicities, the rate of higher-grade nonheme toxicities was essentially the same. And the discontinuation rate for toxicity was essentially identical as well. So, not surprisingly, there was a bit more toxicity. I think sometimes we overuse the term manageable toxicity, but in this case I think it’s appropriate. There was mainly hematologic toxicity, which we can readily adapt to in the clinic, and the nonheme toxicity was essentially identical when looking at higher-grade toxicities.

EBO: Given the findings, will quadruplet therapy become more common in managing multiple myeloma?

Laubach: As a result of this trial—and others—it will become more common. And I think it’s a result of various issues. One, as you alluded to, [is that] the safety is critical. The fact that we are able to safely add [daratumumab] without adding the burden of excess toxicity is huge, because RVd is pretty effective therapy and has been one of the important standards of care for the better part of the past decade. If you were adding an additional agent to a well-tolerated and effective regimen and seeing a lot of toxicity, or if you were seeing better depth of response, that would probably be counteracted by that toxicity concern. But the safety data are really crucial, and I think this study and several others show that we can safely add daratumumab to RVd therapy.

Then, of course, the efficacy data are very strong. I think that the movement of the response rates across time going from the postconsolidation analysis to the analysis after 1 year of maintenance and now the analysis after 2 years of maintenance—and continuing to see improvement in MRD negativity and continuing to see the PFS curve separate—is very encouraging. I think it does put the quad of Dara-RVd now in position to be used in the standard clinical setting for patients with newly diagnosed myeloma.

References

1. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Presented at: 63rd American Society of Hematology Annual Meeting and Exposition, December 11-14, 2021; Atlanta, GA, and virtual. Abstract 79. https://ash.confex.com/ash/2021/webprogram/Paper149024.html

2. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288