Daratumumab Strengthens Efficacy in Treatment of Patients With Transplant-Eligible Myeloma

During a virtual Targeted Oncology Case-Based Roundtable event, David Dingli, MD, PhD, professor of Medicine at the Mayo Clinic in Rochester, MN, discussed the case of a 51-year-old patients with transplant-eligible myeloma.

Targeted Oncology^TM: Please discuss the IFM 2009 (NCT01191060) study that assessed the impact of systemic therapy coupled with stem cell transplantation in patients with newly diagnosed multiple myeloma?

DINGLI: This was a large trial. Patients were randomized to 3 cycles of RVd [lenalidomide (Revlimid), bortezomib (Velcade), dexamethasone], stem cell mobilization with cyclophosphamide [Cytoxan], followed by either 4 to 8 more cycles of therapy with RVd versus transplant, 2 cycles of consolidation, and then maintenance [of 10-15 mg daily of lenalidomide] for 1 year.¹

This study had some important outcomes. One of them is that even in the era of triplet therapy with a very effective regimen, RVd plus transplant still made a difference. There was an improvement in progression-free survival [PFS], although there is no difference in overall survival [OS]. This [asks the question], can we delay transplant because there is no difference in OS?

The answer is yes. But in my opinion, it’s not preferable to delay transplant because if we do for the risk of toxicity, we should expect a reduction in the potential benefit from transplant. Meaning, the duration of the response after transplant and PFS after transplant, is shorter in general if we delay it. The quality of life is probably superior for patients who undergo transplant earlier. However, PFS is superior with early transplant, but OS is not affected.

So, this is our gold standard, what we should be looking for as a minimum.

What were the efficacy data of this study?

Patients who went to transplant and were MRD [minimal residual disease] negative had the best PFS [HR, 0.22; 95% CI, 0.15-0.34; P < .001]. Patients who were MRD negative, even without transplant, also did quite well. For patients who were MRD positive, even after a transplant, their PFS was shorter. Patients who were MRD positive without transplant did the worst.²

So, my take-home message from this point is that transplant is important, and patients who achieve an MRD-negative state after transplant are destined to do the best. If we look at patients who have standard-risk versus high-risk disease, we see the same effect. Patients who are MRD negative and have standard-risk disease do the best. But even patients who are high risk and MRD negative don’t do too badly, but patients who are not MRD negative do inferiorly. So, the quality of the response to therapy is important, and the expectation should be that as more patients achieve deeper responses and achieve more MRD negative states, we should expect patients to do better with respect to PFS.

If we look at OS for patients, half of that impact on survival is defined by what happens to them with first-line therapy. First-line therapy in myeloma is induction, transplant, and maintenance. Fifty percent or more of their OS is defined by that.¹ I would argue that the maximum impact on patient survival is made by our decisions on first-line therapy. Of course, when the patient relapses, we’re going to go with additional lines of therapy, and thank goodness we have second and third lines of therapy and newer classes of agents that help improve survival. But 50% or more of the patient’s expected survival is based on our decision of first-line therapy.

Were there other clinical studies conducted in this patient population?

The FORTE [NCT02203643] trial was a 3-arm study where patients were randomized 1:1:1 either to 4 cycles of KCd [carfilzomib (Kyprolis), cyclophosphamide, dexamethasone] or KRd [carfilzomib, lenalidomide, dexamethasone]. Patients were then randomized to transplant, or the third arm [where] patients would receive a total of 12 cycles of KRd.3 The patients [in the transplant arm] would receive 4 cycles of consolidation therapy with the same agents they received for induction. If the patient got KCd for induction, they would get KCd consolidation; if they got KRd induction, they’d get KRd for consolidation.

Patients would then have a second randomization, either to lenalidomide maintenance therapy alone until progression [of disease] or intolerance, or carfilzomib and lenalidomide with carfilzomib given on days 1, 2, 15, and 16 for 2 years. Lenalidomide was continued until progression.

What can you conclude from the results of the trial?

