Novel Regimens Show Continued Improvements in Newly Diagnosed Myeloma

Elizabeth (Betsy) O'Donnell, MD

The frontline treatment of patients with multiple myeloma continues to evolve with novel, multidrug regimens that are leading to higher, deeper, and more durable responses, as well as increased rates of minimal residual disease (MRD) negativity.

One of the few constants in the treatment of patients with multiple myeloma is transplant, said Elizabeth (Betsy) O'Donnell, MD, in a presentation during the 2020 OncLive^® State of the Science Summit™ on Multiple Myeloma.

While eligibility criteria for transplant have expanded to include older patients between the ages of 65 and 75 years, the same principles that have historically been used to determine a patient’s fitness apply.

“Fitness is defined as an aggregate of the patient’s organ function, comorbidities, frailty, and disability,” said O’Donnell, the latter of which consist of a gestalt assessment of the patient’s daily activities and a concrete measurement of their Charlson Comorbidity Index and Hematopoietic Cell Transplantation-specific Comorbidity Index.

Regardless of transplant eligibility, patients will undergo initial induction therapy, explained O’Donnell. In the transplant-ineligible population, the combination of lenalidomide (Revlimid) and dexamethasone (Rd) served as the frontline standard until the addition of bortezomib (Velcade) to Rd showed a progression-free survival (PFS) advantage to Rd alone in the SWOG S0777 trial.¹ However, the discontinuation rate due to adverse events (AEs) in the RVd arm was more than double that of the combination arm at 23% versus 10%, respectively. Rather than return to the combination, investigators developed “RVd-lite,” which by lowering the dose intensity and frequency of RVd, made the regimen more tolerable for elderly patients, explained O’Donnell.

Several other studies have evaluated multidrug regimens in the transplant-ineligible population, including the phase III CLARION trial,² in which patients received melphalan and prednisone plus carfilzomib (Kyprolis; KMP) or bortezomib (Velcade; VMP). Results showed that the median PFS was comparable between arms (HR, 0.906; 95% CI, 0.746-1.101; 1-sided P =.159). Although KMP conferred a slight, albeit nonstatistically significant advantage versus VMP in overall response rate and complete response (CR), more all-grade AEs were reported with carfilzomib.

Newer agents, such as daratumumab (Darzalex), are leading to continuous improvements, said O’Donnell. In the phase III ALCYONE trial,³ investigators evaluated the addition of daratumumab to VMP in transplant-ineligible patients. The ORR, at a median follow-up of 16.5 months and 40.1 months, was 91% in the D-VMP arm versus 75% in the VMP arm, respectively. Additionally, patients in the D-VMP arm were more likely to achieve MRD negativity and sustain that response, for ≥12 months, versus those in the VMP arm.

The PFS was 36.4 months in the D-VMP arm versus 19.3 months in the VMP arm, translating to a 68% reduction in the risk of progression or death (HR, 0.42; 95% CI, 0.34-0.51; P <.0001). The median overall survival (OS) also favored the D-VMP arm (HR, 0.60; 95% CI, 0.46-0.80; P =.0003).

Similarly, in the phase III MAIA trial, the addition of daratumumab to Rd led to a higher ORR and rate of MRD negativity versus Rd alone.⁴ At a median follow-up of 28 months, median PFS was not reached in the DRd arm versus 31.9 months in the Rd arm (HR, 0.56; 95% CI, 0.43-0.73; P <.001).

Additionally, the addition of daratumumab led to more of an improvement in quality of life (QoL) versus Rd⁵, particularly in patients ≥75 years of age, said O’Donnell. This compares favorably with data from the IFM 2009 trial and ALCYONE trials, which showed marginal improvements in QoL.

“We saw an improvement in QoL, despite the fact that the visit burden may be more significant with DRd,” said O’Donnell.

In the transplant-eligible population, lenalidomide, bortezomib, and dexamethasone (RVd) is the standard induction therapy. However, cyclophosphamide, bortezomib, and dexamethasone can be given to patients with renal insufficiency, said O’Donnell.

