Phase 2 and 3 clinical trials in SMM
| . | Phase . | High-risk definition . | Intervention . | Control arm . | No of patients . | Results . | Safety . |
|---|---|---|---|---|---|---|---|
| QuiRedex | 3 | BMPCs ≥10% and monoclonal component (defined as IgG level ≥3 g/dL, IgA level ≥2 g/dL, or urinary Bence Jones protein level >1 g per 24 h) or only 1 of 2 criteria described above plus at least 95% phenotypically aberrant plasma cells in BMPC compartment, with immunoparesis | Rd: 9 cycles followed by lenalidomide maintenance for 2 y | Observation | 119 | At 6 y, TTP was not reached vs 23 mo, and median OS was not reached vs 117.6 mo | 5% VTE, 6% grade 3 infection; 1 patient died as a result of therapy toxicity |
| CENTERIUS | 2 | BMPCs ≥10% to <60% and at least 1 of the following: serum M protein ≥3 g/dL (IgA ≥2 g/dL), urine M protein >500 mg per 24 h, abnormal FLC ratio (<0.126 or >8), or serum M protein <3 g/dL but ≥1 g/dL | Daratumumab monotherapy in 3 different regimens: intense (weekly in cycle 1, every other week in cycle 2-3, every 4 wk in cycle 4-7, and every 8 wk in cycles 8-20), intermediate (every week in cycle 1 and every 8 wk in cycles 2-20), or short (only 1 cycle of weekly daratumumab) | No | 123 | Coprimary end point of CR >15% was not met; ORR was 56%, 53.7%, and 37.5% in intensive, intermediate, and short arms, respectively | 5.7% stopped therapy because of PD and 5% because of AEs (pneumonia, thrombocytopenia, unstable angina, hypomania, balance disorder, and breast disorder); 2 patients died; in terms of safety, grade 3 or 4 AEs were reported in 44%, 27%, and 15% of patients in intensive, intermediate, and short arms, respectively |
| ECOG E3A06 | 3 | ≥10% BMPCs and sFLC ratio <0.26 or >1.65 | Single-agent lenalidomide (25 mg per day on days 1-21 every 28-d cycle) until progression | Observation | 182 | ORR was 50% and PFS was significantly longer in lenalidomide group (HR, 0.28; 95% CI 0.12-0.62; P = .002) | Grade 3 or 4 nonhematologic toxicity occurred in 25 patients (28%) in intervention arm, and 40% discontinued therapy because of AEs; 3-y cumulative incidence of invasive second primary malignancies was 5.2% in treatment arm vs 3.5% in observation arm |
| GEM-CESAR | 2 | Presence of both ≥10% BMPCs and M protein ≥3 g/dL, or if only 1 criterion was present, patients must have >95% aberrant plasma cells by immunophenotyping and immunoparesis | Induction with KRd followed by ASCT, KRd consolidation, and maintenance for 2 y | No | 90 | At 30-mo follow-up, ORR was 100% (≥CR 76%), and MRD negativity (measured by NGF with LOD 10-6) of 63% | |
| ASCENT | 2 | High-risk was defined as presence of any 2 of the following: serum M spike >2 g/dL or involved to uninvolved FLC ratio >20 or BMPC percentage >20%) or IMWG score ≥9 using risk scoring system using FLC ratio, serum M spike, marrow plasma cell percentage, and presence of high-risk FISH | 6 cycles of daratumumab plus KRd induction followed by additional 6 additional cycles of consolidation with daratumumab KRd and 1-y maintenance with daratumumab and lenalidomide | No | 46 | Pending (end point is sCR) | No treatment-related deaths were observed; grade ≥3 AEs were seen in 52% of patients |
