Treatment of newly diagnosed transplant ineligible multiple myeloma: is there a BENEFIT to adding bortezomib to the standard backbone?

Introduction to transplant ineligible multiple myeloma

Owning to a deeper understanding of disease biology coupled with the introduction of novel agents, the therapeutic armamentarium for treating patients with newly diagnosed multiple myeloma (NDMM) has expanded considerably over the past decade. Classically, the earliest consequential decision for clinicians treating patients with NDMM is whether a patient is appropriate for high-dose chemotherapy with autologous stem cell rescue (widely referred to as stem cell transplant). While there are no universally agreed upon eligibility criteria, several factors such as age, performance status, and comorbidities are important tenets in determining overall fitness and eligibility for transplant. For NDMM patients who are transplant eligible, standard of care induction therapy has shifted from triplet-based combinations to quadruplets as evidenced by the recently reported results of the phase II GRIFFIN, and phase III PERSEUS and ISKIA trials-all of which showed superior efficacy with the addition of an anti-CD38 monoclonal antibody (either daratumumab or isatuximab) to a triplet backbone (1-3). Notably, these trials limited enrollment to patients ≤70 years old; conversely, recent trends suggest more NDMM patients >70 years old are undergoing transplant with similar outcomes compared to younger cohorts (4). While a subgroup analysis of the GRIFFIN trial suggested older patients derived improved benefit with a quadruplet induction compared to a triplet, the larger PERSEUS trial saw poorer outcomes with the quadruplet in older patients, suggesting that the use of a quadruplet induction may be detrimental to this subset of the transplant eligible population (2,5).

For transplant ineligible patients the current standard of care is the combination of daratumumab, lenalidomide, and dexamethasone (Dara-Rd) based on a clear progression-free survival (PFS) and overall survival (OS) advantage compared to lenalidomide and dexamethasone (Rd) with similar tolerance in the phase III MAIA trial (6,7). The PFS (61.9 months) and OS (90.3 months) values for Dara-Rd reported in the MAIA trial were unprecedented in the transplant ineligible population and approached that seen with the use of triplet induction followed by transplant and maintenance therapy (6,8,9). However, a recent retrospective analysis of real-world transplant ineligible NDMM patients treated with Dara-Rd supported the regimen’s efficacy but the PFS and OS values seen in this population (which included patients who would not have been eligible for the MAIA trial) were substantially shorter compared to those seen in the MAIA trial (10). Unlike the GRIFFEN, PERSEUS, and ISKIA trials, the MAIA trial enrolled an older population, with a median age of 73 years old (with nearly half of patients >75 years old) and 46% of patients being defined as frail (7,11). More recently, the phase III IMROZ and CEPHEUS trials showed superior depth of response and PFS with the addition of an anti-CD38 antibody (isatuximab in IMROZ; daratumumab in CEPHEUS) to bortezomib, lenalidomide and dexamethasone (VRd) in transplant ineligible or transplant deferred older NDMM patients (median age of 72 years old for IMROZ and 70 years old for CEPHEUS) (12-14). However, the use of bortezomib in both trials was associated with high rates of peripheral neuropathy irrespective of the presence or absence of an anti-CD38 antibody [IMROZ: 54% isatuximab, velcade, revlimid, and dexamethasone (Isa-VRd) vs. 61% VRd; CEPHEUS: 56% Dara-VRd vs. 61% VRd] (12,14). It should be noted that the bortezomib dosing schedule in both of these trials (days 1, 4, 8, 11, 22, 25, 29 and 32 of a 35-day cycle through cycle 4 in the IMROZ trial, and days 1, 4, 8, and 11 of a 21-day cycle through cycle 8 in the CEPHEUS trial), may have predisposed patients to increased risk of neuropathy as several retrospective studies have shown comparable efficacy with lower rates of peripheral neuropathy when bortezomib is administered on a weekly schedule (15,16). This raises the question of whether the addition of weekly bortezomib to a MAIA like backbone will improve efficacy without adding prohibitive toxicity. The phase III BENEFIT/IFM2020-05 trial was designed to answer this question.

BENEFIT trial methods and results

The BENEFIT trial randomized 270 transplant ineligible NDMM patients 1:1 to either Isa-Rd or Isa-VRd (17). The primary end point of the study was minimal residual disease (MRD) negativity at 10⁻⁵ at 18-month post-treatment initiation. Key secondary objectives are OS, PFS, event-free survival (EFS), and time to next treatment (TTNT), overall response rate (ORR), duration of response (DOR), and safety. Patients on the Isa-VRd arm received bortezomib on days 1, 8 and 15 of a 28-day cycle during cycles 1–12 and days 1 and 15 during cycles 13–18. While patients randomized to the Isa-Rd arm were continued on Isa-R for cycles 13–18. All patients in both arms continued Isa-R starting at cycle 19 until disease progression, unacceptable toxicity, patient withdrawal, or death.

