Curing Multiple Myeloma (MM) with Total Therapy (TT)

Abstract Intra-tumoral heterogeneity is a hindrance to curing malignant disease. By employing all MM-active drugs upfront, TT was designed to overcome such obstacle by targeting all potential MM sub-clones broadly. We are reporting on long-term results of phase-2 TT1, phase-3 TT2 and phase-2 TT3a trials, with median follow-up times of 21yr, 12yr and 9yr, respectively. Five year estimates of OS, PFS and CR duration (CRD) increased from 58%, 28% and 40% with TT1 to 65%, 42% and 50% with TT2’s control arm (TT2-), to 68%, 56% and 58% with TT2’s thalidomide arm (TT2+), and to 74%, 65% and 74% with TT3a (all p Figure 1 ). Importantly, when comparing data from GEP-defined low-risk and high-risk MM, plateaus for both PFS- and CRD-based cure fractions emerged at 10 years in the former and earlier, at 5 years, in the latter (data not shown). PFS-based cure-fraction estimates increasedsignificantly with successive TT trials: 9% in TT1, 16% in TT2-, 25% in TT2+, and 33% in TT3a (p=0.04). CRD-based cure-fraction estimates were 18%, 28%, 36%, and 49%, respectively (p=0.17) (Table 1). When a 5-year landmark was applied to exclude early myeloma-related events, PFS-based cure fraction estimates were 28% in TT1, 39% in TT2-, 51% in TT2+, and 70% in TT3a (p As MM usurps the bone marrow micro-environment (ME) for its growth and survival, we reasoned that ME alterations reflecting an angiogenic switch may persist beyond the state of clinical CR and even MRD. We therefore performed GEP analyses of bone marrow biopsies in CR and compared findings with age- and sex-matched controls. Indeed, biopsy “normalization” was linked to superior CR duration and is being developed as an early “cure surrogate” marker to help define the length of maintenance therapy in future trials. Although about 50% of CR patients treated with TT3a can be considered cured, the median PFS in high-risk MM of 2yr has not improved with successive TT trials. Reasoning that cytokine storms emanating after myelosuppressive therapies to restore normal hematopoiesis may be growth-stimulatory to MM cells, we applied non-myelotoxic metronomic therapy (Papanikolaou, Haematologica, 2014). Six newly diagnosed transplant-ineligible high-risk patients were offered an extended 28-day course of low-dose metronomic therapy with bortezomib, thalidomide, dexamethasone and continuous infusions of doxorubicin and cisplatin, to which were added arsenic trioxide and vincristine infusions. Remarkably, 5 of 6 achieved CR status after a single course and remain disease-free without further therapy 6-8 months later. Our results attest to the curability of MM with TT and, given the short PFS of 2yr in high-risk MM, such patients should be the focus of future novel interventions that yield information in a timely manner. Table 1 . Cure fraction estimates Protocol PFS CR duration N Cure Fraction N Cure Fraction From start of therapy TT1 231 8.8% 79 17.9% TT2 -Thal 345 15.5% 146 28.2% TT2 +Thal 323 25.1% 200 35.6% TT3a 303 32.9% 189 48.8% From 5-yr landmark TT1 65 28.4% 33 32.3% TT2 -Thal 145 39.2% 84 47.4% TT2 +Thal 150 51.1% 134 55.9% TT3a 197 69.8% 148 74.7% PFS CR duration Download : Download high-res image (76KB) Download : Download full-size image Figure 1 . Cure fraction estimates from baseline Disclosures van Rhee:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Heuck:Celgene: Honoraria; Foundation Medicine: Honoraria; Millennium: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees.