Smoldering multiple myeloma: to treat or not to treat

Figures & data

Table 1. Parameters for identifying SMM at elevated risk of progression to active myeloma.

High-risk SMM patients (50 – 79% of progression risk at 2 years)

Parameters correlated with tumor burden: a + b or a + b + c

(a) ≥ 10% clonal plasma cell bone marrow infiltration; (b) ≥ 3 g/dl of serum M-protein; (c) serum-free light chain ratio > 0.125 or < 8;

Parameters correlated with immunophenotyping characterization and immunoparesis: a + b

(a) > 95% of aberrant bone marrow plasma cells measured by flow cytometry; (b) 25% decrease in one or both uninvolved immunoglobulins with respect to the lowest normal value;

Parameters correlated with primary molecular cytogenetic abnormalities and GEP signature: the presence of one of the following

(a) presence of t(4;14); (b) presence of del17p; (c) gains of 1q24; (d) hyperdiploidy; (d) GEP-70 risk;

Parameters correlated with levels of peripheral blood circulating plasma cells: the presence of one of the following

(a) absolute peripheral blood PCs > 5000 × 10^6/l; (b) > 5% cytoplasmic Ig positive PCs per 100 mononuclear cells;

Ultra-high risk SMM patients (≥ 80% of progression risk at 2 years)

Parameters for identifying this category of patients: the presence of one of the following

(a) > 1 focal lesion plus diffuse pattern in whole-body MRI; (b) ≥ 60% of clonal plasma cells in bone marrow biopsy; (c) involved/uninvolved serum-free light-chain ratio > 100.

Table 2. Selected Phase III trials for treatment of SMM.

Authors	Treatment	Schedule	N	Disease	End points	Response	TTE	Key toxicities (% of patients)
Musto et al. (2008) [16]	ZA versus observation	ZA: 4 mg every month	163	SMM	Primary: 5-year PFS Secondary: TTP, SREs, AEs	NA	Median TTP: 67 versus 59 months (p = NS) PFS and OS: not different	SREs: 55 versus 78% (p = 0.04)
Witzig et al. (2013) [15]	T- ZA versus ZA	ZA: 4 mg every 28 days T: 200 mg continuously	68	SMM	Primary: TTP Secondary: ORR, 1-year PFS, DOR, AEs	ORR: 37% versus 0	Median TTP: 2.4 versus 1.2 years (p = 0.02) Median OS: not different	Grade ≥ 3 hematologic: 20 versus 6% Grade ≥ 3 fatigue: 3 versus 9% Grade ≥ 3 venous thromboembolism: 3 versus 3%
Mateos et al. (2013, 2014) [17,18]	RD versus observation	R: 25 mg days 1 – 21 of 28-day cycle for the first 9 cycles, then 10 mg same days for 2 years D: 40 mg on days 1 – 4, 12 – 15 for the first 9 cycles	119	HR SMM	Primary: TTP Secondary: ORR, OS, AEs	RD arm: ORR: 90% CR: 26% sCR: 12%	Median TTP: NR versus 21 months (p <0.0001) 5-year OS: 93 versus 67% (p = 0.008)	Grade ≥ 3 hematologic: 9% versus 0 Grade ≥ 3 infection: 6% versus 0 Grade ≥ 3 rash: 3% versus 0 Grade ≥ 3 asthenia: 6% versus 0 Grade ≥ 3 diarrhea: 2% versus 0

AEs: Adverse events; CR: Complete response; D: Dexamethasone; DOR: Duration of response; HR: High risk; NA: Not applicable; NR: Not reached; NS: Not significant; ORR: Overall response rate; OS: Overall survival; PFS: Progression free survival; R: Lenalidomide; sCR: Stringent complete response; SMM: Smoldering multiple myeloma; SREs: Skeletal-related events; T: Thalidomide; TTE: Time to event; TTP: Time to progression; ZA: Zoledronic acid.

Musto P, Petrucci MT, Bringhen S, et al. A multicenter randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer 2008;113(7):1588-95

 PubMed Web of Science ®Google Scholar

Witzig TE, Laumann KM, Lacy MQ, et al. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia 2013;27(1):220-5

 PubMed Web of Science ®Google Scholar