KRd was superior to KCd with transplant, but KRd with transplant was superior to KRd and KCd [without transplant]. The differences, especially with KRd with transplant versus KCd with transplant, were highly significant. KRd with transplant versus KRd [was statistically quite significant with a] 36% reduction in the risk of progression [HR, 0.53; 95% CI, 0.37-0.77, P < .001].⁴ So, one could argue that KRd is better than RVd, but I think we have data now from 2 large, randomized trials that show that even in the modern era, transplant is quite important, at least with respect to PFS. So, transplant is still quite important in newly diagnosed multiple myeloma.

[Moreover], with KRd with transplant at 36 months, 78% of the patients did not progress, compared with 66% of patients who did not get a transplant, or 58% of patients who got KCd with transplant. Everything seems to favor KRd with stem cell transplant.

At the second randomization, patients were randomized to either lenalidomide maintenance or carfilzomib and lenalidomide after transplant and consolidation. In this study, the doublet maintenance appeared to be superior. The numbers were smaller because these data are still being captured, but at 3 years, 75% of the patients had not progressed while on carfilzomib and lenalidomide maintenance versus 66% for those on lenalidomide alone [HR, 0.63; 95% CI, 0.42-0.95, P = .026]. The confidence intervals are somewhat larger, the data are not yet mature, and patients are still being followed up in this study. So, will this become the new standard of care? I think it’s a little bit too early to tell, and we need to wait for these data to mature more.

How did the phase 3 Cassiopeia (NCT02541383) trial impact the use of quadruplet therapy in this patient population?

Patients were randomized to bortezomib, thalidomide [Thalomid], and dexamethasone [VTd], with or without daratumumab [Darzalex]; probably a regimen that we do not use too much in the United States. I haven’t used thalidomide in patients with newly diagnosed myeloma in many years. This is a very popular regimen in Europe, and this study was done mainly in Europe.

Patients were above 65 years old, with good performance status, and the primary end point was stringent complete response [sCR]. It was a large trial; over 1000 patients were [included and] randomized 1:1 on 4 cycles of VTd versus VTd with daratumumab, stem cell mobilization, conditioning, and transplant. In Europe, many centers would use cyclophosphamide for mobilization, something that I rarely do, and then patients would receive 2 cycles of consolidation with the same regimen they originally received. Patients who achieved a PR [partial response] or better [were put on] a second randomization of observation until progression, or maintenance with daratumumab every 8 weeks for a maximum of 2 years.

What are the highlights from the results of the study?

The study met its primary end point, which was an improvement in the sCR rates, from 20% to 29%. The MRD negativity rate was also superior, by around 20 points, and this was at the level of 10-5. Sixty-four percent of patients achieved MRD negativity, compared with 44%.⁵

If we look at PFS, it was clearly superior for VTd plus daratumumab, with a 53% reduction in the risk of progression at approximately 30 months [HR, 0.47; 95% CI, 0.33-0.67, P < .0001]. The quality of the responses was, in general, superior with the quadruplet therapy, especially with respect to CR and sCR. If we look at the MRD negativity rate after stem-cell transplant, based either on next-generation sequencing or flow cytometry which is 10-5, VTd and daratumumab was superior with both approaches compared with the triplet regimen. Subgroup analysis for PFS favored the quadruplet in all subgroups except stage 3 disease and patients with high-risk cytogenetics. We know that, for example, thalidomide is not a particularly effective drug in patients with high-risk disease, especially in patients with a 17p deletion. The past MRC Myeloma IX trial [ISRCTN68454111] results have shown this, and most of us would not be using thalidomide anyway. However, the study is important because, for the first time, we have efficacy of quadruplet therapy versus a triplet in patients who are transplant eligible and newly diagnosed.

What were the key efficacy takeaways from the GRIFFIN (NCT02874742) trial?

