Phase II Clinical Trial of Personalized-VCD-VTD Sequential Therapy Using VES-13 for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Background

Most patients with newly diagnosed multiple myeloma (MM) are aged > 65 years with 30% aged > 75 years. Many elderly patients are frail because of their comorbid conditions, poor physical or cognitive function that complicate the management of MM. Therefore, personalized therapy using dose-adjusted regimens is urgently needed for these frail elderly patients. The Vulnerable Elders Survey (VES-13) is a 13-item self-administered instrument, validated in the elderly population to predict functional decline and mortality. The VES-13 asks patients to report their age, self-rated health, functional limitations and functional disabilities. The VES-13 has been validated for screening older cancer patients for a Comprehensive Geriatric Assessment (CGA). We conducted a prospective clinical trial to evaluate the feasibility and efficacy of tailored dose-adjusted treatment based on a simplified geriatric assessment (GA) using VES-13 in transplant-ineligible elderly patients with newly diagnosed MM. Furthermore, the current study also aimed to evaluate the efficacy and safety of two sequential triplet regimens (VCD-VTD) to maximize the response rates and minimize potential toxicities for elderly frail MM patients.

Methods

We conducted a multicenter, prospective Phase II clinical trial to investigate the efficacy and safety of personalized sequential therapy with sVCD (subcutaneous bortezomib, cyclophosphamide and dexamethasone), followed by sVTD (subcutaneous bortezomib, thalidomide and dexamethasone) using VES-13 for transplant-ineligible patients with newly diagnosed MM (UMIN000011235). VES-13 is performed before the initiation of the study treatment to evaluate each patient's frailty. Each patient was allocated to one of two groups according to the VES-13 score. In Fit group (VES-13 score 0-2), patients were treated with 4 cycles of standard-dose sVCD (<Cycle 1> (42days/cycle) Bor 1.3mg/m² sc, days 1, 4, 8, 11, 22, 25, 29, 32, CY 300mg/m² po, days 1, 8, 22, 29, Dex 40mg/day po, days 1, 4, 8, 11, 22, 25, 29, 32. <Cycle 2-4> (35days/cycle) Bor 1.3mg/m² sc, CY 300mg/m² po, Dex 40mg/day po, days 1, 8, 15, 22) followed by 4 cycles of standard-dose sVTD (<Cycle5-8> (35days/cycle) Bor 1.3mg/m² sc, days 1, 8, 15, 22, Thal 100mg/body po, days 1-35, Dex 40mg/day po, days 1, 8, 15, 22). In Frail group (VES-13 score 3-10), patients were treated with 4 cycles of reduced-dose sVCD (<Cycle1-4> (35days/cycle) Bor 1.3mg/m² sc, CY 200mg/m² po, Dex 20mg/day po, days 1, 8, 15, 22) followed by 4 cycles of reduced-dose sVTD (<Cycle5-8> (35days/cycle) Bor 1.3mg/m² sc, days 1, 8, 15, 22, Thal 50mg/body po, days 1-35, Dex 20mg/day po, days 1, 8, 15, 22). Patients with performance status (PS) 3 due to skeletal-related events (SRE) were also eligible in this study. The primary endpoint of this study was overall response rate (ORR).

Results

Forty-seven patients were enrolled from 2013 to 2016 at 11 centers in Japan. Median age (range) was 75 years (66-86), 55.3% (26/47) were female, and the distribution of ISS stage was I (10.6%), II (46.8%), III (42.6%). 34% of patients were PS 3. High risk cytogenetic abnormalities (i.e. del17p, t(14;16), t(4;14)) were observed in 7 patients (14.9%). ORR among all 47 patients was 87.2% (95% confidence interval (CI): 74.3 to 95.2%) including 17.0% ≥CR and 46.8% ≥VGPR. Among Fit group (N=16), ORR was 87.5% (95%CI: 61.7 to 98.4%) including 18.8% ≥CR and 56.3% ≥VGPR. Among Frail group (N=31), ORR was 87.1% (95%CI: 70.2 to 96.4%) including 16.2% ≥CR and 41.9% ≥VGPR. Although approximately half of the patients were PS 3 (51.6%) in Frail group, comparable high efficacy was shown in both Fit and Frail groups. The overall incidence of Grade 3/4 adverse events was numerically higher in the Frail group than in the Fit group, but no unexpected Grade 3/4 adverse events were observed. The most frequent Grade 3/4 adverse events were anemia, neutropenia, hyponatremia and thrombocytopenia. Nine patients (19%) discontinued treatment because of adverse events.

Conclusions

Personalized, dose-adjusted sequential triplet therapy based on VES-13 showed high response rates and safety in elderly frail patients with MM. The use of this GA-driven treatment approach may result in optimal outcome in both Fit and Frail elderly MM patients.