Chromosomal 1q21 abnormalities in multiple myeloma: a review of translational, clinical research, and therapeutic strategies

Figures & data

Figure 1. Accumulation of 1q21+ clones.

IgH, immunoglobulin H; MGUS, monoclonal gammopathy of uncertain origin; MM, multiple myeloma; WT, wild type. Colors of the cells depict the development of abnormal MM cells as the disease progresses (green normal cells, blue MM cells). Adapted from Hanamura I. Cancers 2021;13:256 [10]. License MDPI, Basel, Switzerland adapted under a Creative Commons Attribution (CC BY) license and adapted with permission of the author.

Figure 2. Co-occurrence of high-risk cytogenetic abnormalities and genes associated with 1q21 abnormalities.

Pairwise associations between the cytogenetic aberrations present in ≥2% of 794 myeloma patients. Associations are defined with Fisher’s exact test; green color indicates a positive association, whereas purple color indicates a negative association between chromosomal abnormalities. The size of the circle depicts the significance of the q value. Unspecified IGH indicates at least one unspecified IGH abnormality. Adapted from Locher M, et al., Am J Hematol 2020;95:1562–71 [11]. Licensee Wiley Periodicals LLC, Chichester, UK and adapted under a Creative Commons Attribution (CC BY) license and adapted with permission of the authors.

Table 1. Impact of 1q21+ on outcomes in NDMM patients receiving VAD followed by high-dose chemotherapy and ASCT

Author, study design	Reference	No. evaluable patients	1q21+ prevalence	Comparison (1q21+ vs no 1q21+)
				PFS, mo (P value)	OS (P value)
Chang 2006 Single center retrospective observational study	[75]	99	31%	18.5 vs 25.7 (P= 0.035)	44.8 mo vs not reached (P= 0.20)
Nemec 2010 Subgroup analysis of a phase 3 RCT	[12]	91^a	41%	14.9 vs 27.4 (P= 0.044)	4-year: 40.1% vs 76.2% (P< 0.001)
Avet-Loiseau 2012 Subgroup analysis of two pooled RCTs	[5]	520	33%	No significant difference	Shorter OS: HR: 1.58, 95% CI: 1.14−2.19 (P= 0.006)

^a81 were included in the survival analysis.

ASCT, autologous stem cell transplantation; CI, confidence interval; HR, hazard ratio; mo, months; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival; RCT, randomized controlled trial; VAD, vincristine, doxorubicin, and dexamethasone.

Table 2. Impact of 1q21+ outcomes in NDMM patients receiving IMiDs and PIs followed by HDT/ASCT

Author, study design	Reference	No. evaluable patients	1q21+ prevalence	Treatment regimen	Comparison (1q21+ vs no 1q21+)
					PFS, mo (P value)	OS (P value)
Neben 2012 Subgroup analysis of a phase 3 RCT	[25]	344	32%	A. VAD then melphalan and ASCT with thalidomide maintenance B. PAD then melphalan and ASCT bortezomib maintenance	Overall 26.6 vs 39.3 (P= 0.0002) Amp1q21 vs normal 1q21: 17.6 vs 28.0 (P= 0.0062) Treatment B vs A 1q21+: 28.2 vs 23.6 (P= 0.22)	3-year OS Overall: 70% vs 82% (P= 0.0052) Amp1q21 vs normal 1q21: 52% vs 73% (P= 0.032) Treatment B vs A 1q21+: 77 mo vs 62 mo (P= 0.1)
Bock 2016 Single center, retrospective, observational study^a	[76]	58	NA	IMiD or PI or IMiD+PI induction therapy followed by high-dose melphalan and ASCT	15.0 vs 33.0 (P= 0.0018)	2-year OS: 62% vs 91% (P= 0.018)
Shah 2017 Single center, retrospective, observational study	[77]	95	21%	Rd, Vd, or RVd followed by ASCT	2.1 vs 4.3 yr (P= 0.003)	4.4 yr vs not reached (P= 0.005) 2-year OS: 80% vs 93% 3-year OS: 65% vs 86%
Schmidt 2019 Single center, retrospective, observational study	[55]	157	44%	RVd followed by ASCT	42.1 vs 71.5 (P= 0.002)	5-year: 67% vs 88% (P= 0.006)
Varma 2020 Single center, retrospective, observational study^a,b	[54]	85^b	NA	Triplet-based induction (PI, d, and an IMiD or cyclophosphamide) followed by melphalan and ASCT	26.5 vs 38.8 (P= 0.09) 3-year PFS: 41% vs 56%	Not reached vs 81.1 mo (P= 0.73)
Abdallah 2020 Single center, retrospective, observational study	[4]	581	42%	IMiD or PI-based treatment or IMiD+PI-based treatment followed by ASCT	NR	7.5 vs 11.1 yr (P< 0.001)
D’Agostino 2020 Subgroup analysis of a phase 2 trial	[26]	474	32% had Gain1q 13% had Amp1q	Carfilzomib + Rd induction followed by ASCT	Gain1q vs normal 1q: HR: 1.65 (95% CI: 1.14–2.37; P= 0.007) Amp1q vs normal 1q: HR: 3.04 (95% CI: 1.99–4.65; P< 0.001) Amp1q vs Gain1q: HR: 1.84 (95% CI: 1.21–2.81; P= 0.004)	Gain1q vs normal 1q: HR: 1.88 (95% CI: 0.98–3.58; P= 0.056) Amp1q vs normal 1q: HR: 5.88 (95% CI: 3.10–11.17; P< 0.001) Amp1q vs Gain1q: HR: 3.13 (95% CI: 1.73–5.68; P< 0.001)

