Daratumumab in Newly Diagnosed Multiple Myeloma: Understanding the Pros and Cons

TOP - July 2021 Vol 14, No 4 - HOPA Highlights

According to the American Cancer Society, nearly 35,000 new cases of multiple myeloma will be diagnosed in the United States in 2021, and approximately 12,410 deaths will be attributed to the disease.1 However, with the introduction of several novel therapies, the outcomes for patients with newly diagnosed multiple myeloma have improved significantly over the past decade.

During the 2021 Hematology/Oncology Pharmacy Association Annual Conference, Kori Holman, PharmD, BCOP, and Dennis Marjoncu, PharmD, BCOP, Clinical Pharmacy Specialists, Bone Marrow Transplant, Methodist University Hospital, Memphis, TN, discussed the potential advantages and disadvantages associated with the use of daratumumab (Darzalex), a novel CD38-directed monoclonal antibody, in patients with multiple myeloma.

Daratumumab in Transplant-Eligible Patients

For the past several years, the combination of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone has been an effective standard induction therapy for patients with newly diagnosed multiple myeloma. However, as providers strive to maximize duration of response in the first-line setting, they are introducing the use of additional agents, including anti-CD38 monoclonal antibodies.

In the phase 3 CASSIOPEIA trial, patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy and autologous stem-cell transplantation (ASCT) were randomized to receive a combination of bortezomib, thalidomide (Thalomid), and dexamethasone or the same triplet regimen plus daratumumab.

Although overall response rates (ORRs) did not differ between the 2 study arms, said Dr Marjoncu, the addition of daratumumab did improve rates of stringent complete response and progression-free survival (PFS). Rates of minimal residual disease (MRD) also improved by approximately 20% in the overall study population.

According to Dr Holman, a subgroup analysis of the study showed that only very specific cohorts of patients benefited from the addition of daratumumab; male patients and patients aged <50 years received no benefit. Daratumumab was also associated with increased rates of infection.

In the post-consolidation setting, however, patients who received daratumumab reported a significant improvement in their emotional functioning and pain scores compared with patients who did not receive the anti-CD38 monoclonal antibody.

The phase 2 GRIFFIN trial also assessed the efficacy of daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma. In this study, patients were randomized to lenalidomide, bortezomib, and dexamethasone or the same triplet regimen plus daratumumab.

The addition of daratumumab led to an ORR benefit and significant increase in the depth of response as indicated by MRD status, said Dr Marjoncu, although no difference in stringent complete response was seen in the overall population.

Dr Holman noted that high-risk patients received no benefit from daratumumab, and the agent was associated with an increased rate for upper respiratory tract infections.

Daratumumab in Transplant-Ineligible Patients

In the phase 3 MAIA trial, patients with newly diagnosed multiple myeloma who were ineligible for ASCT were randomized to daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone. Treatment continued until the occurrence of disease progression or unacceptable side effects.

The addition of daratumumab led to a significantly improved ORR. Importantly, Dr Marjoncu said, the agent significantly improved complete response rates and rates of MRD-negativity, which conferred longer PFS regardless of treatment arm. The median PFS has still not been reached in the daratumumab arm versus a median PFS of 34 months for lenalidomide and dexamethasone.

In the phase 3 ALCYONE trial, which randomized patients with newly diagnosed multiple myeloma who were ineligible for ASCT to bortezomib, melphalan (Alkeran), and prednisone or the same triplet regimen plus daratumumab, an improvement in PFS was observed in the daratumumab arm. Longer follow-up also found an improvement in overall survival with the addition of daratumumab. MRD-negative status again conferred longer PFS regardless of treatment arm.

Dr Holman noted, however, that no benefit was observed in patients with stage I multiple myeloma or high-risk cytogenetics.

Daratumumab: Cost Analysis

As regimens for multiple myeloma continue to expand from 3 to 4 and even 5 drugs, the cost of medication has become an important consideration.

A Markov analysis conducted by Patel and colleagues compared the addition of daratumumab to lenalidomide plus dexamethasone in the front-line and second-line settings in patients with newly diagnosed multiple myeloma who were not eligible for ASCT.2 The researchers assessed lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio from a US payer perspective.

Using a willingness-to-pay threshold of $150,000 per QALY for analysis, they found that frontline daratumumab costs approximately $1.4 million versus $1.1 million in the second-line setting. The QALYs in the first- and second-line setting were 4.87 versus 4.34, respectively, resulting in an incremental cost-effectiveness ratio of $618,018 per QALY.2

Based on these data, the researchers determined that the cost of first-line daratumumab would need to decrease by approximately 67% to be cost-effective.

“Despite these high costs, however, it’s safe to say that CD38-targeted agents are here to stay and that these agents will continue to be assessed in earlier lines of therapy,” Dr Holman concluded.

References

  1. American Cancer Society. Key statistics about multiple myeloma. Updated January 12, 2021. www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html. Accessed June 16, 2021.
  2. Patel KK, Giri S, Parker TL, et al. Cost-effectiveness of first-line versus second-line use of daratumumab in older, transplant-ineligible patients with multiple myeloma. J Clin Oncol. 2021;39:1119-1128.
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Last modified: August 3, 2021