Solitary plasmacytoma

Introduction

In the International Myeloma Working Group (IMWG) classification, solitary plasmacytomas of bone or soft tissue are defined as meeting the four criteria of (1) biopsy-proven plasmacytoma of bone or soft tissue with evidence of clonal plasma cells, (2) normal bone marrow with no evidence of clonal plasma cells, (3) normal bone X-ray and MRI (or CT) of spine and pelvis (except for the solitary plasmacytoma lesion), and (4) absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) [1]. Solitary plasmacytomas of bone or soft tissue with minimal marrow involvement are further defined as meeting the four criteria of (1) biopsy-proven plasmacytoma of bone or soft tissue with evidence of clonal plasma cells, (2) clonal bone marrow plasma cells < 10%, (3) normal bone X-ray and MRI (or CT) of spine and pelvis (except for the solitary plasmacytoma lesion), and (4) absence of CRAB [1].

Solitary soft tissue plasmacytomas develop at sites such as the nasal cavity, paranasal sinuses, gastrointestinal tract, lungs, thyroid, orbital fossa, and lymph nodes. Over 80% are located in the upper respiratory tract or upper gastrointestinal tract, and many in the upper respiratory tract are located in the paranasal sinuses. Initial symptoms and clinical presentation differ by tumor site. Solitary soft tissue plasmacytomas generally have an indolent course, and only rarely progress to multiple myeloma. In contrast, solitary bone plasmacytomas are prone to progression to multiple myeloma. In a relatively recent study, five-year overall survival (OS) and disease-free survival (DFS) rates after diagnosis of solitary bone plasmacytoma were 70% and 46%, respectively, with approximately half of cases transitioning to multiple myeloma by 5 years [2]. The mean time to transition to multiple myeloma was 21 months after diagnosis. Once a plasmacytoma has progressed to multiple myeloma, the prognosis is equally poor to that of multiple myeloma. Progression to multiple myeloma is generally believed to determine prognosis. In a study that analyzed the outcome of 1472 patients diagnosed with solitary plasmacytoma in the United States from 1998 to 2004, OS and disease-specific survival (DSS) rates increased as patient age decreased, and both OS and DSS rates were significantly poorer for solitary bone plasmacytomas than solitary soft tissue plasmacytomas [3]. DSS rates plateaued at 50% for solitary bone plasmacytomas and at 80% for solitary soft tissue plasmacytomas, demonstrating the major difference in cure rates between the two types.

The main local therapies are radiotherapy and surgical resection. Chemotherapy may also be considered depending on the tumor site and treatment progress. Plasmacytomas are generally considered to be sensitive to radiotherapy, but due in part to the small patient population, details of radiotherapy such as the optimal dose have not been adequately studied and there is no established standard therapy. Young age and a tumor diameter smaller than 5 cm have been identified as favorable prognostic factors [4], and tumor size at diagnosis and presence of M-protein in protein fractions as factors that may predict progression to multiple myeloma [5].

References

1. Rajkumar SV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–48.

2. Knobel D, et al. Prognostic factors in solitary plasmacytoma of the bone: a multicenter Rare Cancer Network study. BMC Cancer. 2006;6:118. (3iiiA)

3. Dores GM, et al. Plasmacytoma of bone, extramedullary plasmacytoma, and multiple myeloma: incidence and survival in the United States, 1992-2004. Br J Haematol. 2009;144(1):86–94. (3iA)

4. Nanni C, et al. 18F-FDG PET/CT in myeloma with presumed solitary plasmocytoma of bone. In Vivo. 2008;22(4):513–7. (3iiDiv)

5. Holland J, et al. Plasmacytoma. Treatment results and conversion to myeloma. Cancer. 1992;69(6):1513–7. (3iiiDiv)


CQ 1 Does adjuvant chemotherapy after primary radiotherapy delay progression of solitary plasmacytoma to multiple myeloma?

