Few fields have experienced a journey of transformation as fast-paced and remarkable as that of multiple myeloma (MM). In the past decade, this field has witnessed an avalanche of innovative drugs, embracing over ten novel agents into its therapeutic arsenal. Among these, the anti-CD38 antibodies daratumumab, and more recently isatuximab, have been game-changers, leading to unprecedented outcomes when integrated into backbone regimens. Paralleling this expansion in therapeutic options, minimal residual disease (MRD) negativity has emerged as a response target, spurring a cascade of clinical trials to explore various triplet and quadruplet drug combinations to identify the best formula for achieving both MRD-negative responses and better survival outcomes for patients with MM.
The researchers of the IsKia trial have found a successful formula, earning them a spot on the ASH Plenary stage this year. The IsKia trial compares induction with four cycles of isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) versus that with carfilzomib, lenalidomide, and dexamethasone (KRd) in transplant-eligible patients, followed by a four-cycle consolidation regimen after autologous stem cell transplant (ASCT) with high-dose melphalan. The concept of the phase III IsKia trial evolved from the pivotal phase II FORTE trial, which demonstrated a high rate of MRD negativity when the KRd combination was given for four cycles before and after ASCT in those with newly diagnosed MM (NDMM).1 These results, coupled with data affirming the safety of prolonged carfilzomib therapy,2,3 shaped the control arm of the IsKia trial, which added an extended phase of consolidation (termed "light consolidation”) spanning one year after the KRd consolidation phase. The experimental arm incorporated isatuximab in the induction and consolidation phases of treatment with the primary objective of achieving MRD negative responses to 10-5.
The long-awaited results of IsKia were unveiled in a masterpiece presentation yesterday by Francesca Gay, MD, PhD, from the University of Torino in Italy. The study included a total of 302 patients, approximately 20% of whom had a high-risk cytogenetic profile. While a similar percentage of patients in the two arms achieved a complete or stringent complete response, next-generation sequencing allowed us to see beneath the surface, exposing deeper responses in the Isa-KRd arm after consolidation, with 77% achieving MRD negativity at the 10-5 sensitivity threshold vs. 67% in the KRd arm (p=0.049). A “deeper dive” to the MRD threshold of 10-6 revealed that 67% of patients in the Isa-KRd arm achieved MRD negativity vs. 48% in the KRd arm (p<0.001).
The investigators illustrated the benefit of the isatuximab quadruplet for patients with high-risk cytogenetics in achieving MRD-negative responses at both the 10-5 and 10-6 thresholds. Remarkably, even patients with double-hit disease achieved high rates of MRD negativity (77%), which were comparable to those observed in patients with standard-risk disease (79%). This is in stark contrast to the control arm, in which high-risk disease was associated with significantly inferior MRD negativity rates of only 27% (vs. 77% in patients with standard risk at the 10-6 threshold). These are compelling results to consider.
Annemiek Broijl, MD, PhD, one of the IsKia investigators, explained, “Isa-KRd in this IsKia trial shows very promising results in MRD negativity; however, progression-free survival (PFS) data still have to follow. Therefore, it is too early to draw conclusions and make suggestions on Isa-KRd as the new standard of care for transplant-eligible NDMM.” At the 1-year mark, the PFS rate was similar in both arms (95%), and longer follow-up is needed to confirm whether these deeper responses will indeed translate into durable remissions. There are other challenges, too. She shared, “Despite strong evidence that KRd is effective and safe in the treatment of transplant-eligible NDMM (FORTE data), this regimen was not approved by the EMA or FDA in the treatment of this patient group and therefore not a standard regimen to which the experimental arm with the addition of isatuximab was compared.” Ultimately, we will have to wait for longer follow-up and results of validation trials to understand how this regimen compares with other quadruplets containing anti-CD38 agents.
As deeper responses and longer remissions are achieved through novel combinations, an important question arises: What effect do these interventions have on patients’ quality of life (QoL)? Dr. Broijl expressed concern that continuous treatment may negatively affect a patient’s QoL and increase the risk of secondary malignancies — the concern for which has heightened given increases in life expectancy. She said that this is the focus of the IsKia and several other ongoing clinical trials evaluating shorter maintenance periods, which aim to improve QoL without compromising treatment efficacy. The IsKia trial using isatuximab in a quadruplet certainly takes a deeper “dive” by looking at two MRD thresholds, demonstrating exceptional responses in transplant-eligible patients and underscoring the evolving utility of MRD negativity as a clinical tool.
References
1 Gay F, Cerrato C, Scalabrini DR, et al. Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: analysis of the randomized FORTE trial in newly diagnosed multiple myeloma (NDMM). Blood. 2018;132(Suppl 1):121.
2 Stewart AK, Rajkumar SV, Dimopoulos MA, et al; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-152.
3 Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120(9):1801-1809.
Drs. Abdallah and Cook indicated no relevant conflicts of interest.
