Quadruplets in newly diagnosed transplant-ineligible multiple myeloma

To the Editor:

With the advent of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (CD38mAbs), the outcomes of transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (MM) have substantially improved in the last decade.^1-3 Currently, there are two widely accepted standard-of-care regimens in newly diagnosed TIE MM: daratumumab-lenalidomide-dexamethasone (DRd) and bortezomib-lenalidomide-dexamethasone (VRd), based on the MAIA and S0777 trials, respectively, both of which showed significant progression-free survival (PFS) and overall survival (OS) benefit over Rd.^{1, 2, 4, 5} The major toxicity of concern with the addition of CD38mAb is infection and with bortezomib is peripheral neuropathy. While these triplet regimens have been considered the standard of care, two RCTs have been recently reported that compared a quadruplet regimen to these triplet regimens.^{6, 7} The IMROZ phase III trial evaluated the CD38mAb isatuximab on the backbone of bortezomib, lenalidomide, and dexamethasone (Isa-VRd) compared with VRd alone. The IFM-2020/BENEFIT (hereafter, referred to as BENEFIT) trials evaluated Isa-VRd compared with IsaRd alone. Additionally, a third RCT named GEM2017FIT compared the quadruplet regimen daratumumab-carfilzomib-lenalidomide-dexamethasone (Dara-KRd) against KRd and alternating VMP/Rd (VMP: bortezomib-melphalan-prednisone) in this patient population.⁸ The study design and key outcomes of these trials are summarized in Table 1. Here, we will discuss three key aspects of these trials (inclusion criteria, toxicity, and efficacy) and future directions for optimizing therapy for this patient population.

The first key aspect relates to eligibility criteria and the included patient population in these trials. Even though these RCTs were designed for a TIE population, they all had an upper age limit of 80 years, and approximately two-thirds of patients were within the age brackets of 65–75.^6-8 Additionally, the BENEFIT and GEM2017FIT trials specifically excluded frail patients as defined by the IMWG or Geriatric Assessment in Hematology (GAH) frailty scores, respectively. Objective assessment of frailty is critical in older adults, since frailty predicts treatment-related toxicities and OS.⁹ Hence, the external validity of safety and efficacy of quadruplet regimens in patients who are frail or >80 years of age, which constitutes at least ~20% of TIE population,⁹ remain unclear. An ongoing RCT comparing Dara-VRd vs. VRd (CEPHEUS) in TIE patients does not have an upper age limit or exclusion based on frailty and will potentially generate data on the benefit of quadruplets for older patients (NCT03652064). However, it remains to be seen as to what proportion of patients in CEPHEUS trial are frail based on objective criteria. Future RCTs in this population should target specific subgroups such as fit, intermediate fit, and frail rather than arbitrarily defined category based on transplant-eligibility, which may include both patients that are truly not fit for transplant and those in whom either a transplant is deferred or not done due to patient/physician preference.

Second, early mortality and cumulative treatment-related toxicity is an important concern in older adults when adding drugs to current backbones, with real-world data showing substantial early mortality even in the modern era.¹⁰ Reassuringly, both IMROZ and BENEFIT trials demonstrated that there was no increase in the risk of early mortality with the addition of 4th drug (isatuximab and bortezomib, respectively).^{6, 7} However, in IMROZ, the cumulative incidence of treatment-related deaths at a median follow-up of ~5 years was approximately 2-fold higher in Isa-VRd versus VRd arm (11% vs. 5.5% respectively), with the most common cause of these deaths being infection.⁶ The increase in these treatment-related deaths in the Isa-VRd arm was largely driven by events beyond 6 months from treatment initiation. This highlights the deleterious impact of prolonged immunosuppression with continuous CD38mAb and dexamethasone until progression. Furthermore, it reiterates the urgent need for de-escalation strategies in frail older adults who particularly value minimizing treatment toxicity and optimizing health-related quality of life (HRQoL).¹¹ De-escalation strategies are currently being explored in two RCTs that are randomizing patients to continuous versus fixed-duration daratumumab in the DRd regimen (NCT05561387 and NCT06182774). In the BENEFIT trial, addition of once-weekly subcutaneous bortezomib increased the risk of Grade ≥2 peripheral neuropathy from 10% in the Isa-Rd arm to 27% in Isa-VRd arm.⁷ However, the incidence of all-grade peripheral neuropathy with Isa-VRd in BENEFIT trial was almost half of that in IMROZ (28% vs. 54.4%, respectively), which is likely due to once-weekly bortezomib in BENEFIT versus once-weekly in IMROZ.^{6, 7} Since bortezomib-induced neuropathy can be reversible in about two-thirds of patients with dose-reduction or dose-discontinuation,¹² it remains to be seen what proportion of these patients develop permanent neuropathy. Nevertheless, close monitoring for new-onset peripheral neuropathy while on bortezomib with prompt dose modification remains paramount if using a bortezomib-containing quadruplet regimen in this age group. Notably, in the GEM2017FIT trial, a substantial increase in toxicity-related deaths in the first 18 months was noted in the quadruplet arm (toxic deaths-4.5%, 3.2%, and 8.5% in VMP/Rd, KRd, and Dara-KRd arms, respectively).⁸ Furthermore, a substantial proportion of patients in the carfilzomib-containing arms (11% in KRd and 14% in Dara-KRd) developed Grade 3–4 cardiac toxicities. This is in line with the GMMG-CONCEPT trial (Isa-KRd) where the incidence of Grade 3–5 cardiac toxicities was ~10× higher in the TIE cohort compared with the TE cohort (20% vs. 2.1%, respectively).¹³ Together, these data imply caution with CD38mAb and carfilzomib-containing quadruplet regimens in older adults, including those who are fit and <80 years old.

