Forging Ahead: Quadruplet Regimens for the Treatment of Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma

Quadruplet-based induction regimens are becoming the standard of care (SOC) for newly diagnosed multiple myeloma (NDMM) based on the positive results of recent studies. The randomized phase II GRIFFIN and phase III PERSEUS trials both demonstrated improved depth of response and progression-free survival (PFS) for transplant-eligible (TE) patients as a result of adding the anti-CD38 monoclonal antibody (mAb) daratumumab to induction/consolidation therapy with bortezomib, lenalidomide, and dexamethasone (VRd), as well as to post-transplant lenalidomide maintenance.^1,2  However, for transplant-ineligible (TI) patients, triplet-based approaches continue to be widely used. The combination of daratumumab, lenalidomide, and dexamethasone has emerged as a popular choice after the phase III MAIA study demonstrated improved PFS and overall survival (OS) with the triplet compared to treatment with only lenalidomide and dexamethasone (Rd).³  VRd therapy (with dose reductions for tolerability, as needed) has also remained a frontline option after the SWOG S0777 study demonstrated the treatment’s PFS and OS benefits compared with Rd alone; however, it should be noted that this study administered intravenous bortezomib twice weekly to a population with a median age of 63 (i.e., without an intent to transplant), and the OS benefit was not confirmed in patients aged 65 or older.^4,5  The phase III ALCYONE trial also demonstrated improved PFS and OS with the quadruplet of daratumumab, bortezomib, melphalan, and dexamethasone compared to the same combination without daratumumab,⁶  but oral melphalan is rarely used as initial therapy in the U.S., with lenalidomide-containing regimens generally preferred. Recently, two important studies have shown promise for the treatment of TI NDMM patients with anti-CD38 and lenalidomide-containing quadruplet-based induction therapy.

The phase III IMROZ study included 446 TI patients aged 80 or younger with NDMM (median age, 72) randomized to treatment with either the anti-CD38 antibody isatuximab plus VRd (Isa-VRd) or VRd alone. The study’s dosing and treatment schedule are highlighted in the table below; notably, bortezomib subcutaneous (SQ) was given twice weekly for six months. Crossover from the Rd regimen during maintenance to study treatment was allowed in case of progression. The primary endpoint of the study was PFS. After a median follow-up of 60 months, the quadruplet Isa-VRd study arm had an estimated five-year PFS of 63%, compared to 45% in the control/triplet VRd arm (hazard ratio [HR] = 0.60; 98.5% CI 0.41-0.88; p<0.001). While the majority of study subgroups appeared to benefit, those patients with high-risk cytogenetics did not demonstrate substantial improvement (HR = 0.97; 95% CI 0.48-1.96), though there were only approximately 40 patients in each arm. In comparison to triplet therapy, quadruplet treatment was also associated with greater rates of complete response (CR) or better (75% vs. 64%, p= 0.01), as well as minimal residual disease (MRD) negativity at the 10^-5 threshold (56% vs. 41%, p=0.003). The estimated five-year OS was 72% for Isa-VRd, compared with 66% for VRd (HR = 0.78; 99.97% CI 0.41-1.48). While there was no difference in deaths not due to multiple myeloma (MM) progression, death that was attributable to MM progression was significantly reduced with the addition of isatuximab (HR = 0.394; 95% CI, 0.199–0.783). This is an important finding supporting the upfront use of anti-CD38 mAbs in TI patients who, unlike TE patients, may not otherwise have a chance to undergo next-line therapy. The Isa-VRd and VRd arms reported similar rates of both serious adverse events (AEs) (71% vs. 67.4%, respectively) and AEs leading to discontinuation (23% vs. 26%, respectively). Dose reductions for bortezomib, lenalidomide, and dexamethasone occurred in 35%, 61%, and 53% of Isa-VRd patients, respectively, compared with 42%, 56%, and 53% of VRd patients, respectively, with approximately 10% of patients in both arms prematurely discontinuing bortezomib. The incidence of grade 3 or higher infection was 45% in the Isa-VRd arm, compared with 38% in the VRd arm, while grade 5 infections were reported in 6.5% of the quadruplet group and 3.9% of the triplet group. However, when adjusted for time on therapy, the event rate per patient year was 1.181 for the Isa-VRd arm compared to 1.166 for the VRd arm.

