Part 2: Daratumumab Shows Greater PFS Benefit Early On in Multiple Myeloma

Saad Zafar Usmani, MD

Director, Plasma Cell Disorders Program

Director, Clinical Research in Hematologic Malignancies

Levine Cancer Institute/Carolinas Healthcare System

Charlotte, NC

Targeted Oncology^TM: What did the CASSIOPEIA study show in this setting?

USMANI: The other important study here is CASSIOPEIA [NCT02541383], which is probably not as relevant to the US practice because we don’t use VTd [bortezomib (Velcade), thalidomide, and dexamethasone] as induction, but I like the initial concept of adding daratumumab [Darzalex] to a PI-IMiD [protease inhibitor-immunomodulatory drug] induction and consolidation schema.¹ The first randomization already had been reported and read out, and it was published in [The] Lancet 2 years ago, showing that the daratumumab arm had better progression-free survival [PFS]. But the second randomization was also interesting, in which daratumumab was given every 8 weeks as maintenance compared [with] observations. This kind of trial will not fly today in the US for sure, and even in Europe now, because lenalidomide [Revlimid] is not now approved by [the] European Medicines Agency for maintenance treatment in Europe.

The original daratumumab-VTd vs VTd comparison showed better minimum residual disease [MRD] negativity, better PFS [HR, 0.58; 95% CI, 0.47-0.72; P < .0001], and a trend toward better overall survival in the daratumumab arm of the trial [HR, 0.54; 95% CI, 0.37-0.79]. Part 2 showed daratumumab vs observation. If you look at the groups who benefited the most—the patients who got daratumumab at any time—you will see that the PFS curves appear to be similar at the 24-month mark. If you look at the curve, which represents VTd induction, vs the other 2 curves, which are daratumumab-VTd induction, you see an initial drop-off, but the VTd curve makes up for it later because they’re getting daratumumab maintenance. The bottom line is you’re probably getting the most benefit from daratumumab during that early part of the induction, and for the daratumumab arms, there appears to be no difference at the 24-month mark between daratumumab vs observation.¹

Can you go over the GRIFFIN trial?

The GRIFFIN trial [NCT02874742] that Peter Voorhees, MD, presented—and was published later on—is probably going to be more relevant to the United States practice.² It compares data throughout that schema of induction/consolidation/maintenance with RVd [lenalidomide, bortezomib, and dexamethasone] induction/consolidation and maintenance with lenalidomide [vs daratumumab-RVd]. With each of these trials I presented, I can tell you most of us are not using the consolidation part. This consolidation part comes from the way the IFM/DCFI2009 trial [NCT01191060] was designed, and at the behest of regulatory authorities the way they want to see some of these trials designed and regulatory questions answered.

The GRIFFIN data were updated by Peter Voorhees, MD, and Jonathan Kaufman, MD, showing the complete response [CR] or better rate and MRD negativity rate. A stringent CR [sCR] rate was superior in the daratumumab arm, whether it’s at the end of induction, transplant consolidation, or 12 months of maintenance.³ And that response continues to deepen over time. Again, the median follow-up for the maintenance part was only [approximately] 27 months when these data were reported.

For subgroup analyses, all these prespecified subgroups were analyzed for sCR and MRD negativity, favored toward daratumumab, for the most part.⁵ But again, I’m not convinced until I see further follow-up, and all these confidence intervals tightening up a bit more. But certainly, trending toward the addition of daratumumab. The most common adverse events appear to be hematologic. [In the GRIFFIN trial], grades 3 or 4 AEs appear to be somewhat similar between RVd and daratumumab-RVd.^2,3

Can you summarize what these trials tell us in terms of PFS benefit?

In the CASSIOPEIA trial, the median PFS had not been reached, and in the VTd arm was 52 months.¹ GRIFFIN is too early to say, because we do not have that much of a long-term follow-up.^2,3 We see that, in absence of using plerixafor [Mozobil] as part of stem cell mobilization, we may see differences in the numbers of the stem cells mobilized. We had shared that there were no differences in stem cell mobilization if you’re using plerixafor, compared [with] the [cyclophosphamide]-based or chemo-mobilization. But across the board here, you can see that the depth of response continues to get better and better, with better induction chemotherapies over time.

Do you use subcutaneous daratumumab [Darzalex Faspro] vs intravenous infusion for the treatment of multiple myeloma?

Because subcutaneous daratumumab has been approved for almost 11 months, we switched to subcutaneous data last year, and that’s the only formulation we use right now.⁴ One of our pharmacists published our initial experience of switching over 50- or 60-odd patients from intravenous to subcutaneous, and none of them had any AEs related to [the switch].⁵ Honestly, during the pandemic, that subcutaneous formulation was a blessing, because it helped us reduce our traffic in the infusion center and cycle patients through quickly. Issam Hamadeh, [PharmD, BCPS, BCOP], was the first author for that. So if your pharmacist needs some help, you can look that paper up. It was published this year.

_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 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}

_{3. 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}

_{4. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2021. December 10, 2020. Accessed March 22, 2021. https://bit.ly/3fa9Yx5}

_{5. Hamadeh IS, Moore DC, Martin A, et al. Transition from intravenous to subcutaneous daratumumab formulation in clinical practice. Clin Lymphoma Myeloma Leuk. 2021;21(7):470-475. doi:10.1016/j.clml.2021.02.014}