figure a

Explanation

Progression of solitary plasmacytoma to multiple myeloma results in a poor prognosis. In one study of 258 patients with solitary plasmacytoma (206 of bone, 52 of soft tissue), 214 patients received radiotherapy alone and 34 received radiotherapy along with a median of six cycles of chemotherapy (22 with melphalan and prednisone [MP regimen]; 7 with vincristine, doxorubicin, and dexamethasone [VAD regimen]; and 5 with other combination regimens). Over a mean follow-up period of 56 months, the median time to progression to multiple myeloma was 21 months [1]. The 10-year rate of progression to multiple myeloma was 64% in patients who underwent radiotherapy alone and 74% in patients who received additional chemotherapy, indicating that there was no benefit to adding chemotherapy. In addition, the prognosis of tumors with a diameter less than 4 cm was better than the prognosis of tumors with a diameter of 4 cm or more. In summary, addition of combination chemotherapy such as the MP regimen to local radiotherapy has not been shown to be useful for solitary plasmacytoma. On the contrary, this approach can increase the risk of complications such as secondary leukemia. MRI of the vertebrae and ilium was not performed in studies conducted before the publication of the IMWG diagnostic criteria, so it is possible that multiple myeloma would be diagnosed in some of these patients if they had undergone a detailed MRI or PET/CT evaluation as is now possible today. Moreover, no previous study used novel agents. Future research in a large number of patients diagnosed more rigorously using imaging modalities such as PET/CT and MRI for determining whether the lesion is truly solitary should be conducted to evaluate whether solitary tumor size at diagnosis and the presence of monoclonal plasma cells not meeting the diagnostic criteria for multiple myeloma regarding M-protein and iliac bone marrow aspiration could be risk factors for progression to multiple myeloma and whether adjuvant chemotherapy with novel agents could slow progression to multiple myeloma in patients with such risk factors.

References

1. Ozsahin M, et al. Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients. Int J Radiat Oncol Biol Phys. 2006;64(1):210–7. (3iiA)

Light chain (AL) amyloidosis

Overview

Light chain (AL) amyloidosis is a disease in which systemic deposition of amyloid proteins derived from the light chain of monoclonal immunoglobulin (M-protein) produced by abnormal plasma cells causes various organ damage [1, 2]. A disease caused by deposition of proteins from the immunoglobulin heavy chain is called AH amyloidosis and is extremely rare. Together, these conditions are called immunoglobulin-related amyloidosis. When AL amyloidosis develops in the absence of underlying diseases such as multiple myeloma or primary macroglobulinemia, it is called primary AL amyloidosis, and when it develops secondary to an underlying disease it is called secondary AL amyloidosis. However, these two diseases are difficult to differentiate in some cases and, thus, are both classified as primary amyloidosis in the 2017 WHO classification [3]. In addition, the disease is called systemic when lesions are present in two or more organs and localized when lesions are localized to one organ. AL amyloidosis is a rare disease and was estimated to affect 3200 patients between 2012 and 2014 in a national epidemiological survey conducted in 2014 [4]. Amyloid proteins deposit in various organs including the heart, kidneys, liver, gastrointestinal tract, and peripheral nervous system, causing a variety of clinical symptoms. Definitive diagnosis is based on pathological findings. Specimens must stain reddish orange with Congo red and exhibit green birefringence under a polarizing microscope. The type of AL amyloidosis is determined by immunostaining with anti-immunoglobulin light chain antibody. When the type cannot be determined, samples from sites of amyloid deposition are collected by laser microdissection and mass spectrometry is performed. Serum and urine protein electrophoresis and immunofixation electrophoresis are performed to detect M-protein, but measurement of free light chain (FLC) is useful due to its high sensitivity. Amyloidosis has a poor prognosis; median survival time after diagnosis in untreated patients is approximately 13 months, and the prognosis is particularly poor in patients with cardiac lesions. The objective of treatment is to promptly suppress production of the monoclonal FLCs that are the source of the amyloid protein to conserve organ function. Eligibility for autologous peripheral blood stem cell transplantation should be considered carefully due to its high treatment-related mortality (TRM) associated with organ damage, and it is important to consider whether to reduce the conditioning dose based on risk when performing this treatment [5–7]. Melphalan plus dexamethasone and low-dose dexamethasone are recommended for patients who are not eligible for autologous peripheral blood stem cell transplantation, but recent studies have shown that bortezomib and other novel agents are useful as well for multiple myeloma [8–11].

