Double-Hit/Triple-Hit Myeloma: An Adverse Prognostic Factor That Can be Overcome By Minimal Residual Disease Negativity
Authors: Yang Yang , Wang Wenjing , Ren Liang , Wang Yawen , Maihemaiti Aziguli , Lan Tianwei , Zhou Chi , Li Panpan , Wang Pu , Li Jing , Xu Jiadai , Xu Tianhong , Chen Fei-fei , Liu Peng 
Published: December 2024

Objective：
The outcome of double-hit/triple-hit multiple myeloma (DH/TH MM) remains poor. We aimed to demonstrate the clinical characteristics, response, minimal residual disease (MRD) status and survival of DH/TH MM in novel drug era.
Methods：
Newly diagnosed (ND) MM patients (pts) in Zhongshan Hospital Fudan University from January 2013 to October 2021 were retrospectively enrolled. Patient demographics, clinical characteristics, treatment, response rate, MRD, evaluated by next-generation flow-cytometry, 1×10-6) and survival were collected. The definition of DH/TH MM was in accordance with the Mayo Clinic mSMART3.0.
Results：
Of the 572 NDMM, 235 (41.1%), 222 (38.8%), 101 (17.7%) and 14 (2.4%) pts had standard risk (StR, 0 HRCA), single-hit (SH, 1 HRCA), DH and TH. The most frequently seen DH/TH combinations were gain/amp(1q)+t(4;14) (n=69) and del(17p)+gain/amp(1q)+t(4;14) (n=8).
DH/TH MM had a higher disease burden and more aggressive pattern. The highest bone marrow plasma cell (BMPC) infiltration (50%, vs 15% in StR and 40% in SH pts, p&lt;0.001), and the highest proportions of pts with ISS III stage (60.4% vs 24.1% vs 52.5%, p&lt;0.001) , hypercalcemia (14.8% vs 3.9% vs 8.1%, p=0.002), anemia (67.0% vs 28.1% vs 62.6%, p&lt;0.001) and complex karyotype (22.2% vs 3.6% vs 10.9%, p&lt;0.001) were observed in DH/TH group.
All pts received at least one novel agent (proteasome inhibitor, [PI] or immunomodulatory drug [IMiDs]). Around 40% received a PI+IMiD-based treatment. Median cycle was 8. 79 pts (13.8%) had first-line autologous stem cell transplantation. The overall ORR, ≥ VGPR rate and CR rate were 90.8%, 69.1% and 40.8%. DH/TH pts had an ORR of 86%, with a ≥ VGPR response rate of 62.6% and a CR rate of 36.4%, while no difference with StR or SH pts was observed.
Of the 389 patients who received MRD assessment, 151 patients (38.8%) reached MRD-negative status and 110 maintained negativity during induction or maintenance therapy (MRDneg) while 41 of them turned to MRD-positive status during the follow-up (MRDtransient). The rest 238 patients remained MRD positivity (MRDpos). MRDneg% was similar among the 3 groups (StR 44.2%, SH 36.6%, DH/TH 33.7%), but MRDtransient/MRDneg% was much higher in DH/TH than in StR and SH pts (60.0% vs 18.4% vs 19.6%, p&lt;0.001). The median time to MRDneg was 3.4 months and of no difference among subgroups. The median MRD duration was 10.9 months (15.6, 7.8 and 7.7 months in StR, SH and DH/TH pts,p=0.059).
The median progression-free survival (mPFS) was not reached (NR), 34.7 and 18.0 months (ms) in StR, SH and DH/TH group (p&lt;0.001). The median overall survival (mOS) was 48.8m in DH/TH group while NR in the other two groups (p&lt;0.001). Del(17p)+gain/amp(1q), del(17p)+t(4;14) (n=2), gain/amp(1q)+t(4;14) (n=69) and gain/amp(1q)+t(14;16) (n=9) pts had an mPFS of 13.1, 3.0, 21.3 and 21.5 ms. The mOS was 21.6, 3.2, 48.8 and 41.6 ms (no statistically significant difference).
The PFS and OS of MRDneg group was superior to those of MRDpos pts (2-year PFS% 98.9%/40.6%, p&lt;0.001, 2-year OS% 98.9%/78.1%, p&lt;0.001). MRDtransient pts had similar 2-year PFS% (57.5%) and OS% (85.1%) with the MRDpos ones. In MRDpos group, DH/TH pts had the worst survival (2-year PFS% 26.3% and 2-year OS% 74.3%) comparing with StR (2-year PFS% 76.6% and 2-year OS% 90.0%) or SH group (2-year PFS% 59.8% and 2-year OS% 86.7%). MRDneg pts had a satisfying 2-year PFS% and 2-year OS% of both 97.1-100.0%, regardless of CA stratification.
SH del(17p)+ pts (n=12) had similar poor CR rate to DH del(17p)+ pts (n=23) (33.3% vs 25%, p=0.572) and equivalent mPFS [13.3 vs 13.1 months (ms)] and mOS (28.7 vs 21.6 months, p=0.828). DH del(17p)- pts (n=78) had a superior CR rate (38.4%), mPFS (21.3 ms) and mOS (48.8ms). Conversely, SH t(4;14)+ pts (n=71) had a better mPFS (42.3 vs 30.8 ms, p=0.041) and a trend of better mOS (NR vs 48.8 ms, p=0.068) than DH t(4;14)+ pts (n=21). This also referred to gain/amp(1q)+ SH (n=186) and DH (n=99) pts (mPFS: 34.7 vs 18.5 ms, p=0.003, mOS: NR vs 48.8 ms, p=0.159).
Conclusion：
DH/TH MM had advanced disease patterns. They had a similar response rate to StR/SH pts but a prominently inferior outcome. For the first time, we revealed that MRD negativity could overcome the poor prognosis of DH/TH MM. MRD negativity of DH/TH pts could be achieved like StR/SH pts but easily got lost. An extra del(17p) lesion could exacerbate the adverse prognosis of a single HRCA, while adding gain/amp(1q) or t(4;14) did not have such a negative effect.