The majority of patients (80%) were ≥70 years old with 33% ≥75 years old (Figure 1). Most patients (90%) had a good performance status [Eastern Cooperative Oncology Group (ECOG) score of 0–1, Figure 2], and only 14% had an estimated glomerular filtration rate of less than 60 mL/min suggesting that they were deemed transplant ineligible largely due to advanced age. Additionally, most patients were standard risk, with high-risk cytogenetics present in only 8.5% of patients, and Revised International Staging System (R-ISS) stage 1 or 2 (92%).

Figure 1 Differences in age range distribution between MAIA, IMROZ and BENEFIT clinical trials.

Figure 2 Differences in ECOG performance status between MAIA, IMROZ and BENEFIT clinical trials. ECOG, Eastern Cooperative Oncology Group.

At 12-month post-treatment 53% of patients in the Isa-VRd arm achieved MRD negativity at 10⁻⁵ vs. only 26% in the Isa-Rd arm [odds ratio (OR) =3.88; 95% confidence interval (CI): 2.27–6.62; P<0.0001]. Similarly, MRD negativity at 10⁻⁶ rates were also increased in the Isa-VRd arm (32% vs. 13%; OR =2.97; 95% CI: 1.6–5.5; P=0.0005). At 18-month (the timepoint where patients in the Isa-VRd arm have completed the full course of bortezomib therapy), MRD negativity at 18-month was still significantly improved with the addition of bortezomib at both the 10⁻⁵ (Isa-VRd: 53%, Isa-Rd: 26%; OR =3.16; 95% CI: 1.89–5.28; P<0.0001), and 10⁻⁶ level (Isa-VRd: 36%, Isa-Rd: 17%; OR =2.74; 95% CI: 1.54–4.87; P=0.0006). This data suggests that the addition of bortezomib to Isa-Rd resulted in nearly 3-fold increase of achieving an MRD negative state after completion of bortezomib, but the improvement in depth of response between 12-months and 18-month (when bortezomib dosing is decreased to every 14 days) is relatively modest. Subgroup analysis showed that there was no improvement in the primary endpoint (18-month MRD negativity at 10⁻⁵) in patients with high-risk cytogenetics, R-ISS stage III disease, or eGFR <60 unit, although these populations were underrepresented in the trial. Multiple studies have shown a significant correlation between MRD negativity and PFS, and rate of MRD negativity was recently recognized as an acceptable endpoint for accelerated approval in multiple myeloma (MM) by the United States Food and Drug Administration (US FDA) (18-20). At a median follow-up of 23.5 months, the median progression free survival was not reached in either group. The 24-month PFS estimation was 85.2% (95% CI: 79.2–91.7%) and 80.0% (95% CI: 73.3-87.4%) in the Isa-VRd and Isa-Rd arms, respectively. Given the increased rate of MRD negativity at 18-month with the addition of bortezomib it is assumed that with further follow-up the improvement in MRD negativity may translate to a significant improvement in PFS in this arm.

The rates of peripheral neuropathy were significantly higher in the bortezomib containing arm and most of the neuropathy was high grade ≥3 (52% all grades; 27% grade ≥3) compared with the triplet arm (28% all grades; 10% grade ≥3). Additionally, rates of all-grade and high-grade peripheral edema were also increased with the bortezomib containing regimen (36% all grades; 14% grade ≥3 for Isa-VRd vs. 20% all grades; 7% grade ≥3 for Isa-Rd).

