Background: IgM multiple myeloma (MM) are very rare plasmaproliferative disorders representing 0.5–1.2% of all cases of MM and < 0.2% of all IgM monoclonal gammopathies. Clinical criterion are not always helpful in differentiating IgM MM from Waldenstrom macroglobulinemia. However, the presence of lytic bone lesions, absence of lymphadenopathy and/or hepatosplenomegaly, presence of translocation of the immunoglobulin heavy chain locus at 14q32 [t(11;14), t(14;16), t(4;14)], and strong expression of CD138 by the plasma cells are useful in the diagnosis of IgM MM. It has been our experience and of others that these cases have an aggressive behavior at presentation, shorter survival than IgG and IgA MM and poor response to therapy for lymphoplasmacytoid lymphomas. We present here 2 cases of IgM MM with a dramatic response to Lenalidomide and low dose dexamethasone (Rev/Dex)Results: Baseline patient characteristics at time of diagnosis of IgM MM and therapy outcome are presented in the following 2 tables:Table 1.Case12Age and sex72 (F)73 (F)Serum M-spike (g/dL)5.36.2Urine M-spike (mg/dl/24 hrs)72412Serum IgM (mg/dL)8,59011,000BM plasma cells percentage9020Plasma cell immunophenotypingCD138+++, partial CD20, CD56−CD138+++, partial CD20, CD56−Cytogenetics (Standard and/or FISH)Standard: normal FISH: not done on initial biopsy. On follow up there were insufficient number of plasma cells to perform testStandard: of 20 metaphases, 6 had a complex hypotetraploid karyotype with relative loss of 13q, 14, 15, 16, 20, and 22, and numerous unbalanced rearrangements. FISH: a plasma cell clone with monosomy 13 and IGH/c-MAF fusion, t(14;16). In addition, approximately 60% of plasma cells had a tetraploid clone with the same anomalies as well as relative loss of p53Bone lesionsMultiple non-traumatic spinal fractures and of stenumSeveral lytic lesions of long bonesRenal insufficiencyNoNoAnemia (Hbg g/dL)Yes (8.7)Yes (8.1)Hypercalcemia (Ca mg/dL)Yes (12.5)Yes (11.4)Beta 2 microglobulin (mg/dL)5.798.51Serum viscosity (cpoise)5.94.8Table 2. Best Response to therapyCaseTherapyBest ResponseComments1Rituxan, then Fludarabine based therapyTransient responseRapid progression after partial and transient response to each therapy1Lenalidomide + LD-DexsCR after cycle #6. Currently on CR 18 months laterIgM declined from 8,590 to 43 mg/dL after 4 cycles of Rev/Dex.2Lenalidomide + LD-DexVGPR after cycle #2IgM declined from 11,000 to 463 mg/dL after cycle 3. Complete disappearance of M-spike in serum; BM to be done after cycle #4Conclusions: This is the first report that we are aware of a rapid and dramatic response to lenalidomide and low dose dexamethasone in these rare cases of IgM MM with poor response to NHL-type treatment. Lenalidomide-based therapy might abrogate poor prognosis cytogenetics in this unusual subtype of MM (case #2), however, follow up for this patient is still very short.