Third, all three RCTs met their primary efficacy endpoint (PFS in IMROZ and MRD negativity at 10⁻⁵ by NGS in BENEFIT and GEM2017FIT). However, IMROZ trial has the most mature data thus far with a median follow-up of ~5 years.⁶ Importantly, in the GEM2017FIT trial, the efficacy of Dara-KRd was modulated by frailty status, with 30-month PFS in fitter patients (GAH <20) being 88% and that in patients with GAH >20 being just 71% with Dara-KRd.⁸ Notably, the BENEFIT trial demonstrated a ~2× increase in MRD negativity at 10⁻⁶ with the addition of bortezomib to Isa-Rd. An important caveat is that the MRD-negativity rates at 12 and 18 months were comparable in the Isa-VRd arm of BENEFIT trial, which raises the question whether bortezomib can be limited to 12 months to reduce toxicity without compromising efficacy. Additionally, the time to achievement of very good partial response or better was significantly shorter with Isa-VRd compared with Isa-Rd (2.1 vs. 3.7 mo., respectively; p = 0.0002), which highlights the importance of addition of bortezomib in situations where a rapid reduction in paraprotein is desirable such as myeloma cast nephropathy.¹⁴ Of note, the MRD-negativity rate at 10⁻⁵ (NGS) in the intention-to-treat population was comparable in the Isa-VRd arms of IMROZ and BENEFIT trials (58% vs. 53%, respectively) despite twice-weekly bortezomib in IMROZ and once-weekly in BENEFIT.^{6, 7} Thus far, no difference in PFS or OS has been noted with the addition of bortezomib to Isa-Rd. Unlike IMROZ trial where addition of CD38mAb led to early separation of PFS curves, addition of bortezomib has not led to the separation of PFS curves yet at a median follow-up of ~2 years. In a recent meta-analysis, MRD negativity was shown to have a strong trial-level correlation with PFS (R² = 0.85) and medium trial-level correlation with OS (R² = 0.79) in the TIE cohort,¹⁵ which makes it likely that the benefit in MRD negativity will translate into benefit in PFS and possibly OS with longer follow-up. Nevertheless, due to the trade-off of increased peripheral neuropathy, which has important HRQoL implications in frail older adults, mature data are needed to understand the magnitude of PFS/OS benefit to enable shared decision-making in this population. Of note, IMROZ was the only RCT that had HRQoL as an endpoint, and failed to show superiority of Isa-VRd over VRd in the Global Health Status/Quality of Life domain of EORTC-QLQ-C30 instrument.⁶ In a prospective cohort study in adults with MM over the age of 50, compared with younger adults (50–69 years), older adults (≥70 years) were significantly more likely to prioritize QoL, functional independence, maintaining cognitive ability, and living free from pain compared with longer OS.¹¹ Hence, clinical trials in this population should rigorously measure HRQoL, and clinicians should be cognizant of unique patient preferences in this age group during treatment decision-making.

In summary, the outcomes of patients with newly diagnosed TIE MM are poised to improve in coming years with the introduction of effective drugs in the frontline setting; however, it remains unclear how we should translate the results of these trials in our routine clinical setting. For healthcare systems that are using VRd as the current standard of care in this population, we believe IMROZ trial provides convincing evidence to add CD38mAb to VRd backbone and should lead to a change in the standard of care. This is particularly important in fit patients and those under the age of 80. Further trials are eagerly awaited investigating the optimal duration of CD38mAb and whether routine quadruplet therapy is feasible and beneficial in frail adults including over the age of 80. However, in settings where CD38mAb + Rd is being currently used as a standard of care, it remains unclear whether addition of bortezomib is essential for all patients since enthusiasm from the benefit in terms of MRD-negativity rate is tempered by the rise in clinically significant peripheral neuropathy, and long-term follow-up will be crucial to understand the magnitude of PFS and potentially OS benefit. We believe that future trials should move away from transplant “ineligibility” as an inclusion criterion given the heterogeneity of this large category and rather focus on frailty-specified subgroups—fit, intermediate fit, and frail. Additionally, incorporating frailty-adapted attenuated dosing strategies and more dynamic fitness measures may allow us to both decrease potential toxicity and improve efficacy, allowing for more personalized treatment strategies in routine clinical practice for this heterogenous group of TIE patients.