References

1. Falk RH, et al. The systemic amyloidosis. N Engl J Med. 1997;337(13):898–909.

2. Merlini G, et al. Dangerous small B cell clones. Blood. 2006;108(8):2520–30.

3. Mckenna RW, et al. Plasma cell neoplasms. Swerdlow SH, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC. 2017, pp 254–5.

4. Ando Y. 2015 Annual Report. The Amyloidosis Research Committee, Intractable Disease Division, of the Japanese Ministry of Health and Welfare. 2016, pp 1–23.

5. Jaccard A, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 2007;357(11):1083–93. (1iiA).

6. Comenzo R, et al. Autologous stem cell transplantation for primary systemic amyloidosis. Blood. 2002;99(12):4276–82.

7. Skinner M, et al. High-dose melphalan and autologous stem cell transplantation in the patients with AL amyloidosis: An 8-year study. Ann Intern Med. 2004;140(2):85–93. (3iiiA).

8. Palladini G, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with in AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004;103(8):2936–38. (3iiiDiv).

9. Palladini G, et al. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015;126(5):612–5. (3iiiA).

10. Shimazaki C, et al. Phase 1 study of bortezomib in combination with melphalan and dexamethasone in Japanese patients with relapsed AL amyloidosis. Int J Hematol. 2016;103(1):79–85. (3iiiDiv).

11. Shimazaki C, et al. Nationwide survey of 741 patients with systemic amyloid light-chain amyloidosis in Japan. Intern Med. 2017;57(2):181–7.

Algorithm

figure g

MEL/DEX: melphalan/dexamethasone, BOR: bortezomib, LEN: lenalidomide, BMD: bortezomib/melphalan/dexamethasone, BCD: bortezomib/cyclophosphamide/dexamethasone, CTD: cyclophosphamide/thalidomide/dexamethasone.

*Not covered by Japanese National Health Insurance.

The first step is to carefully consider eligibility for autologous transplantation (AL: CQ1, evidence level 2A). If the patient is eligible for autologous transplantation, melphalan dose reduction should also be considered based on risk. The patient should be observed without further treatment if a complete response (CR) is achieved. If the patient is not eligible for transplantation, melphalan and dexamethasone are recommended as standard therapy (AL: CQ2, evidence level 1iiA). In the case of relapse or failure to achieve VGPR, the use of novel agents such as bortezomib and lenalidomide should be considered.


CQ 1 Does autologous hematopoietic stem cell transplantation with high-dose melphalan improve the prognosis of systemic amyloidosis?

figure b

Explanation

In a retrospective analysis of autologous peripheral blood stem cell transplantation for AL amyloidosis, mean OS was 4.6 years and OS in patients with CR who survived at least 1 year was over 10 years [1]. A hematologic CR was achieved in 40% of patients, and 66% of those patients showed improvement in at least one organ. This treatment was reported to have greater benefit than standard chemotherapy in a case–control study [2]. However, an Intergroupe Francophone du Myélome (IFM) study, which is the only randomized study to date, compared high-dose melphalan followed by autologous transplantation with standard-dose melphalan plus high-dose dexamethasone and showed that OS was significantly better in the group that underwent chemotherapy alone than in the group that also underwent autologous transplantation (56.9 months vs. 22.2 months, p = 0.04) [3]. There was no significant difference in OS in the high-risk group, but 3-year OS rates in the low-risk group were 58% for high-dose melphalan plus autologous transplantation and 80% for melphalan plus high-dose dexamethasone. However, several design problems have been noted in this study, including lenient eligibility criteria for transplantation causing inclusion of some patients with severe disease in the transplantation group, the resulting high TRM (24%) in the transplantation group, the small number of patients who underwent transplantation, and the short follow-up period. Consequently, it is not considered as the evidence against autologous transplantation. TRM can be reduced to approximately 5% by strict compliance with transplantation eligibility criteria and reduction of the melphalan dose used for conditioning in accordance with risk, and autologous hematopoietic stem cell transplantation (HSCT) should be considered at an experienced institution [1, 4–6].

References

1. Skinner M, et al. High-dose melphalan and autologous stem cell transplantation in the patients with AL amyloidosis: An 8-year study. Ann Intern Med. 2004;140(2):85–93 (3iiiA).

2. Dispenzieri A, et al. Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: A case–control study. Blood. 2004;103(10):3960–3. (2A).