This was a randomized phase 2 trial for newly diagnosed patients with multiple myeloma. The patients received standard RVd versus daratumumab with RVd.⁶ Patients had to be between the ages of 18 and 70, with a good ECOG performance status and good kidney function. Daratumumab was given on days 1, 8, and 15, lenalidomide [was given] for 14 days as bortezomib [was given on] days 1, 4, 8, and 11. Twenty mg of dexamethasone [was given] on the day of, and the day after, daratumumab was given, and RVd was standard dosing. So, these were 21-day cycles and after 4 cycles, patients were mobilized, had stem cell collection, and then transplant. Patients were then given consolidation with the same regimen that they received for induction, either RVd versus daratumumab or RVd [alone]. This was followed by maintenance therapy, either with lenalidomide or daratumumab with lenalidomide.⁶

The study’s primary end point was sCR, and secondary end points were MRD negativity by next-generation sequencing at the level of 10-5, CR rates, overall response rate, and VGPR [very good partial responses]-or-better response rate. Fourteen percent of these patients had ISS [stage] III, and high-risk disease was found in about 15%. High-risk disease was defined as deletion 17p, t(4;14) and t(14;16). There were fewer patients who underwent transplant in the RVd arm due to early discontinuation and [disease] progression.

In the quadruplet [arm], the response rates that were CR or better were consistently superior to the triplet, and these got progressively better at the end of subsequent therapy. At the end of induction, 19% had CR or better, which increased to 27% after transplant. CR was up to 51% at the end of consolidation and 81% after 1 year of maintenance therapy.⁷ Of course, the study is still ongoing, and patients are still being monitored, but clearly, the addition of a CD38 antibody is leading to deeper responses.

Overall, a subgroup analysis also suggested that the quadruplet is superior. Of course, in some scenarios, the data are not powered enough to be definitive, especially in high-risk disease. Remember, only 15% of the patients had high-risk disease, so the number is quite small, and the same for ISS stage III disease. The MRD negativity rate was 62.5% with quadruplet versus 27% with the triplet.

It’s too early to discuss PFS data because these data are not mature enough, but the data seem to suggest that the quadruplet cohort are destined to do better with respect to PFS. If you look at PFS at 2 years, it’s quite impressive [at 90% and greater].

Were there any notable adverse effects from the GRIFFIN study to discuss?

RVd and daratumumab was quite well tolerated. The main increase in toxicity was hematologic, with some more significant neutropenia [of 41.4% at grade 3/4], some thrombocytopenia [at 16.2%], and [16.2%] with leukopenia.8 CD38 is expressed by some hematopoietic progenitor cells, and neutropenia with the regimen is to be expected. In my experience, most neutropenia occurs within the first 1 to 2 cycles, and I generally do not miss doses or reduce doses. Usually, in time, the neutropenia resolves and becomes a less significant problem.

Daratumumab is generally very well tolerated with respect to fatigue. There is some increased risk of upper respiratory infections, but not much else. I’ve switched all patients to the use of subcutaneous daratumumab. There are many advantages, such as rapid infusion, fewer reactions, the patient spends much less time at the infusion therapy center, and the efficacy is the same. I think we have very good data to show that. The subcutaneous route is also very well tolerated, in my experience. I haven’t seen any patients who develop local reactions to the daratumumab, and patients love it.

_References:

_{1. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311- 1320. doi:10.1056/NEJMoa1611750}

_{2. Perrot A, Lauwers-Cances V, Cazaubiel T, et al. Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 Trial. Blood. 2020;136(suppl 1):39. doi:10.1182/blood-2020-134538}

_{3. Gay F, Cerrato C, Petrucci M, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. J Clin Oncol. 2019;37(suppl 15): 8002. doi:10.1200/JCO.2019.37.15_suppl.8002}

_{4. Gay F, Musto P, Scalabrini D, et al. Survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the randomized forte trial. Presented at: 2020 ASH Annual Meeting; December 4-6, 2020. Abstract 141. Accessed April 1, 2021. https://bit.ly/2Odh9ta}

_{5. 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}

_{6. Voorhees P, Kaufman JL, Laubach J, et al. Daratumumab + lenalidomide, bortezomib & dexamethasone improves depth of response in transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Presented at: The 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract 906.}

_{7. Kaufman JL, Laubach JP, Sborov D, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of Griffin after 12 months of maintenance therapy. Blood. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-137109}

_{8. 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}