While the phase III BENEFIT trial also evaluated the quadruplet of Isa-VRd, the experimental question in this study was the impact of adding bortezomib to the triplet therapy of an anti-CD38 mAb and Rd (as in the MAIA study), whereas the IMROZ control arm was a VRd backbone. Conducted by the Intergroupe Francophone of Myeloma, BENEFIT randomized 270 TI patients with NDMM and a median age of 73 to either Isa-VRd or isatuximab, lenalidomide, and dexamethasone (Isa-Rd). The table highlights the study’s dosing and treatment schedule; notably, bortezomib SQ was given only once weekly for 12 months. The primary endpoint of the study was 18-month MRD negativity at the 10^-5 threshold based on next-generation sequencing. After a median follow-up of 23.5 months, the primary endpoint was met for 53% of the Isa-VRd arm and 26% of the Isa-Rd arm (MRD negativity odds ratio [OR] = 3.16; 95% CI 1.89-5.28, p<0.0001). At an MRD negativity threshold of 10^-6, the rates were 43% for the quadruplet arm, compared with 18% for the triplet arm (OR = 2.97; 95% CI 1.6-5.5). All subgroups, including those with an International Staging System (ISS) score of 3, favored the quadruplet arm. For those patients with high-risk cytogenetics, the OR was 2.29 (95% CI 0.55-9.5). The rates of CR or better also favored the quadruplet arm (58% vs. 31%, p<0.0001). PFS and OS data were immature, with estimated two-year PFS and OS of 85% and 91%, respectively, for the Isa-VRd arm and 80% and 92%, respectively, for the Isa-Rd arm. While overall safety profiles were similar between the two arms, the quadruplet arm had comparatively higher rates of both peripheral neuropathy (any grade: 52% vs. 28%; grade 2 or higher: 27% vs. 10%) and thrombocytopenia (any grade: 27% vs. 14%; grade 3 or higher: 12% vs 5%). The relative dose intensity of bortezomib was 92%, with 11% of patients prematurely discontinuing the medication due to AEs.

Consistent with other quadruplet studies, the results of the IMROZ and BENEFIT trials demonstrate that such a therapy regimen can improve depth of response and lead to high rates of MRD negativity. In the IMROZ study, this translated into a significant improvement in PFS, with the five-year PFS of 63% for the Isa-VRd arm among the highest ever observed in a clinical trial for TI NDMM. For context, the five-year PFS for daratumumab-Rd treatment in the MAIA study was 52%; however, caution should be used in making cross-study comparisons.⁷  For example, 40% of patients in the MAIA trial were over age 80, while such patients were excluded from the IMROZ and BENEFIT studies. The relatively long follow-up and significant improvement in PFS seen in the IMROZ trial support quadruplet-based induction with Isa-VRd as a new SOC option for TI NDMM.

The main consideration that arises in looking at these results is whether all patients need upfront quadruplet-based treatment or whether triplet regimens are sufficient for some. As the use of upfront anti-CD38 antibody therapy is now common following the results of the MAIA study, the more clinically relevant question is whether the addition of bortezomib is advantageous. While the BENEFIT trial demonstrated MRD negativity improvement with the addition of bortezomib, PFS data is immature and current median follow-up is only approximately eight months after discontinuation of bortezomib. Whether the addition of weekly bortezomib for 12 months followed by an additional six months of treatment every two weeks will lead to PFS improvements in the typical MM patient beyond the five-plus years seen in the MAIA study remains to be seen. Short of an eventual PFS readout in BENEFIT, the difference in sustained MRD negativity after one and two years following discontinuation of bortezomib will be very informative. The study’s Isa-VRd arm was associated with increased rates of neuropathy, an important consideration given the advanced age of TI patients. Such considerations as quality-of-life (including the additional visits required for administration of a parenteral agent), degree of frailty, and concurrent comorbidities may prove equally as important as PFS and depth of response when evaluating treatment options for this patient population.

Although a common practice may be a risk-adapted approach, with quadruplet therapy preferred over triplet therapy for those with high-risk cytogenetics, both the IMROZ and BENEFIT studies demonstrated that quadruplet therapy primarily benefits those with standard-risk disease. Another question is whether similar outcomes can be achieved via a response-adapted approach, such as escalating from an initial triplet therapy to quadruplet treatment in patients with suboptimal responses as an alternative to upfront quadruplet therapy. Identifying the optimal dose level, frequency, and duration of treatment for each component of quadruplet therapy remains an area of investigation. These studies demonstrate that it is not necessarily the number of drugs that should be lowered for MM patients older than 70 but perhaps the dose intensity, keeping in mind that a sizable percentage of real-world MM patients are not eligible for clinical trials and may not tolerate full dose-intensity regimens. Indeed, given that patients in the IMROZ study received six months of bortezomib induction therapy administered twice a week, it is likely that many of them were fit and therefore potentially eligible for stem cell transplantation (SCT). However, the outstanding results demonstrated by IMROZ and BENEFIT suggest that, particularly in an era of the outstanding efficacy of T-cell redirection therapies for relapsed disease, many fit patients over age 70 may do well without SCT, especially if the melphalan dosing needs to be reduced from 200 mg/m2 to 140 mg/m2 for this patient population. Until definitive randomized study results are available, the decision to transplant older fit patients should be individualized based on baseline Revised ISS risk status, response, and tolerance to induction therapy.