3. Jaccard A, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007;357(11):1083–93. (1iiA).

4. Comenzo R, et al. Autologous stem cell transplantation for primary systemic amyloidosis. Blood. 2002;99(12):4276–82.

5. Wechalekar AD, et al. Perspectives in treatment of AL amyloidosis. Br J Haematol. 2007;140(4):365–77.

6. D’Souza A, et al. Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a center for International Blood and Marrow Transplant Research Study. J Clin Oncol. 2015;33(32):3741–9. (3iiiA).


CQ 2 What treatment is recommended for transplant-ineligible patients withsystemic AL amyloidosis?

figure c

Explanation

No standard therapy has been established for AL amyloidosis in transplant-ineligible patients. A randomized trial comparing the MP regimen with colchicine demonstrated the superiority of the MP regimen, but this regimen cannot be recommended due to the short mean survival time of 18 months [1]. After that, the VAD regimen and high-dose dexamethasone were used, but these are not recommended due to the neurotoxicity of vincristine, the cardiotoxicity of doxorubicin, and the toxicity of high-dose dexamethasone. MD (melphalan plus dexamethasone) is the most commonly used regimen today. In a study of 96 patients, a hematologic response of PR or better was achieved in 67% of patients, time to response was short (within 4.5 months), and functional improvement in involved organs was observed in 48% of patients [2]. This therapy was very tolerable and mean survival time and progression-free survival (PFS) in subsequent long-term follow-up were 5.1 years and 3.8 years, respectively [3]. A randomized controlled trial comparing the MD regimen with autologous transplantation also demonstrated the usefulness of the MD regimen, with median survival time of 56.9 months [4]. However, it has limited efficacy in patients with serious cardiac damage. Recent studies have shown novel agents such as bortezomib to be useful, and though these drugs are becoming more widely used, currently there are not sufficient data on their efficacy or safety [5–7].

References

1. Kyle RA, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone and colchicines. N Engl J Med. 1997;336(17):1202–7. (1iA).

2. Palladini G, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with in AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004;103(8):2936–8. (3iiiDiv).

3. Palladini G, et al. Treatment with oral melphalan plus dexamethasone produces long-term remission in AL amyloidosis. Blood. 2007;110(2):787–8. (3iiiDiv).

4. Jaccard A, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007;357(11):1083-93. (1iiA).

5. Palladini G, et al. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015;126(5):612–5. (3iiiA).

6. Shimazaki C, et al. Phase 1 study of bortezomib in combination with melphalan and dexamethasone in Japanese patients with relapsed AL amyloidosis. Int J Hematol. 2016;103(1):79–85. (3iiiDiv).

7. Shimazaki C, et al. Nationwide survey of 741 patients with systemic amyloid light-chain amyloidosis in Japan. Intern Med. 2017;57(2):181–7.

POEMS syndrome

Overview

POEMS syndrome (also known as Crow–Fukase syndrome and Takatsuki disease) is a systemic disorder associated with an underlying plasma cell dyscrasia presenting peripheral neuropathy due to polyneuritis; organomegaly (hepatosplenomegaly); endocrinopathy; edema, pleural effusion, and ascites; skin symptoms (hair bristling, hyperpigmentation, and hemangioma); sclerotic bone lesions; and monoclonal gammopathy. Though rare, its incidence is higher in Japan than in Western countries. Of its varied symptoms, peripheral neuropathy has a particularly damaging effect on a patient’s activities of daily living (ADL), progressing to limb paralysis and multiple organ failure in its terminal stage and has a poor prognosis. Although the pathology of POEMS syndrome is not well understood, it is conjectured that an abnormally high serum concentration of vascular endothelial growth factor (VEGF) triggers a variety of symptoms [1]. Patients with this syndrome have a very low M-protein level, and it is almost always of the lambda type. This rearranged lambda light chain belongs to the Vλ1 subfamily and was found to be derived from just two germline genes [2].

