Research progress on treatment of extramedullary multiple myeloma

Figures & data

Table 1. Incidence and outcome of EMM patients in selected available studies.

No. of MM patients	EMM incidence and classification	Therapy	PFS (EMM vs. MM)	OS (EMM vs. MM)	Author and Ref.
226	10% secondary EMB 14% secondary EMS	Conventional chemotherapy, novel agents, ASCT	Median time to progression after EMM relapse (5.4 months)	Median OS (38 vs. 109 months) Median OS EMB vs. EMS (45 vs. 30 months)	Pour et al. [3]
174	7.5% primary EMS 3% secondary EMS	Pomalidomide plus low-dose dexamethasone within a phase II clinical trial	Not provided	Median OS (16 months vs. not reached)	Short et al. [6]
3744	14.5% primary EMB 3.7% primary EMS	All patients received an upfront single ASCT within 12 months of diagnosis or a tandem ASCT within 6 months from first ASCT as first line therapy	EMB: 3-year PFS (50% vs. 47.9%) EMS: 3-year PFS (39.9% vs. 47.9%)	EMB: 3-year OS (77.7% vs. 80.1%) EMS: 3-year OS (58% vs. 80.1%)	Gagelmann et al. [15]
117	32.5% primary EMB 1.7% primary EMS 27.4% secondary EMB 16.2% secondary EMS	Eight clinical trials of first line treatment with bortezomib-based regimens, with or without lenalidomide		Median OS secondary EMB: 2.47 years secondary EMS: 0.9 years	Varga et al. [22]
329	14% primary EMM 28% secondary EMM (36% EMB, 52% EMS, 12% both)	Induction regimen with novel agents (thalidomide, lenalidomide, bortezomib), and ASCT		Median OS MM: 11years primary EMM vs. secondary EMM (3.1 vs. 2 years) EMS vs. EMB (1.6 vs. 2.4 years)	Mangiacavalli et al. [25]
2332	11.4% primary EMM (91% EMB, 4.5% EMS, 4.5% not classified)	Three trials enrolled transplant eligible and five trials transplant ineligible patients. Three trials included an IMiD, lenalidomide in almost all cases, three trials a PI, and four trials both. Six out of eight trials included maintenance	Median PFS (25.3 vs. 25.2 months) 5-year PFS (19% vs. 22%)	Median OS (63.5 vs. 79.9 months) 5-year OS (51% vs. 59%)	Montefusco et al. [54]
1965	Primary EMM: 2.41% in TT, 4.35% in non-TT, and 4.5% in non-protocol patients. Secondary EMM (5 years after ASCT): 3.43% in TT, 5.2% in non-TT, and 7.24% of non-protocol patients	ASCT within TT protocols, non-TT protocols, and non-protocol patients	Primary EMM: 5-year PFS (21% vs. 50%)	Primary EMM: 5-year OS (31% vs. 59%)	Usmani et al. [7]
1003	7% primary EMM (85% EMB and 15% EMS), 6% secondary EMM	Conventional chemotherapy (1971–1993), high-dose therapy for younger patients (1994–1999) and novel agents (2000–2007)	Median PFS (18 vs. 30 months)	Median OS (36 vs. 43 months)	Varettoni et al. [10]
70	14.3% secondary EMM (after transplants)	ASCT-allo-SCT or allo-SCT with reduced-intensity conditioning	NA	NA	Perez-Simon et al. [19]
172	20.4% secondary EMM (after transplants)	Sequential ASCT-allo-SCT. EMM were treated with donor lymphocyte infusion, radiotherapy, or chemotherapy, especially with novel agents	Median PFS did not differ significantly between patients with and without EMM at relapse	Median OS did not differ significantly between patients with and without EMM at relapse	Minnema et al. [20]
271	16.2% primary EMM (after transplants)	Induction regimen using novel agents, VAD, or alkylating agents. All patients underwent ASCT	Median PFS (18 vs. 44 months)	Median OS (32 vs. 100 months)	Kumar et al. [67]
663	1.2% primary EMS 6.3% secondary EMS 0.8% primary and secondary EMS (after transplants)	All 55 EMS patients received a median of 4 different treatment regimens prior to the development of EMS. All underwent ASCT and 15 also underwent allo-SCT		Median OS from EMM diagnosis was 1.3 years	Weinstock et al. [14]
488 (No. of EMM)	77% primary EMB 18% primary EMS 5% both	All 488 EMM patients received induction regimen with or without bortezomib. All patients underwent first line ASCT, tandem ASCT or auto-allogeneic transplant	4-year PFS first line ASCT: 43% tandem ASCT: 52% auto-allogeneic transplant: 58%	4-year OS first line ASCT: 70% tandem ASCT: 83% auto-allogeneic transplant: 88%	Gagelmann et al. [68]
226 (No. of EMM)	57.5% primary EMM (29.2% EMB and 70.8% EMS) 42.5% secondary EMM (12.5% EMB and 87.5% EMS)	Inittial therapy with IMiD-based or PI-based regimens followed by ASCT	Median PFS: primary EMB 51.7 months primary EMS 38.9 months secondary EMB 20.9 months secondary EMS 13.6 months	Median OS: primary EMB not reached primary EMS 46.5 months secondary EMB 39.8 months secondary EMS 11.4 months	Beksac et al. [69]

