Multiparameter flow cytometry (MFC) and next generation sequencing (NGS) for minimal residual disease (MRD) evaluation: Results of the FORTE trial in newly diagnosed multiple myeloma (MM).

Abstract

8533 Background: The role of MRD by MFC and NGS is well known in MM, with few data on the concordance of the two techniques. We analyzed and compared MRD data from the FORTE trial both by MFC and NGS. Methods: Newly diagnosed MM patients (pts) ≤65 years were randomized to: carfilzomib, lenalidomide, dexamethasone (KRd) induction-autologous stem cell transplant (ASCT) - KRd consolidation (KRd_ASCT); 12 KRd cycles (KRd12); carfilzomib, cyclophosphamide, dexamethasone (KCd) induction-ASCT-KCd consolidation (KCd_ASCT). Pts were then randomized to maintenance: lenalidomide alone or plus carfilzomib. MRD was assessed by 8-color second generation flow cytometry (sensitivity 10−5) in pts with ≥very good partial response (VGPR) before maintenance. In a subgroup of these pts, next generation flow (NGF; sensitivity 10−5-10−6) was performed. In ≥CR pts, MRD pre-maintenance was also assessed by NGS (Adaptive Biotechnologies; sensitivity 10−5-10−6). Thus, both MFC and NGS evaluations were available only in ≥CR pts. 1-year sustained MRD negativity by MFC and NGS was also analyzed in pts with at least one sample available at least 1 year apart. Results: MFC and NGS data were available in 184/233 (79%) CR pts (66 KRd_ASCT, 67 KRd12 and 51 KCd_ASCT). Median age of this ≥CR population was 57 years (IQR 52-62), 13% had International Staging System (ISS) III and 27% high risk cytogenetics by FISH [either del(17p) or t(4;14) or t(14;16)]. Table reports MRD negativity rate by MFC and NGS at a cut-off of 10−5 and 10−6 among ≥CR negative pts in the 3 arms. NGS negativity at a cut-off 10−6 was found in 36/133 (27%) ≥CR pts (for 51/184 CR pts 10−6 sensitivity was not reached). In evaluable pts, 1-year sustained 10−5 MRD negativity by MFC and NGS was superimposable (83%). We evaluated concordance of MRD results by the two techniques and observed agreement was 86% for MFC and NGS at 10−5 evaluable samples (n: 335; r: 0.61) and 78% for MFC and NGS at 10−6 evaluable samples (n: 56; r: 0.77). Conclusions: In pts who achieved ≥CR, similar rate of pre-maintenance 10−5 negativity by MFC and NGS has been reached in each arm, with 83% pts maintaining 1-year MFC or NGS 10−5 sustained MRD negativity. Concordance between MFC and NGS was good, particularly when the same sensitivity was reached. Longer follow up is needed to draw definitive conclusions. Clinical trial information: NCT02203643 . [Table: see text]

Daratumumab for the Management of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: Current and Emerging Treatments

“…After a median follow-up of 56 months, 5-year PFS and OS were 72 and 84%, respectively. These results are similar to those reported by the phase II randomized FORTE trial ( 12 , 13 ) in which 474 newly diagnosed MM patients were randomized to receive four KRd induction cycles, ASCT, four consolidation KRd cycles; 12 KRd cycles or four KCd induction cycles, ASCT, four KCd consolidation cycles. The rates of post consolidation ≥VGPR, ≥CR, and MRD negativity (at a cut-off of at least 10 −5 ) were 89, 60, and 58%, respectively.…”

Treatment Strategies Considering Micro-Environment and Clonal Evolution in Multiple Myeloma

“…In FORTE trial, PFS in the patients treated with four cycles of KRd (carfilzomib (CFZ) + LEN + DEX) followed by ASCT followed by four cycles of KRd (KRd-ASCT group) was significantly longer than those with 12 cycles KRd (KRd12), although the MRD negativity ratio was similar using multicolor flow cytometry (cut-off = 10 −5 ) [ 184 , 185 ]. In addition, in a long follow-up, the MRD ratios were similar between the KRd12 and KCd (CFZ + cyclophosphamide + DEX)-ASCT groups.…”

Treatment Strategy for Multiple Myeloma to Improve Immunological Environment and Maintain MRD Negativity

“…In addition, various treatment agents, including IMiDs, PIs, and MoAbs, have been developed in the last two decades, thus increasing CR ratios [ 1 , 2 ]. Many clinical trials have demonstrated that the administration of several treatment agents with different modes of action helps achieve MRD negativity in addition to CR [ 5 , 7 , 8 , 111 , 112 , 114 , 115 , 122 , 123 , 124 ]. For MM patients who achieve MRD negativity after induction therapy and ASCT, consolidation and/or maintenance therapy is needed to enhance and maintain the therapeutic effect.…”