Table 1 Diagnostic criteria for POEMS syndrome [3]

Mandatory major criteria

 1. Polyneuritis (typically demyelinating)

 2. Monoclonal plasma cell proliferative disorder (almost always λ)

Other major criteria (one required)

 3. Castleman diseasea

 4. Sclerotic bone lesions

 5. VEGF elevation

Minor criteria

 6. Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)

 7. Extravascular volume overload (edema, pleural effusion, or ascites)

 8. Endocrinopathy (adrenal, thyroidb, pituitary, gonadal, parathyroid, pancreasb)

 9. Characteristic skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangioma, plethora, acrocyanosis, flushing, white nails)

10. Papilledema

11. Thrombocytosis/polycythemiac

Other symptoms and signs

Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease, thrombotic diathesis, diarrhea, low vitamin B12 values

  1. A diagnosis of POEMS syndrome requires that all the mandatory criteria are met, at least one of the other major criteria is met, and at least one of the minor criteria is met
  2. aThere is a Castleman disease variant of POEMS syndrome that occurs without obvious monoclonal plasma cell proliferation
  3. bBecause of the high prevalence of diabetes mellitus and thyroid abnormalities, this diagnosis alone is not sufficient to meet this minor criterion
  4. cAnemia and/or thrombocytopenia are distinctively unusual in this syndrome unless Castleman disease is present

Table 1 lists diagnostic criteria for POEMS syndrome [3]. Peripheral neuritis and an increase in monoclonal plasma cells (lambda type) are mandatory, and elevated VEGF is also required (note that VEGF measurement has not been approved in Japan). In addition to hematologic response criteria, another set of response criteria that consider other factors such as VEGF response and improvement in clinical symptoms has been proposed [4].

Due to the rarity of this disease, it has never been investigated in a large prospective randomized controlled study. Recently, treatment targeted at plasma cells as is performed for multiple myeloma with autologous HSCT and novel agents such as thalidomide have been shown to be effective, and treatment outcomes and prognosis have improved considerably. Surgical resection and radiotherapy have been shown to be effective in patients with plasmacytomas. Patients with POEMS syndrome have poor performance status (PS) due to peripheral neuropathy, but the peripheral neuropathy is reversible and, thus, PS improves along with peripheral neuropathy in patients who respond to treatment. Therefore, these points must also be considered when deciding on a course of treatment.

References

1. Watanabe O, et al. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome. Lancet. 1996;347(9002):702.

2. Abe D, et al. Restrictive usage of monoclonal immunoglobulin lambda light chain germline in POEMS syndrome. Blood. 2008;112(3):836–9.

3. Dispenzieri A. POEMS syndrome: 2017 Update on diagnosis, risk stratification, and management. Am J Hematol 2017;92(8):814–29.(Review).

4. D’Souza A, et al. Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood. 2012;120(1):56–62. (3iiA).


CQ 1 What treatments are recommended for transplant-ineligible patients and patients with relapsed or refractory disease?

figure d

Explanation

No standard therapy has been established for patients with POEMS syndrome who are ineligible for transplantation due to the age of 65 years or older or organ failure or those who have relapsed or refractory disease. Chemotherapy regimens and novel agents used for multiple myeloma have been tried.

In 2011, a study by Li et al. showed that melphalan plus dexamethasone (MDex regimen) was effective in patients with newly diagnosed POEMS syndrome [1]. A hematologic response was achieved in 25 of 31 patients (80.6%), and a CR defined as disappearance of M-protein was achieved in 12 patients (38.7%). Neurological improvements and reduction of serum VEGF level were observed in all patients.

As for novel agents, thalidomide has been demonstrated effective in studies mainly conducted in Japan, and lenalidomide and bortezomib were later shown to be effective as well. However, none of these treatments is covered by Japanese National Health Insurance.

Thalidomide is a potent suppressor of VEGF production and is theoretically suited to treating POEMS syndrome. Kuwabara et al. treated transplant-ineligible patients with thalidomide plus dexamethasone (Td regimen) and observed favorable outcomes such as reduced serum VEGF levels and improvement in peripheral neuropathy [2]. A multicenter randomized placebo-controlled study (the J-POST trial) was subsequently conducted in Japan [3]. This study was an investigator-initiated clinical trial aiming to expand the indications of thalidomide. Patients were allocated to receive either the Td regimen or placebo plus dexamethasone for 24 weeks, and patients in the control group who progressed on treatment were switched to the Td regimen. The rate of serum VEGF reduction after 24 weeks, which was the primary endpoint, was significantly better with the Td regimen [4]. The Td regimen is associated with a high incidence of adverse events such as bradycardia and venous thrombosis, so it is necessary to be cautious of these.