Pour L, Sevcikova S, Greslikova H, et al. Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse. Haematologica. 2014;99(2):360–364.

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Short KD, Rajkumar SV, Larson D, et al. Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma. Leukemia. 2011;25(6):906–908.

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Gagelmann N, Eikema DJ, Iacobelli S, et al. Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: A study from the chronic malignancies working party of the EBMT. Haematologica. 2018;103(5):890–897.

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Varga C, Xie W, Laubach J, et al. Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations. Br J Haematol. 2015;169(6):843–850.

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Mangiacavalli S, Pompa A, Ferretti V, et al. The possible role of burden of therapy on the risk of myeloma extramedullary spread. Ann Hematol. 2017;96(1):73–80.

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Montefusco V, Gay F, Spada S, et al. Outcome Of paraosseous extra-medullary disease in newly diagnosed multiple myeloma patients treated with new drugs. Haematologica. 2020;105(1):193–200.

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Usmani SZ, Heuck C, Mitchell A, et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica. 2012;97(11):1761–1767.

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Varettoni M, Corso A, Pica G, et al. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol. 2010;21(2):325–330.

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Perez-Simon JA, Sureda A, Fernandez-Aviles F, et al. Reduced-intensity conditioning allogeneic transplantation is associated with a high incidence of extramedullary relapses in multiple myeloma patients. Leukemia. 2006;20(3):542–545.

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Minnema MC, van de Donk NW, Zweegman S, et al. Extramedullary relapses after allogeneic non-myeloablative stem cell transplantation in multiple myeloma patients do not negatively affect treatment outcome. Bone Marrow Transplant. 2008;41(9):779–784.

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Kumar L, Gogi R, Patel AK, et al. Multiple myeloma with extramedullary disease: impact of autologous stem cell transplantation on outcome. Bone Marrow Transpl. 2017;52(10):1473–1475.

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Weinstock M, Aljawai Y, Morgan EA, et al. Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation. Br J Haematol. 2015;169(6):851–858.

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Gagelmann N, Eikema DJ, Koster L, et al. Tandem autologous stem cell transplantation improves outcome in newly diagnosed multiple myeloma with extramedullary disease and high-risk cytogenetics: a study from the chronic malignancies working party of EBMT. Biol Blood Marrow Transplant. 2019;25(11):2134–2142.

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Beksac M, Cengiz Seval G, Kanellias N, et al. A real world multicenter retrospective study on extramedullary disease from Balkan myeloma study group and Barcelona university: analysis of parameters that improve outcome. Haematologica. 2020;105(1):201–208.

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