Page 44 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - IgM monoclonal gammopathies of clinical significance J. Khwaja et al.
Figure 3. Management of IgM-associated amyloidosis. *Histological assessment includes targeting affecting organ, consider abdominal fat biopsy. Exclude other acquired and hereditary amyloidoses. **Organ assessment includes comprehensive evaluation of organs including cardiac, renal, neurological, gastrointestinal and soft tissue involvement. M-protein: monoclonal protein; SPEP: serum protein electrophoresis; SFLC: serum free light chains; LPL: lymphoplasmacytic lymphoma; CT: computed tomography; PET: positron emission tomography; MRI: magnetic resonance imaging; PPCN: pure plasma cell neoplasm; R- Bendamustine: rituximab plus bendamustine; BEAM: carmustine, etoposide, cytarabine, melphalan; Mel, melphalan; ASCT: autologous stem cell transplantation; AL: AL amyloidosis.
poorer outcomes. These findings need independent con- firmation to hone treatment approaches.
Treatment
There are no consensus guidelines, approved treatments or prospective clinical trials for IgM amyloidosis. The aims of treatment are to reduce the clonal burden and improve performance status with a view to extending survival. A treatment algorithm is summarized in Figure 3. Evidence is largely limited to retrospective series with heterogene- ous regimens. Criteria developed for response assessment in non-IgM AL amyloidosis are applicable to IgM-associ- ated AL amyloidosis with assessment of hematologic re- sponse and organ response. Response assessment by both free light chains and M-protein had prognostic sig- nificance in retrospective series35,36 alongside age, Mayo stage, cardiac involvement, liver involvement40 and prior WM treatment.38 b2-microglobulin and lactate dehydro- genase levels do not independently affect survival,41 unlike in WM,42 which may be related to the low tumor burden. Despite less cardiac involvement, patients with IgM-as- sociated amyloidosis do not have superior survival com- pared to those with non-IgM-associated amyloidosis,38 attributable to the inability to achieve deep clonal re- sponses.
Induction of hematologic response is more challenging with a reported 6-month overall response rate of 39% ver- sus 59% (P=0.008), deep responses are seen in only 24%.38
Organ response rates are consequently poor (5% cardiac, 18% renal) and lower than those in a non-IgM-associated cohort.43
Strategies to target the lymphoplasmacytic and plasma cell clones have been employed. The best outcomes have been achieved by autologous stem cell transplantation, with more than 90% achieving a hematologic re- sponse.40,41,44 However, up to just 25% of all-comers were eligible for this intense therapy. The largest series of auto- logous stem cell transplantation in 38 patients44 included 58% who had received prior therapy and the 100-day mor- tality was 5%. There was, however, a relatively low rate of cardiac involvement (26%), demonstrating the importance of the selection of patients. Induction chemotherapy prior to autologous stem cell transplantation is not universally utilized. Conditioning most commonly involves melphalan, however the BEAM (carmustine, etoposide, cytarabine, melphalan) regimen has also been used.44
As the majority of cases have an underlying lymphoplas- macytic clone, induction therapy with rituximab-based combination chemotherapy is strongly preferred. In 27 cases, the bendamustine-rituximab combination resulted in an intention-to-treat hematologic response rate of 59%, with complete responses in 11%, and a median progres- sion-free survival of 34 months. Sixty percent of patients treated with this combination in second line achieved a very good partial response.45 Bendamustine is neither neu- rotoxic nor cardiotoxic. Bortezomib in combination with
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