Lenalidomide has a lower rate of peripheral neuropathy than thalidomide, and has been shown to be effective. Royer et al. retrospectively analyzed data from 20 patients who received lenalidomide plus dexamethasone (Rd regimen), including 4 newly diagnosed patients [5]. A response was achieved in 19 patients, and VGPR or better was achieved in 68% of patients. A significant decrease in serum VEGF level was observed in all 17 evaluable patients. Nozza et al. also conducted a prospective single-arm clinical study with the Rd regimen alone and observed neurological or clinical improvement in 13 of 18 patients (72%) and 3-year PFS rate of 59% [6].

Though the high rate of peripheral neuropathy seen with bortezomib is concerning as it could exacerbate peripheral neuropathy already occurring with POEMS syndrome, bortezomib has also been shown to be effective [7]. However, this finding has only been reported in case reports. Subcutaneous injection of bortezomib is recommended as it can reduce the severity of bortezomib-induced peripheral neuropathy.

References

1. Li J, et al. Combination of melphalan and dexamethasone for patients with newly diagnosed POEMS syndrome. Blood. 2011;117(24):6445–9. (3iiA).

2. Kuwabara S, et al. Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome. J Neurol Neurosurg Psychiatry. 2008;79(11):1255–7. (3iiDiv).

3. Katayama K, et al. Japanese POEMS syndrome with Thalidomide (J-POST) Trial: study protocol for a phase II/III multicentre, randomised, double-blind, placebo-controlled trial. BMJ Open. 2015;5(1):e007330. (1iDiv).

4. Misawa S, et al. Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2016;15(11):1129–37. (1iDiv).

5. Royer B, et al. Efficacy of lenalidomide in POEMS syndrome: a retrospective study of 20 patients. Am J Hematol. 2013;88(3):207–12. (3iiA).

6. Nozza A, et al. Lenalidomide and dexamethasone in patients with POEMS syndrome: results of a prospective, open-label trial. Br J Haematol. 2017;179(5):748–55. (2Diii).

7. Tang X, et al. Successful bortezomib-based treatment in POEMS syndrome. Eur J Haematol. 2009;83(6):609–10. (3iiiDiv).


CQ 2 Does high-dose melphalan with autologous hematopoietic stem cell transplantation improve the prognosis of POEMS syndrome?

figure e

Explanation

Mean survival time for POEMS syndrome was poor (33 months) during the period when it was primarily treated with corticosteroids, up through the 1980s. Mean survival time later improved to 5 to 10 years in the 1990s when the MP regimen was performed, but the treatment was not very effective and even patients with PR relapsed quickly [1]. The rate of secondary myelodysplasia syndrome was also high with long-term use.

Around 2000, studies began showing that high-dose melphalan with autologous HSCT was effective in patients younger than 65 years, and a case report of 16 Mayo Clinic patients was published in 2004 [2] Neurological improvement was observed in all 14 evaluable patients, and all 9 patients who needed to use a wheelchair before transplantation became able to walk unassisted. Long-term outcomes in 59 Mayo Clinic patients were also published in 2012 [3]. Over a median follow-up period of 45 months, one- and five-year PFS rates were 98% and 75%, respectively, and five-year OS rate was 94%. In a retrospective analysis by the European Society for Blood and Marrow Transplantation (EBMT) of 127 patients who underwent autologous HSCT between 1997 and 2010, median age was 50 years (range 26-69 years) and median time from diagnosis to transplantation was 7.5 months. Engraftment syndrome was observed at a rate of 23%. A hematologic CR was achieved in 48.5% of patients, and 3-year PFS and OS rates were 84% and 94% [4].

In Japan, autologous HSCT was demonstrated effective in 4 patients with early disease at a single institution [5], and 5-year OS and PFS rates were later reported as 90% and 63%, respectively, in a study of 36 patients [6]. In a retrospective analysis using the Japan Society for Hematopoietic Stem Cell Transplantation database [7], data from 95 patients who underwent autologous HSCT between 2000 and 2011 were evaluated. Median age was 53 years (range 28-72 years) and engraftment syndrome was observed in 11 patients (15.7%), which was a lower rate than in the Mayo Clinic and EBMT studies. Three-year PFS and OS rates were 78.3% and 88.8%, respectively. PS improved significantly after transplantation due to improvement in neurological findings.

