About the Authors
Issam S. Hamadeh, PharmD, BCPS, BCOP, is a clinical pharmacy specialist in the Department of Pharmacy at Memorial Sloan Kettering Cancer Center in New York, New York.
Shebli Atrash, MD, is a hematologist in the Division of Plasma Cell Disorders Division and Department of Hematologic Oncology & Blood Disorders at Atrium Health Levine Cancer Institute in Charlotte, North Carolina.
Carlyn Rose Tan, MD, is a myeloma specialist in the Division of Hematologic Oncology and Department of Medicine at Memorial Sloan Kettering Cancer Center in New York, New York.
Given the ever-expanding therapeutic armamentarium available for treating patients with multiple myeloma, we have witnessed a dramatic evolution in the treatment landscape of this disease over the past decade, particularly in the first-line setting. With more therapeutic agents available, the paradigm has shifted from the up-front use of doublet to triplet drug regimens and most recently quadruplets, which have become the new standard of care for patients with newly diagnosed multiple myeloma (NDMM) who are transplant eligible.
The SWOG S0777 study (NCT00644228) was the first to demonstrate the clinical benefits of a triplet drug regimen compared with a doublet as induction therapy for patients with NDMM. In this study, the combination of bortezomib (Velcade; Takeda Oncology), lenalidomide (Revlimid; Celgene Corporation), and dexamethasone (VRd) resulted in a significant improvement in progression-free survival (PFS) at 43 months (95% CI, 39-52) vs 30 months with lenalidomide and dexamethasone (Rd; 95% CI, 25-39; P = .0037). Interestingly, VRd also prolonged overall survival (OS; 95% CI, 65-not reached [NR]), at 75 months vs 64 months with Rd (95% CI, 56-NR; P = .025). Nonetheless, the depth of response remained low with either regimen, with the complete response (CR) rate at 15.7% with VRd vs 8.4% with Rd. Consequently, new therapeutic approaches were developed to improve outcomes and deepen responses.
The randomized phase 2 GRIFFIN study (NCT02874742) and most recently the phase 3 PERSEUS study (NCT03710603) sought to evaluate the impact of adding the anti-CD38 monoclonal antibody daratumumab to the VRd backbone (D-VRd) in patients with transplant-eligible NDMM. After a median follow-up of 47.5 months, the PERSEUS study met its primary end point where the estimated 48-month PFS rate was 84.3% (95% CI, 79.5-88.1) in the D-VRd arm vs 67.7% (95% CI, 62.2-72.6) in the VRd arm. The HR for disease progression or death in the D-VRd group relative to the VRd group was 0.42 (95% CI, 0.30-0.59; P < .001).
Additionally, deeper response rates were noted in the quadruplet arm, typified by the higher rates of CR (87.9% with D-VRd vs 70.1% with VRd; P < .001) and minimal residual disease (MRD)–negative status at 10-5 (75.2 vs 47.5%; P < .001). Based on subgroup analysis by age, patients who were at least 65 years old derived no additional benefit with the quadruplet combination of D-VRd (HR, 0.97; 95% CI, 0.52-1.81). This observation was contrary to what was detected among patients younger than 65 years (HR, 0.30; 95% CI, 0.20-0.46). Despite the small number of patients in this age category (≥ 65 years: 94 patients on D-VRd and 87 on VRd), this raised the concern of whether a quadruplet regimen is warranted for patients who are 65 years or older and ineligible for an autologous stem cell transplant. This knowledge gap paved the way for the IMROZ study (NCT03319667), which was specifically designed to answer this question.
IMROZ was an open-label, phase 3 study that was conducted at 93 sites in 21 countries and sought to investigate the efficacy of a quadruplet regimen of isatuximab (Isa; Sarclisa; Sanofi) in combination with VRd in patients with NDMM not eligible for an autologous stem cell transplant (due to being >/= 65 years or coexisting conditions). Of note, patients older than 80 years were precluded from participating in this study.
Patients who met the study eligibility criteria were randomly assigned in a 3:2 ratio to one of the study treatment arms: Isa-VRd or VRd. Irrespective of the randomization arm, all patients received a total of 4 induction cycles (6 weeks per cycle) followed by continuous treatment (4-week cycles) with either Isa-Rd or Rd until disease progressionor unacceptable toxicity. The primary end point of the study was PFS, and key secondary end points included CR rates, MRD-negative status in patients with a complete or better response (assessed at 10-5 sensitivity by means of next-generation sequencing), and OS.
The study enrolled 446 patients with 265 randomly assigned to the Isa-VRd arm and 181 to the VRd arm. The baseline characteristics were balanced between the 2 arms, with the median age being 72 years (range, 60-80) in the Isa-VRd arm and 72 years (55-80) in the VRd arm. Notably, 6.8% and 3.3% of the patients in the Isa-VRd and VRd arms had extramedullary disease, respectively; high-risk cytogenetic features (defined as the presence of del[17p], t[4;14], t[14;16], or a combination of these) were present in 15.1% of the patients in the Isa-VRd arm and 18.8% in the VRd arm. After a median follow-up of 59.7 months, the 60-month PFS rate was significantly higher in the Isa-VRd arm (63.2%) compared with the VRd arm (45.2%), which translated into an HR for disease progression or death of 0.60 (98.5% CI, 0.41-0.88; P < .001). Similarly, the percentage of patients who achieved a CR was higher with Isa-VRd (74.7%) compared with VRd (64.1%; P = .01). MRD-negative status was reached in 58.1% and 43.6% of patients in the Isa-VRd and VRd arms, respectively (odds ratio [OR], 1.7; 95% CI, 1.22-2.63); importantly, a higher percentage of patients in the quadruplet arm (46.8%) had sustained MRD-negative status for at least 12 months compared with 24.3% in the VRd arm (OR, 2.73; 95% CI, 1.80-4.14). The estimated 60-month OS was not statistically different between the 2 treatment arms (72.3% in Isa-VRd group vs 66.3% in the VRd group; HR of death: 0.78; 95% CI, 0.41-1.48). Given the short follow-up time, it is probably premature to discern whether the quadruplet regimen is associated with an improvement in OS.
The addition of Isa to VRd was generally well tolerated. Infusion reactions and infections, namely pneumonia, were the 2 most common adverse events associated with the quadruplet regimen. Improved patient outcomes reported in the IMROZ study may help establish Isa-VRd as a standard-of-care regimen for patients with NDMM who are not candidates for an autologous stem cell transplant and are younger than 80 years. It is important to note that the difference in PFS did not reach statistical significance in the following 2 subgroups: patients whose age range fell within either 70 to 75 years (HR, 0.78; 95% CI, 0.47-1.29) or 75 to 80 years (HR, 0.58; 95% CI, 0.33-1.02).
The daratumumab-Rd (DRd) combination is currently the most widely used triplet for older patients who are transplant ineligible based on the results of the MAIA clinical trial (NCT02252172). The study included 368 patients with a median age of 73 years (range, 70-78) and demonstrated an OS advantage with DRd compared with Rd. It is worth noting that 43% of the patients in the MAIA study were older than 75 years compared with 26% in the IMROZ study, as illustrated in the Figure. Patients who are more frail with multiple comorbidities may fare better with a triplet drug regimen such as DRd than a quadruplet regimen.
Conclusion
In terms of incorporating the findings from IMROZ into clinical practice, it is imperative that patients’ performance status and other comorbid conditions be considered. These can guide decisions around the selection of the optimal up-front combination regimen (ie, a quadruplet or a triplet regimen).