One of the studies of particular interest in the transplant-eligible population is the FORTE trial,⁶ which randomized patients to 1 of 3 arms: carfilzomib, lenalidomide, and dexamethasone (KRd), followed by transplant and KRd consolidation; carfilzomib, cyclophosphamide, and dexamethasone (KCd), followed by transplant and KCd consolidation; or continuous KRd. Patients underwent a second randomization to lenalidomide or KRd after consolidation.

At a median follow-up of 26 months, the very good partial response rate or better (≥VGPR) with KRd was 73% versus 57% with KCd.

“Continuous KRd seemed very comparable in terms of ORR, rate of ≥VGPR, and MRD negativity compared with KRd and transplant,” said O’Donnell.

The phase III CASSIOPEIA trial⁷ evaluated the addition of daratumumab to another multi-drug combination of bortezomib, thalidomide (Thalomid), and dexamethasone (VTd). Patients were randomized to receive D-VTd or VTd followed by transplant and consolidation with their initial induction regimen. Following consolidation, the stringent complete response (sCR) rate was 29% in the D-VTd arm versus 20% in the VTd arm (odds ratio, 1.60; 95% CI, 1.21-2.12; P =.0010). The rate of MRD negativity was 64% in the D-VTd arm versus 44% in the VTd arm.

PFS favored the daratumumab regimen compared with VTD alone (HR, 0.47; 95% CI, 0.33-0.67; P <.0001). Additionally, the 18-month PFS rate was 93% in the D-VTd arm versus 85% in the VTd arm, and PFS favored patients who were MRD negative in the D-VTd and VTd arms, added O’Donnell. Notably, the PFS curves were superimposable among patients who achieved a CR with D-VTd and VTd, suggesting that MRD is not the sole determinant of outcomes.

One of the most exciting studies to emerge over the past year was the phase II GRIFFIN trial,⁸ said O’Donnell. The study evaluated the addition of daratumumab to RVd in transplant-eligible patients. Following consolidation, 42.4% of patients in the D-RVd arm achieved a sCR versus 32.0% in the RVd arm, meeting the study’s primary endpoint (odds ratio, 1.57; 95% CI, 0.87-2.82; 1-sided P =.068). Response rates and the depth of response favored the triplet following induction, transplant, consolidation, and clinical cutoff, said O’Donnell, translating to higher rates of MRD negativity in the D-RVd arm following consolidation.

Notably, the addition of daratumumab did not affect the ability to collect stem cells prior to transplant, said O’Donnell. In the ongoing phase III PERSEUS trial (NCT03710603), investigators are evaluating the same regimens with subcutaneous daratumumab.

While RVd remains a standard of care, KRd has very deep responses with high rates of MRD negativity, said O’Donnell. This may change pending the results of the phase III E1A11 Endurance trial (NCT01863550), which is comparing RVd with KRd, as well as further follow-up from the FORTE trial, which may show a reduced need for transplant.

“Four-drug combinations with daratumumab are very promising, but there are a lot of unanswered questions about what happens beyond that when you’ve used all 4 major classes of drugs in the upfront setting,” said O’Donnell.

While MRD is being used as a surrogate marker for efficacy in clinical trials, it may soon have therapeutic implications as well, said O’Donnell, citing the MASTER trial (NCT03224507), in which the duration of therapy will be guided by MRD negativity.

References

1. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;389(10068):519-527. doi: 10.1016/S0140-6736(16)31594-X.
2. Facon T, Hoon Lee J, Moreau P, et al. Phase 3 study (CLARION) of carfilzomib, melphalan, prednisone (KMP) v bortezomib, melphalan, prednisone (VMP) in newly diagnosed multiple myeloma (NDMM). Clin Lym, Myel & Leuk. 2017;17(1):26-27. doi: 10.1016/j.clml.2017.03.045.
3. Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141. doi: 10.1016/S0140-6736(19)32956-3.
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7. Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA part 1 results. J Clin Oncol. 2019;37(suppl 15; abstr 8003). doi: 10.1200/JCO.2019.37.15_suppl.8003.
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