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Front-Line Daratumumab Combination Regimen Improves Outcomes in Multiple Myeloma


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In patients with newly diagnosed multiple myeloma who are not eligible for stem cell transplantation, the addition of daratumumab (Darzalex) to lenalidomide (Revlimid) and dexamethasone significantly reduced the risk of death or disease progression by 44%, according to a late-breaking abstract presentation by Thierry Facon, MD, of the Hospital Claude Huriez in Lille, France, at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.1


Daratumumab plus lenalidomide/dexamethasone significantly reduced the risk of disease progression or death and induced significantly deeper responses, including a more than threefold higher rate of minimal residual disease negativity.
— Thierry Facon, MD

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“Daratumumab plus lenalidomide/dexamethasone induced significantly deeper responses, including a more than threefold higher rate of minimal residual disease negativity,” Dr. Facon announced. “These results support this regimen as a new standard of care for patients with transplant-ineligible newly diagnosed myeloma.”

Dr. Facon presented a prespecified interim analysis of the global phase III MAIA study of 737 transplant-ineligible patients whose median age was 73 years and 14% of whom had high-risk cytogenetics. Patients were randomly assigned to receive lenalidomide/dexamethasone with or without daratumumab. All patients received 28-day cycles of dexamethasone at 40 mg on days 1, 8, 15, and 22. The experimental arm also received daratumumab at 15 mg/kg weekly for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and every 4 weeks thereafter, until disease progression or unacceptable toxicity.

Update on MAIA Trial

  • The phase III MAIA trial evaluated the benefit of adding daratumumab to lenalidomide/dexamethasone in transplant-ineligible patients with multiple myeloma.
  • The median progression-free survival was not reached in the daratumumab arm but was 31.9 months with lenalidomide/dexamethasone (P < .0001). At 30 months, 56% and 71% of patients, respectively, were progression-free.
  • A threefold higher rate of minimal residual disease negativity was observed in daratumumab-treated patients.

After a median follow-up of 28 months, the hazard ratio for progression-free survival favoring the addition of daratumumab was 0.56 (P < .0001). The median progression-free survival was 31.9 months with lenalidomide/dexamethasone and was not reached for the daratumumab/lenalidomide/dexamethasone arm (hazard ration [HR] = 0.56; P < .0001). The 30-month progression-free survival rate was 56% vs 71%, respectively.

Dr. Facon reported that the addition of daratumumab to the combination regimen resulted in deeper responses, with rates of very good partial responses or better observed in 79% of the triplet-regimen arm compared with 53% of the doublet-regimen arm (odds ratio = 3.4; P < .0001) and complete response was achieved in 48% and 25%, respectively (P < .0001). Minimal residual disease (10-5 threshold) was negative in 24% and 7% of patients, respectively, for a 3.4-fold difference (P < .0001). With just 19% of patients having died, the overall survival analysis is not mature, but the hazard ratio at the interim analysis was 0.78.

The daratumumab arm experienced more grade 3 or 4 pneumonia, neutropenia, and leukopenia, with the safety profile consistent with prior studies. Infusion reactions occurred in 41% of patients receiving daratumumab, but 3% were grade 3 or 4. Invasive secondary malignancies occurred in 3% of those treated with daratumumab and 4% of those who were not.

Clinical Implications

Dr. Facon told The ASCO Post that it is possible that daratumumab/lenalidomide/dexamethasone will yield longer progression-free survival than bortezomib (Velcade)/lenalidomide/dexamethasone, which is commonly used in the United States but not available in many countries. The SWOG S0777 trial, for example, found that bortezomib/lenalidomide/dexamethasone yielded a median progression-free survival of 34 months, although the population was younger and bortezomib was limited to 8 cycles,2 he acknowledged. However, the data from this and a few other studies have suggested that remission with bortezomib/lenalidomide/dexamethasone lasts about 3 years. Dr. Facon predicted that the daratumumab combination regimen may extend this remission.

“It’s difficult to speculate, but if the control arm [lenalidomide/dexamethasone] in the MAIA study yielded a median progression-free survival of 32 months, and the hazard ratio was 0.56, this means patients treated with daratumumab should receive at least 15 additional months,” he figured.

In addition to the potential for longer remission with the daratumumab regimen, Dr. Facon continued, the lack of bortezomib may prove to be a benefit, because bortezomib has a problematic side effect profile over time. “The bortezomib/lenalidomide/dexamethasone regimen is not a friendly regimen for elderly or frail patients,” Dr. Facon indicated. “The daratumumab regimen, on the other hand, is gentler and manageable.”

Ongoing studies are evaluating the addition of daratumumab to bortezomib/lenalidomide/dexamethasone, “but this population is different,” added Dr. Facon. “For this four-drug regimen, they will probably need to be younger or fit elderly patients.” 

DISCLOSURE: Dr. Facon is an advisor/consultant for Sanofi, Celgene, Janssen, Takeda, Amgen, Karyopharm Therapeutics, and Oncopeptides; and is on the speakers bureau for Celgene, Janssen, and Takeda.

REFERENCES

1. Facon T, Kumar SJ, Plesner T, et al: Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma ineligible for transplant (MAIA). 2018 ASH Annual Meeting & Exposition. Abstract LBA-2. Presented December 4, 2018.

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 with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant. 2018 ASH Annual Meeting & Exposition. Abstract 1992. Presented December 1, 2018.


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