Quadruplet Therapy with Daratumumab Improves Outcomes in NDMM

Chakra Chaulagain, MD​

Hematologist/oncologist

Cleveland Clinic​

Weston, FL

CASE SUMMARY

• The patient is a 54-year-old woman.
• Laboratory results:​
  • Hemoglobin, 7.0 g/dL; ß₂ microglobulin, 6 mg/dl; albumin, 3.2 g/dL.
  • Calcium, 11.3 mg/dL; lactate dehydrogenase, 200 U/L; creatinine, 45 mL/min​
  • Bone marrow: 22% monoclonal plasma cells​
• Serum k free-light chain: 240.0 mg/L​
• Serum monoclonal protein: 5 g/dL​
• Cytogenetic (fluorescence in situ hybridization and karyotyping) abnormalities: None​
• ECOG performance status: 1​
• PET-CT: Multiple bone lesions in vertebrae without extramedullary disease
• Diagnosed with revised-International Staging System (ISS) stage 2/revised 2-ISS stage 3 IgG-k myeloma; identified as being transplant eligible.

Targeted Oncology^TM: What was the design of the GRIFFIN trial (NCT02874742) for patients with newly diagnosed multiple myeloma (NDMM)?

CHAULAGAIN: It was a phase 2 randomized trial of D-RVd [daratumumab (Darzalex), lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone] vs RVd, before transplant.1 The eligibility criteria [of this trial] were slightly expanded to include patients up to age 70. Conventionally, all the studies have included patients who are 18 to 65 years old, but the GRIFFIN trial allowed [for recruited patients to be up to] age 70, so it's a little bit generous...but they were still stratifying [these patients] based on ISS stage and creatinine levels. D-RVd or RVd was given for 4 cycles, followed by transplant, and patients [in both arms of the trial] got 2 additional cycles of treatment for consolidation therapy. Patients who were in the D-RVd arm got [daratumumab and lenalidomide] maintenance vs patients in the RVd group who got just lenalidomide maintenance. The primary end point was the efficacy of the stringent complete response [sCR] rate, and secondary end points included minimal residual disease [MRD] negativity and progression-free survival [PFS]. The median age of patients on the trial was 60, which [is interesting to note], because in other triplet therapy studies the median age is closer to 50.¹

What were the baseline characteristics of patients on this trial?

The baseline characteristics were well balanced. These trials are sometimes criticized for not enrolling enough high-risk cytogenetic patients, but they have revised [this stance and included] high-risk cytogenetic patients because they are also including patients...[with other factors] like an amplification of 1q.² Still...those with high-risk disease are a small number of the population [recruited for GRIFFIN], and that's why it’s hard to say that RVD helps these patients. There were [not many with high-risk disease treated in this study,] which is why it’s hard to assess its abilities [in this patient population].²

What were the primary efficacy results on the GRIFFIN trial?

The results of the overall population on [this trial show a benefit with the quadruplet therapy with a sCR rate of 63.0% vs 40.7% in the triplet arm]. We can also see that the D-RVD treatment benefited across subgroups of patients, including high risk and ultra-high risk. However, we have to keep in mind that…this is a small sample size [for some of the subgroups].²

How was MRD negativity impacted by the quadruplet therapy in this study?

With the MRD negativity rate [in the intention-to-treat population at 64.4% in the D-RVd arm vs 30.1% in the RVd arm], the quadruplet therapy is a clear winner.2 [It continues to show a benefit] across all the subgroups, but maybe not so much [for patients with a high] cytogenetic risk. However, in most subgroups D-RVd is much better.... [These results bolster] the conclusion of the study that treatment with quadruplet therapy is the way to go for patients with NDMM.

What were the other results to highlight from this trial?

For PFS, everything favors the quadruplet therapy. [Even without reaching a median PFS, the HR favored the quad therapy vs triplet regimen at 0.45 (95% CI, 0.21-0.95)].² Except maybe not as much in the high-risk cytogenetic population...but again, that's a much smaller population to [get results from]. After the initiation of [treatment] in this clinical trial, all patients also noted improvement in their global health status and physical functioning.³ All the patients noted that everybody had improved their routine, but the patient who were on quadruplet therapy surprisingly had a much better improvement in pain and fatigue. So, a lot of times we say, [more drugs might make the patient have more adverse events], but that wasn't the case in this analysis.

^References:

^{1. 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 Aug 20;136(8):936-945. doi:10.1182/blood.2020005288}

^{2. Chari A, Kaufman J, Lubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients (Pts): final analysis of GRIFFIN among clinically relevant subgroups. Blood. 2022;140(1):7278-7281. doi:10.1182/blood-2022-162339}

^{3. Silbermann R, Laubach J, Kaufman J, et al. Health-Related Quality of Life in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma Treated with Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone: Patient Reported Outcomes from GRIFFIN​. Blood. 2022;140(1):1146-1149. doi:10.1182/blood-2022-162313}