Discussion

The definition of transplant eligible MM continues to evolve and is subject to significant variation by geography, practice patterns, and reimbursement mechanisms among other factors. Even though there is no agreed upon guideline for determining transplant eligibility, it is estimated that only 20–50% of MM patients will undergo a transplant, which likely represents a fraction of those that are eligible (21). This discrepancy is also represented in the inclusion and exclusion criteria of clinical trials evaluating induction regimens for patients with NDMM who are not planning for upfront transplant. Some trials only include transplant ineligible patients (with significant variability in how that is defined) and some allow transplant deferred patients, who would be eligible to receive a transplant, but have elected to postpone transplant to a later time. Further, many of the trials that require a patient to be transplant ineligible exclude frail and/or elderly patients—a population who often represents the majority of transplant ineligible NDMM commonly seen in clinical practice. This likely explains the discordance often seen between results observed in clinical trials and real-world data sets. The MAIA trial, which should be applauded for including a substantial proportion of frail and elderly patients, showed a PFS of 61 months for Dara-Rd which was far superior to what was observed when this combination was used in real-world clinical practice (PFS 22.7 months) (6,10). Given the variation in eligibility criteria, examining AEs in trials of transplant ineligible regimens is critical-as these regimens are often used in less robust patients then those represented in the trial when used in clinical practice. This population is more likely to suffer from significant complications should they experience treatment related adverse effects. Bortezomib is associated with increased risk of peripheral neuropathy which can be especially debilitating and associated with numerous complications in the frail/elderly population, and its absence in the MAIA regimen likely contributed to the treatment being well-tolerated overall (22-25).

The BENEFIT trial evaluated the addition of bortezomib to a backbone regimen like that evaluated in the MAIA trial (the anti-CD38 antibody isatuximab, lenalidomide, and dexamethasone) in transplant ineligible NDMM. Frail patients, patients with ECOG >2, and patients ≥80 years old were excluded. Additionally, the trial did not include patient with significant renal dysfunction [defined as a creatinine clearance (CrCl) <40 mL/min or serum creatinine ≥2 mg/dL] and only enrolled a small proportion (8.5%) of patients with high-risk cytogenetics. In this population, the addition of bortezomib demonstrated a significant improvement in MRD negativity rate at 18-month (the primary endpoint) in transplant ineligible NDMM, but with increased rates of AEs including peripheral neuropathy and edema. While the trial enrolled transplant ineligible patients similar to the IMROZ trial (as opposed to transplant deferred like the CEPHEUS trial), these patients were required to be “nonfrail” based on an International Myeloma Working Group (IMWG) frailty score of <2. By comparison, the MAIA trial enrolled 341 frail patients using the same scoring system which represented 44% of the total enrolled population. Subgroup analysis of the frail patients treated in the MAIA trial showed improved ORR, MRD negativity rate, and PFS in the frail population treated with Dara-Rd compared with Rd, but these improvements were not as profound as those seen in the nonfrail patients (11). The relatively modest improvement in depth of response based on MRD negativity at 18-month compared to 12-month after an additional 6 months of bortezomib exposure leads to a discussion on whether continuing this therapy after 1-year is justified, especially if this combination is to be extended to a frailer population than that included in the BENEFIT trial. Importantly, 58.5% of patients required discontinuation of bortezomib at some point during their treatment (11% required permanent discontinuation) with the most common reasons being infection, cytopenias, and neuropathy (17). The neuropathy rates in the Isa-VRd arm of the BENEFIT trial were in line with those reported for prior trials of transplant eligible and ineligible NDMM patients receiving a bortezomib containing induction regimen including those enrolling younger, fitter patients. Conversely, the MAIA trial which utilized a proteasome inhibitor free regimen was associated with significantly lower rates of peripheral neuropathy in the Dara-Rd arm (30% all grades; 2.5% grade ≥3) even though it included a large number of frail patients (7). Similarly, the Isa-KRd arm of the ISKIA trial, which utilized the proteasome inhibitor carfilzomib rather than bortezomib, also showed lower rates of peripheral neuropathy (15% all grades; 0% grade ≥3) (3). As peripheral neuropathy is associated with more significant morbidity and mortality in older, more frail patients, stopping bortezomib after 12 cycles may be a better strategy especially as this combination is extended to a less robust transplant ineligible patient population (22-25). Future trials evaluating a bortezomib containing quadruplet in more frail and/or elderly patients, and investigating a less lengthy bortezomib course are warranted to determine if this strategy would show similar efficacy with improved tolerance.

Conclusions

In conclusion, the BENEFIT trial showed superior efficacy of the combination of Isa-VRd to Isa-Rd in newly diagnosed transplant ineligible multiple myeloma patients with acceptable safety and tolerability. While the trial showed improved MRD negativity rates at 12- and 18-month with the addition of bortezomib, there were increased rates of peripheral neuropathy and peripheral edema in this arm. It will be important to follow the PFS and OS values as the data matures as these values are particularly important in the transplant ineligible population who are not candidates for aggressive therapy. Additionally, real-world experience with this regimen will be informative-especially as it pertains to older/more frail patients a population who were excluded and patients with high-risk cytogenetics who were underrepresented in the BENEFIT trial.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-276/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-276/coif). B.P. has received research funding from Bristol-Myers Squibb and participated in the advisory boards for Janssen Oncology and Abbvie. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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