Patients with POEMS syndrome have poor PS and tend to develop fluid retention due to increased vascular permeability, so greater caution must be exercised regarding transplantation-related toxicity in these patients compared to patients with multiple myeloma. According to the above-mentioned Mayo Clinic report from 2004, six of 16 patients required treatment in the intensive care unit after transplantation, five of those patients required artificial ventilation, and one died. High rates of engraftment syndrome have also been reported [8]. Therefore, as described in CQ3, it is best to perform induction therapy using novel agents in transplant-eligible patients and delay transplantation until improvement in PS and reduction in serum VEGF level is observed.

References

1. Kuwabara S, et al. Long term melphalan-prednisolone chemotherapy for POEMS syndrome. J Neurol Neurosurg Psychiatry. 1997;63(3):385–7. (3iiA).

2. Dispenzieri A, t al. Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood. 2004;104(10):3400–7. (3iiA).

3. D’Souza A, et al. Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood. 2012;120(1):56–62. (3iiA).

4. Cook G, et al. High-dose therapy and autologous stem cell transplantation in patients with POEMS syndrome: a retrospective study of the Plasma Cell Disorder sub-committee of the Chronic Malignancy Working Party of the European Society for Blood & Marrow Transplantation. Haematologica. 2017;102(1):160–7. (3iiA).

5. Kuwabara S, et al. Autologous peripheral blood stem cell transplantation for POEMS syndrome. Neurology. 2006;66(1):105–7. (3iiDiv).

6. Ohwada C, et al. Long-term evaluation of physical improvement and survival of autologous stem cell transplantation in POEMS syndrome. Blood. 2018;131(19):2173–6.(3iiA).

7. Kawajiri-Manako C, et al. The Efficacy and Long-Term Outcomes of Autologous Stem Cell Transplantation in POEMS Syndrome: A Nation-wide Survey in Japan. Biol Blood Marrow Transplant. 2018;24(6):1180–6. (3iiA).

8. Dispenzieri A, et al. Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome. Eur J Haematol. 2008;80(5):397–406. (3iiDiv).


CQ 3 What is the recommended regimen for primary induction therapy in transplant-eligible patients?

figure f

Explanation

Patients with POEMS syndrome have poor PS due to peripheral neuropathy and tend to develop systemic fluid retention, which causes them to experience higher transplantation-related toxicity including engraftment syndrome when undergoing autologous transplantation without prior treatment [1]. Serum VEGF is a biomarker of response to treatment, and VEGF level after transplantation is a strong prognostic factor for relapse [2]. Therefore, as is done in multiple myeloma, it is best to take a safer approach to transplantation by performing appropriate induction therapy and waiting for improvement in PS and reduction in serum VEGF before transplantation. Studies conducted to date have shown thalidomide and other novel agents to be effective in transplant-ineligible patients and relapsed/refractory patients [3], and thalidomide plus dexamethasone has been shown to be effective as induction therapy even in transplant-eligible patients [4]. Thalidomide should be started at 100 mg/day and the dose should then be adjusted based on response and adverse reactions. Treatment with lenalidomide plus dexamethasone or with bortezomib should be considered in non-responders to thalidomide. Lenalidomide treatment must be kept short (3–4 cycles) to avoid a reduction in stem cell harvesting efficiency. At present, these novel agents are not covered by Japanese National Health Insurance for the indication of POEMS syndrome.

References

1. Dispenzieri A, et al. Peripheral blood stem cell transplant for POEMS syndrome is associated with high rates of engraftment syndrome. Eur J Haematol. 2008;80(5):397–406. (3iiDiv).

2. Misawa S, et al. Vascular endothelial growth factor as a predictive marker for POEMS syndrome treatment response: retrospective cohort study. BMJ Open. 2015;5(11):e009157. (3iiDiv).

3. Kuwabara S, et al. Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome. J Neurol Neurosurg Psychiatry. 2008;79(11):1255-7. (3iiDiv).

4. Nakaseko C. Autologous stem cell transplantation for POEMS syndrome. Clin Lymphoma Myeloma Leuk. 2014;14(1):21–3. (3iiA).