^aPropensity score matched analysis.

^bAll patients also had 1p deletion.

ASCT, autologous stem cell transplantation; CI, confidence interval; d, dexamethasone; HDT, high-dose therapy; HR, hazard ratio; IMiDs, immunomodulatory drugs; mo, months; NA, not applicable; NDMM, newly diagnosed multiple myeloma; NR, not reported; OS, overall survival; P, pomalidomide; PAD, bortezomib, doxorubicin and dexamethasone; PFS, progression-free survival; PI, proteasome inhibitors; R, lenalidomide; RCT, randomized controlled trial; V, bortezomib; VAD, vincristine, doxorubicin, dexamethasone; yr, years.

Table 3. Impact of 1q21+ on outcomes in RRMM patients receiving therapeutic monoclonal antibodies

Author, study design	Reference	No. of evaluable patients	1q21+ prevalence	Treatment regimen	Comparison mAb arm vs control arm in patients with 1q21+ and non-1q21+
					PFS		OS
					1q21+	non-1q21+	1q21+	non-1q21+
Lonial 2015 Dimopoulos 2020 Subgroup analysis of a phase 3 RCT	[92,93]	646	48%	Elotuzumab + Rd vs Rd	HR: 0.75 (95% CI: 0.56–0.99)	NA	HR: 0.81 (95% CI: 0.61–1.06)	HR: 0.89 (95% CI: 0.68–1.16)
Dimopoulos 2018 Subgroup analysis of a phase 2 RCT	[94]	117	44%	Elotuzumab + Pd vs Pd	HR: 0.56 (95% CI: 0.29–1.09)	HR: 0.43 (95% CI: (0.15–1.24)	NR	NR
Usmani 2021 SWOG-1211 Phase 1/2 trial	[95]	100	47%	Elotuzumab + RVd vs RVd	HR: 0.761 (80% CI: 0.459–1.261) Median PFS: 32 mo (95% CI: 18 mo–NR) vs 41 mo (95% CI: 22 mo–NR)	NA	NR	NR
Mohan 2020 Single center, prospective, observational study	[100]	81	44%	Daratumumab or daratumumab + other agents	Median PFS: 0.5 yr (95% CI: 0.3–1.4 yr)	Median PFS: 2.1 yr (95% CI: 1.9 yr–NR)	Median OS: 0.9 yr (95% CI: 0.7–2.3 yr)	Median OS: NR (95% CI: 1.9 years–NR)
Harrison 2021 Subgroup analysis of a phase 3 RCT	[106]	307	41.7%	Isa-Pd vs Pd	Median PFS: 9.5 vs 3.8 mo HR: 0.40 (95% CI: 0.25–0.63)	Median PFS: 11.6 vs 9.8 mo HR: 0.75 (95% CI: 0.40–1.41)	NR	NR
Spicka 2021 NCT03275285 Subgroup analysis of a phase 3 RCT	[108]	302	41%	Isa-Kd vs Kd	Median PFS: NR vs 16.2 mo HR: 0.46 (95% CI: 0.22–0.97)	Median PFS: NR vs 20.3 mo HR: 0.40 (95% CI: 0.20–0.79)	NR	NR

CI, confidence interval; d, dexamethasone; HR, hazard ratio; Isa, isatuximab; K, carfilzomib; Mab, monoclonal antibodies; mo, months; NR, not reported; OS, overall survival; P, pomalidomide; PFS, progression-free survival; RBd, lenalidomide, bortezomib and dexamethasone; RVd, lenalidomide, bortezomib and dexamethasone; RRMM, relapsed/refractory multiple myeloma; yr, year.

Figure 3. Targeting 1q specific vulnerabilities: Important gene located on chromosome 1q21 band and on 1q arm.

Adapted from Garcia JB, et al Cells 2021;10:1360 [107]. License MDPI, Basel, Switzerland adapted under a Creative Commons Attribution (CC BY) licenseHanamura I. Cancers 2021;13:256 [10]. License MDPI, Basel, Switzerland adapted under a Creative Commons Attribution (CC BY) license and adapted with permission of the authors

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