Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients (pts) with newly diagnosed multiple myeloma (NDMM) for whom transplant is not planned as initial therapy: A multicenter, randomized, phase III study (CEPHEUS).

Abstract

TPS8056 Background: DARA is a human, anti-CD38 IgGκ monoclonal antibody that significantly reduced the risk of progression/death with a manageable safety profile across several phase 3 studies in relapsed/refractory MM and NDMM. DARA + VRd (D-VRd) demonstrated efficacy and tolerability in the safety run-in cohort of the ongoing phase 2 GRIFFIN study that included transplant-eligible NDMM pts. To determine whether D-VRd demonstrates efficacy and tolerability in NDMM pts for whom transplant is not intended as initial therapy, the phase 3 CEPHEUS study will evaluate the efficacy and safety of D-VRd vs VRd alone in this pt population. Methods: This is an ongoing multicenter, open-label, randomized phase 3 study of D-VRd vs VRd alone in pts with NDMM for whom transplant is not intended as initial therapy. Approximately 360 pts will be stratified by ISS stage and age/transplant eligibility (age < 70 years and transplant-ineligible, or age < 70 years and refusal to transplant, or age ≥70 years) and will be randomized in a 1:1 ratio. All pts will receive eight 21-day cycles of VRd (V: 1.3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-14; d: 20 mg PO/IV Days 1, 2, 4, 5, 8, 9, 11, 12), followed by 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg PO/IV Days 1, 8, 15, 22) until progressive disease (PD). Patients in the DARA group will also receive subcutaneous DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) weekly in Cycles 1-2, every 3 weeks in Cycles 3-8, and every 4 weeks in Cycles 9+ until PD. All pts will receive preinfusion medications. Minimal residual disease (MRD)-negative rate at 10–5 sensitivity threshold by NGS is the primary endpoint. MRD will be evaluated at suspected complete response or better. Secondary endpoints include progression-free survival (PFS), MRD-negative rate at 1-year, durable MRD negativity, overall response rate, time to and duration of response, PFS on next line of therapy, overall survival, clinical efficacy in high-risk molecular subgroups, health-related quality of life, pharmacokinetics, immunogenicity, and safety. Clinical trial information: NCT03652064.

Emerging immunotherapies in multiple myeloma

“…More recent studies are now including the monoclonal antibodies daratumumab, elotuzumab, and isatuximab in the upfront setting as part of a quadruplet regimen that includes a monoclonal antibody with standard triplet combinations to improve depth of response and thus outcomes 52138139140141142143144…”

The Role of Monoclonal Antibodies in the Era of Bi-Specifics Antibodies and CAR T Cell Therapy in Multiple Myeloma

“…However, there was no significant difference in the stem cell harvest between the D or the control arm in either of these two clinical trials, albeit the goal of the stem cell harvest was relatively low at approximately 5 × 10 6 CD34 cells/kg [ 10 ] and the liberal application of plerixafor was encouraged. Results of the ongoing phase III studies PERSEUS investigating the quadruple regimen of D-VRD in NDMM are much awaited [ 20 , 21 ]. Minimal residual disease (MRD) status is emerging as a robust predictor of clinical outcome independent of cytogenetic risk factors, treatment regimen, or disease burden and there have been attempts for MRD risk-adapted treatment approaches to offer treatment-free intervals or intensification of treatment in some situations [ 22 , 23 ].…”

<p>Updated Perspectives on the Management of Multiple Myeloma in Older Patients: Focus on Lenalidomide</p>

“…The primary endpoint is the rate of minimal residual disease by next-generation sequencing. 37 The CEPHEUS trial is anticipated to provide valuable information about the safety and efficacy of D-VRd in older adults who are newly diagnosed with multiple myeloma.…”

“…Although lenalidomide, either alone or in combination, is a part of the current treatment standard for older adults, the treatment landscape for myeloma is rapidly evolving. It is likely that the role of lenalidomide will continue to evolve as new drugs and combinations demonstrate efficacy in older adults with myeloma, whether it be through novel drug combinations as in the CEPHEUS trial, 37 or through lenalidomide-free regimens. The ALCYONE trial showed the efficacy of a lenalidomide-free regimen by using the combination of daratumumab plus bortezomib, melphalan, 56 While the results support a viable lenalidomide-free treatment regimen, a direct comparison of this regimen versus lenalidomide-containing regimens has not been conducted.…”