Survival Benefit in Transplant-Ineligible Multiple Myeloma Seen With Frontline Vs Second Line Use of Daratumumab Combos

Rafael Fonesca, MD

For transplant ineligible multiple myeloma, daratumumab (DARA; Darzalex), lenalidomide (Revlimid), and dexamethasone (D-Rd) given to patients as first-line (1L) treatment resulted in an overall survival (OS) benefit vs waiting for second-line (2L) treatment, according to a presentation from the 2021 American Society of Hematology Conference.¹

Data from this study showed that patients had a 2.5-year OS benefit when given D-Rd followed by regimens that contained pomalidomide (Pomalyst) and carfilzomib (Kyprolis) compared with those receiving bortezomib (Velcade), lenalidomide, and dexamethasone (VRd) first and then a DARA-containing regimen.

“Given the totality of these data, D-Rd should be the standard of treatment for patients with transplant-ineligible newly diagnosed multiple myeloma,” Rafael Fonesca, MD, director for Innovation and Transformational Relationships at the Mayo Clinic in Phoenix, Arizona, stated during the presentation.

Investigators looked at data from 3 previously reported trials to formulate a clinical question regarding optimal treatment sequences. The phase 3 SWOG S0777 trial (NCT00644228)2 helped establish VRd as standard of care for newly diagnosed multiple myeloma without intent for immediate transplants, with statistically significant OS benefit noted vs Rd (P = .0114). Patients in this group younger than 65 had a better OS benefit. In the phase 3 MAIA trial (NCT02252172),3 previously untreated patients who were given D-Rd had a statistically significant PFS (HR, 0.53; 95% CI, 0.43-0.66; P <.0001) and OS benefit (HR, 0.68; 95% CI, 0.53-0.86; P = .0013) vs those given Rd alone.

Fonseca then turned to the POLLUX trial (NCT02076009), which looked at D-Rd vs Rd in this patient population with relapsed disease. The data indicated that D-Rd resulted in a 66% reduction in the risk of disease progression or death vs Rd in the overall population (HR, 0.44; 95% CI, 0.35-0.54; P <.0001).4 He noted that the patient population was much younger than those from MAIA and about 60% had been given transplant prior to enrollment.

Additionally, a study that was published in 2020 involving a real-world data set of almost 22,000 patients showed an attrition loss of almost 50% with each line of therapy.

“We wanted to integrate data regarding attrition rates,” Fonseca said. “There is significant attrition between lines of therapy [with] up to 50% loss of patients per line of therapy. [Therefore, we wanted to know if] it makes sense to save treatments for later.”

Three clinical scenarios were explored. In one, patients were treated with 1L D-Rd and then at relapse, received a pomalidomide- or carfilzomib-containing regimen. The other 2 scenarios included those who were treated with VRd or Rd in the 1L who then received DARA regimens at relapse. A conservative attrition rate of 27.2% derived from the MAIA trial that excluded censored patients was utilized for this study.

The OS in the 27.2% attrition rate group showed that D-Rd in the 1L had estimated 5-, 10-, and 15-year OS rates of 69.9%, 46.7%, and 30.1%, respectively. Corresponding rates in the 1L VRd and Rd arms at the 5- (60.7% and 54.9%, respectively), 10- (35.4% and 28.6%), and 15-year (21.2% and 15.8%) timepoints were lower than those seen with 1L D-Rd. Results were similar assuming a higher attrition rate of 58.8%.

The median OS for D-Rd in the 1L was 9.1 years compared with VRd in the 1L at 6.7 years and 5.7 years for Rd in 1L, with results consistent regardless of attrition rates.

Fonesca also detailed some strengths such as attrition rates accounting for patients who do not receive therapy beyond the 1L and use of real-world data in the 2L. The limitations included that no variation in attrition rates were considered for individual treatments and mixed data sources from clinical trials and real-world data were used in the analysis.

_References

_{1.Fonesca R, Facon T, Hashim M, et al. First-Line Use of Daratumumab, Lenalidomide, and Dexamethasone Confers Survival Benefit Compared with Second-Line Use of Daratumumab-Based Regimens in Transplant-Ineligible Patients with Multiple Myeloma: Analysis of Different Clinical Scenarios. Presented at the 2021 American Society of Hematology Annual Congress. December 11-14, 2021. Virtual. Abstract 118. https://bit.ly/3pLLttF}

_{2.Durie BGM, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020;10(5):53. doi:10.1038/s41408-020-0311-8}

_{3.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}

_{4.Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020;34(7):1875-1884. doi:10.1038/s41375-020-0711-6}