Upfront 28-Day Metronomic Therapy for High-Risk Multiple Myeloma (HRMM)

Introduction: Despite major advances in MM therapy with the inclusion of novel agent combinations for induction prior to and after autotransplant-supported high-dose melphalan, the 15% of patients with GEP-defined HRMM continue to fare poorly with PFS and OS not exceeding 2 and 3 years, respectively. This poor outcome has not been improved with less dose-intense and more dose-dense Total Therapy 5. Having previously reported on 16-day metronomic therapy with low-dose doxorubicin (DOX) and cisplatin (DDP) plus VTD (Papanikolaou, Haematologica), we explored further extension of such metronomic treatment to 28 days (metro-28) also in newly diagnosed HRMM patients.

Patients and Methods: All patients signed a written informed consent and data analysis was approved by our IRB. In the outpatient setting, a  single cycle of metro-28 comprised DOX and DDP each at 1.0mg/m2/d for 28d by continuous infusion (CI), along with VTD (bortezomib 1.0mg/m2 on days 1-4, 7-10, 13-16, 19-22, 25-28; DEX 12mg on days 1-4, 7-10, 13-16, 19-22, 25-28; thalidomide 50-100mg/d x 28d; some patients also received vincristine [VCR] at a flat daily dose of 0.07mg/d x 28d by CI.

Results: Fourteen patients were initiated on metro-28. Their characteristics included age >=65y in 12; albumin <3.5g/dL in 8; B2M >5.5mg/L in 7; cytogenetic abnormalities [CA] were present in 10; GEP70 HRMM in 9/13; PR subgroup in 8/13 (Table 1). The median follow up is 11mo. As portrayed in Figure 1A, no patient has died; the 6mo PFS estimate was 85% (Figure 1B); responses included CR in 3/14, VGPR in 7/14 and PR in 10/14 (Figure 1C); and the PR duration estimate at 6mo is 80% (Figure 1D). Of interest, GEP70 scores morphed to low risk in 3/13. Vascular density (CD34) decreased markedly in most patients evaluated. Toxicities were minor; myelosuppression was virtually absent; alopecia was not encountered. Subsequent salvage therapies included repeat metro-28, combination chemotherapy (PACMED) and autotransplants.

Conclusion: We conclude that metro-28 is a promising and safe strategy for elderly patients with HRMM, and we hypothesize an anti-angiogenic mechanism of action in addition to direct anti-MM effects.

 

Table 1: Patient characteristics

Factor	n/N (%)
Age >= 65 yr	12/14 (86%)
Albumin < 3.5 g/dL	8/14 (57%)
B2M >= 3.5 mg/L	9/12 (75%)
B2M > 5.5 mg/L	7/12 (58%)
Hb < 10 g/dL	10/14 (71%)
Cytogenetic Abnormalities	10/14 (71%)
CA within 1 Year of Therapy	10/14 (71%)
CA within 90 Days of Therapy	9/14 (64%)
GEP 70-Gene High Risk	9/13 (69%)
GEP PR Subgroup	8/13 (62%)
GEP Proliferation Index >= 10	7/13 (54%)
GEP Centrosome Index >= 3	7/13 (54%)
n/N (%):  n- Number with factor, N- Number with valid data for factor

 

Figure 1