Daratumumab Plus Lenalidomide/Dexamethasone Prolong OS When Administered Long-Term in Myeloma

Philippe Moreau, MD

In the phase 3 MAIA study (NCT02252172), treatment with daratumumab (Darzalex) plus lenalidomide (Revlimid) and dexamethasone for at least 18 months achieved deep clinical responses in patients with treatment-naïve multiple myeloma who were transplant ineligible, according to data from post hoc analyses.¹

At a median follow-up of 56.2 months, patients treated with the humanized IgGx CD38-targeted monoclonal antibody daratumumab in combination with lenalidomide and dexamethasone for at least 18 months derived a significant overall survival (OS) benefit compared with those who received the regimen for less than 18 months (HR, 0.16; 95% CI, 0.1-0.25; P < .0001). Notably, the median OS was not reached in the group with the longer treatment duration vs 20.5 months among patients who were treated for less than 18 months.

Moreover, patients who were treated with the daratumumab-containing regimen for at least 9 months experienced benefits in OS (HR, 0.63; 95% CI, 0.47-0.85; P = .0025) and progression-free survival (PFS; HR, 0.49; 95% CI, 0.38-0.62; P < .0001) compared with those who only received lenalidomide and dexamethasone. Patients who were treated with the triplet for at least 18 months also experienced a benefit in terms of PFS (HR, 0.57; 95% CI, 0.43-0.76; P < .0001) and OS (HR, 0.68; 95% CI, 0.47-0.98; P = .0379) vs the doublet.

“In the [previously reported] primary analysis of MAIA, with a median follow up of 28 months, the clear PFS benefit was discussed,” Philippe Moreau, MD, the head of the Hematology Department at the University Hospital of Nantes in France, said. “Now with longer follow-up, we also see an OS benefit with the continued PFS and depth of response benefits of daratumumab plus lenalidomide and dexamethasone vs lenalidomide and dexamethasone. The issue of cost is a very important one, and some physicians may believe that we could potentially stop daratumumab plus lenalidomide and dexamethasone early when the patients are reaching a very good response.”

The MAIA trial enrolled adult patients with newly diagnosed multiple myeloma who were ineligible for high-dose chemotherapy with autologous stem cell transplantation because of their age or comorbidities. Patients were randomized 1:1 to receive either daratumumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone.

Patients in the investigational arm were treated with intravenous daratumumab in 28-day cycles at a dose of 16 mg/kg once per week during cycles 1 and 2, once every 2 weeks in cycles 3 through 6, and once every 4 weeks thereafter. Both arms received 25 mg of oral lenalidomide on days 1 through 21 of each cycle and 40 mg of dexamethasone on days 1, 8, 15, and 22 of each cycle.²

The primary end point was PFS. Secondary end points included OS, duration of response, time to response, and overall response rate.

In the post hoc analyses, investigators evaluated OS in patients who received daratumumab plus lenalidomide and dexamethasone for less than 18 months vs at least 18 months. Patients who discontinued the regimen due to disease progression during the first 18 months were excluded.

Study authors compared PFS and OS among patients who received the daratumumab-containing regimen with that of those treated with lenalidomide and dexamethasone only for at least 9 months and at least 18 months. PFS and OS were also evaluated in patients who received daratumumab but discontinued only daratumumab or only lenalidomide and dexamethasone but remained on treatment. Patients in both arms who experienced a best response of very good partial response (VGPR) by 6 months and converted to a complete response (CR) by 9 months or 18 months were also evaluated in terms of PFS and OS.

The median age in the intent-to-treat population (n = 368) was 75 years (range, 50-90). Most patients displayed standard risk cytogenetic abnormalities (85%) and had an ECOG performance status of 0 or 1 (82.9%).

Among patients who were treated with the daratumumab-containing regimen for at least 18 months (n = 283) the median age was 73 years (range, 55-88). ECOG performance statuses at baseline in this group were 0 (38.9%), 1 (45.6%), and 2 or higher (14.5%).

Forty-six patients received daratumumab plus lenalidomide and dexamethasone for less than 18 months. Their median age was 75 years (range, 50-90). Most patients in this subgroup had an ECOG performance status of 1 (52.1%) and standard risk cytogenetic abnormalities (86.4%).

Lenalidomide and dexamethasone only were discontinued by 48 patients, 44 of whom discontinued treatment due to an adverse effect (AE). The most common AEs that led to discontinuation included diarrhea (18.8%), peripheral sensory neuropathy (10.4%), and neutropenia (8.3%).

The median duration of treatment with daratumumab for patients who stopped receiving lenalidomide and dexamethasone was 58.1 months. The median time to lenalidomide discontinuation was 34.4 months (range, 1-58). The 60-month PFS and OS rates in this subgroup were 97.9% and 100%, respectively.

Additional findings from the post hoc analyses showed responses deepened over time with continued treatment with daratumumab plus lenalidomide and dexamethasone. CR or better rates among patients who were treated for at least 18 months increased from 9.2% at 6 months to 19.1% at 9 months to 49.8% by 18 months.

A PFS benefit was also observed among patients who achieved a VGPR by 6 months and converted to a CR or better by 9 months (HR, 0.15; 95% CI, 0.05-0.45; P < .0001) and by 18 months (HR, 0.34; 95% CI, 0.19-0.62; P = .0002).

Similarly, patients who experienced a VGPR by 6 months and converted to a CR or better by 9 months also experienced an OS benefit (HR, 0.25; 95% CI, 0.07-0.86; P = .0175). A benefit was also reported if a conversion occurred by 18 months (HR, 0.33; 95% CI, 0.17-0.65; P = .0006).

Investigators noted that no new safety concerns were identified with the triplet regimen for patients who were treated for at least 18 months. The most common grade 3/4 treatment-emergent AEs (TEAEs) in the daratumumab plus lenalidomide and dexamethasone arm included neutropenia (56.9%), pneumonia (19.8%), anemia (17%) and lymphopenia (17%). In the lenalidomide plus dexamethasone arm (n = 204), common grade 3/4 TEAEs consisted of neutropenia (41.2%), anemia (18.1%), and cataracts (18.6%).

Overall, 96.5% and 91.2% of patients in the daratumumab plus lenalidomide and dexamethasone arm and the lenalidomide plus dexamethasone arm, respectively, experienced at least 1 grade 3/4 TEAE after being treated for at least 18 months. Investigators also noted that grade 3/4 hematologic TEAEs with daratumumab plus lenalidomide and dexamethasone generally decreased over time.

References

1. Moreau P, Facon T, Usmani S, et al. Treatment duration and long-term outcomes with daratumumab in transplant-ineligible newly diagnosed multiple myeloma from the phase 3 MAIA study. Presented at: 19th International Myeloma Society Annual Meeting. August 25-27, 2022. Los Angeles, CA. Abstract OAB-039.
2. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6