| Kazandjian 2021 | 2 | Serum M protein ≥3 g/dL, IgA isotype, immunoparesis, sFLC ratio ≥8, clonal BMPCs 50%-60%, abnormal BMPC immunophenotype by flow; it also included criteria not previously included in SMM clinical trials: high-risk FISH abnormalities [t(4;14) or del(17p) or 1q gain], progressive increase in M protein level (evolving type of smoldering myeloma; increase in serum M protein by ≥25% on 2 successive evaluations within 6 mo), increased circulating plasma cells, and MRI with diffuse abnormalities or 1 focal lesion, PET/CT with focal lesion, increased uptake without underlying osteolytic bone destruction | KRd followed by 24 cycles of lenalidomide maintenance | No | 54 | Median rate of MRD-negative CR was 70% with median duration of 5.5 y; ORR was 100% and median duration of response was not reached with 96-mo duration of response of 77.4% | Nonhematologic grade 3 AEs were reported in 39% of cohort and included all-grade VTE in 11 patients (20%) and grade 3 VTE in 6 patients (11%); only 1 patient had grade 3 hypertension, 1 had grade 3 heart failure after 6 cycles and discontinued therapy, and 1 had grade 3 atrial fibrillation |
| Manasanch 2019 | 2 | Not reported in ASH abstract | Isatuximab monotherapy | No | 24 | ORR 63% (≥VGPR in 22%) | 5 grade 3 AEs that resolved to baseline; QOL was improved by end of cycle 6 |
| Nadeem 2021 | 2 | Defined criteria proposed by Rajkumar et al4 | Ixazomib plus Rd for 9 cycles followed by ixazomib and lenalidomide for 15 cycles for total of 24-mo period | No | 61 | ORR in participants who completed at least 2 cycles of treatment was 90.9% (CR, 21.8%; VGPR, 18.2%; PR, 50.9%) | No patients discontinued treatment because of toxicity; most common grade ≥3 toxicities were neutropenia (20%), hypophosphatemia (13%), leukopenia (11%), rash (9%), lymphocytopenia (5%), and thrombocytopenia (5%) |
| . | Phase . | High-risk definition . | Intervention . | Control arm . | No of patients . | Results . | Safety . |
|---|---|---|---|---|---|---|---|
| QuiRedex | 3 | BMPCs ≥10% and monoclonal component (defined as IgG level ≥3 g/dL, IgA level ≥2 g/dL, or urinary Bence Jones protein level >1 g per 24 h) or only 1 of 2 criteria described above plus at least 95% phenotypically aberrant plasma cells in BMPC compartment, with immunoparesis | Rd: 9 cycles followed by lenalidomide maintenance for 2 y | Observation | 119 | At 6 y, TTP was not reached vs 23 mo, and median OS was not reached vs 117.6 mo | 5% VTE, 6% grade 3 infection; 1 patient died as a result of therapy toxicity |
| CENTERIUS | 2 | BMPCs ≥10% to <60% and at least 1 of the following: serum M protein ≥3 g/dL (IgA ≥2 g/dL), urine M protein >500 mg per 24 h, abnormal FLC ratio (<0.126 or >8), or serum M protein <3 g/dL but ≥1 g/dL | Daratumumab monotherapy in 3 different regimens: intense (weekly in cycle 1, every other week in cycle 2-3, every 4 wk in cycle 4-7, and every 8 wk in cycles 8-20), intermediate (every week in cycle 1 and every 8 wk in cycles 2-20), or short (only 1 cycle of weekly daratumumab) | No | 123 | Coprimary end point of CR >15% was not met; ORR was 56%, 53.7%, and 37.5% in intensive, intermediate, and short arms, respectively | 5.7% stopped therapy because of PD and 5% because of AEs (pneumonia, thrombocytopenia, unstable angina, hypomania, balance disorder, and breast disorder); 2 patients died; in terms of safety, grade 3 or 4 AEs were reported in 44%, 27%, and 15% of patients in intensive, intermediate, and short arms, respectively |
| ECOG E3A06 | 3 | ≥10% BMPCs and sFLC ratio <0.26 or >1.65 | Single-agent lenalidomide (25 mg per day on days 1-21 every 28-d cycle) until progression | Observation | 182 | ORR was 50% and PFS was significantly longer in lenalidomide group (HR, 0.28; 95% CI 0.12-0.62; P = .002) | Grade 3 or 4 nonhematologic toxicity occurred in 25 patients (28%) in intervention arm, and 40% discontinued therapy because of AEs; 3-y cumulative incidence of invasive second primary malignancies was 5.2% in treatment arm vs 3.5% in observation arm |
| GEM-CESAR | 2 | Presence of both ≥10% BMPCs and M protein ≥3 g/dL, or if only 1 criterion was present, patients must have >95% aberrant plasma cells by immunophenotyping and immunoparesis | Induction with KRd followed by ASCT, KRd consolidation, and maintenance for 2 y | No | 90 | At 30-mo follow-up, ORR was 100% (≥CR 76%), and MRD negativity (measured by NGF with LOD 10-6) of 63% | |
| ASCENT | 2 | High-risk was defined as presence of any 2 of the following: serum M spike >2 g/dL or involved to uninvolved FLC ratio >20 or BMPC percentage >20%) or IMWG score ≥9 using risk scoring system using FLC ratio, serum M spike, marrow plasma cell percentage, and presence of high-risk FISH | 6 cycles of daratumumab plus KRd induction followed by additional 6 additional cycles of consolidation with daratumumab KRd and 1-y maintenance with daratumumab and lenalidomide | No | 46 | Pending (end point is sCR) | No treatment-related deaths were observed; grade ≥3 AEs were seen in 52% of patients |
| Kazandjian 2021 | 2 | Serum M protein ≥3 g/dL, IgA isotype, immunoparesis, sFLC ratio ≥8, clonal BMPCs 50%-60%, abnormal BMPC immunophenotype by flow; it also included criteria not previously included in SMM clinical trials: high-risk FISH abnormalities [t(4;14) or del(17p) or 1q gain], progressive increase in M protein level (evolving type of smoldering myeloma; increase in serum M protein by ≥25% on 2 successive evaluations within 6 mo), increased circulating plasma cells, and MRI with diffuse abnormalities or 1 focal lesion, PET/CT with focal lesion, increased uptake without underlying osteolytic bone destruction | KRd followed by 24 cycles of lenalidomide maintenance | No | 54 | Median rate of MRD-negative CR was 70% with median duration of 5.5 y; ORR was 100% and median duration of response was not reached with 96-mo duration of response of 77.4% | Nonhematologic grade 3 AEs were reported in 39% of cohort and included all-grade VTE in 11 patients (20%) and grade 3 VTE in 6 patients (11%); only 1 patient had grade 3 hypertension, 1 had grade 3 heart failure after 6 cycles and discontinued therapy, and 1 had grade 3 atrial fibrillation |
| Manasanch 2019 | 2 | Not reported in ASH abstract | Isatuximab monotherapy | No | 24 | ORR 63% (≥VGPR in 22%) | 5 grade 3 AEs that resolved to baseline; QOL was improved by end of cycle 6 |
| Nadeem 2021 | 2 | Defined criteria proposed by Rajkumar et al4 | Ixazomib plus Rd for 9 cycles followed by ixazomib and lenalidomide for 15 cycles for total of 24-mo period | No | 61 | ORR in participants who completed at least 2 cycles of treatment was 90.9% (CR, 21.8%; VGPR, 18.2%; PR, 50.9%) | No patients discontinued treatment because of toxicity; most common grade ≥3 toxicities were neutropenia (20%), hypophosphatemia (13%), leukopenia (11%), rash (9%), lymphocytopenia (5%), and thrombocytopenia (5%) |
AE, adverse event; CI, confidence interval; HR, hazard ratio; IgA, immunoglobulin A; LOD, limit of detection; ORR, overall response rate; PD, progressive disease; QOL, quality of life; VTE, venous thromboembolism.