Biclonal Multiple Myeloma- A Case Series

Multiple myeloma is a prototype of plasma cell dyscrasias characterized by monoclonal abnormal proliferation of immunoglobulin secreting plasma cell in the bone marrow ; resulting in production of monoclonal (M) protein (IgG,IgA,IgM,IgD) and or light chain concentrations (kappa or lamda) identied by protein electrophoresis and or immunoxation of serum or urine. The term biclonal multiple myeloma are dened by coexistence of two different M components, which could be either from a single clone or two separate clones producing two distinct bands in electrophoresis and or immunoxation of serum or urine. Biclonal gammopathy is a rare entity with upto 1% of newly diagnosed case of multiple myeloma have two M component in serum immunoxation electrophoresis. Here we share our experience of four cases of biclonal myeloma successfully diagnosed and treated with standard chemotherapy with satisfactory clinical outcome from a single tertiary care centre.


Introduction
Multiple myeloma is a plasma cell disorder characterized by proliferation of single clone of immunoglobulin (Ig) secreting plasma cells with secretion of monoclonal M protein detected by serum protein electrophoresis (SPEP) and or immuno xation (IF) of serum or urine. Biclonal myeloma is de ned by coexistence of two distinct M bands in immuno xation electrophoresis due to either proliferation of two separate clones of plasma cell, each producing an unrelated monoclonal Ig or it may result from a single clone of plasma cell producing two monoclonal proteins 1 .
Biclonal myeloma is a rare entity and accounts for approximately 1% of newly diagnosed case of multiple myeloma have two M component in serum immuno xation electrophoresis 2 . It presumed that the neoplastic clones which secrete one type of M protein might have undergone isotype switching resulting in secretion of another subtype of M protein by the same clones producing biclonal spikes 3 . Although light chain isotypes reported in literature, but the most common biclonal combination is IgG and IgA (33%) followed by IgM and IgG (24%) 4 . It usually presents with common clinical signs and symptoms like monoclonal gammopathy although subsets of population having features of waldenstrom macroglobulinaemia. Treatment with biclonal myeloma is similar with monoclonal gammopathy with comparable survival outcome.

Case History
From May 2019 to January 2020 total four cases of biclonal myeloma was diagnosed in our centre based upon history, clinical examination, routine blood investigations, skeletal survey, serum protein electrophoresis with immuno xation, bone marrow aspiration with trephine biopsy along with cytogenetic study by FISH (Myeloma Panel).
In our series there were one female and three male with median age of 52 years. In all the patients common presenting symptoms was weakness, fatigue with one patient presented with back pain. The baseline details of four cases are summarized in Table 1. As all of them were transplant ineligible, three patients were treated with induction chemotherapy with Bortezomib, Lenalidomide and Dexamethasone regimen (VRD) along with monthly Zoledronic acid. One patient was treated with ve cycles of Bortezomib, Dexamethasone, Rituximab chemotherapy (BDR) regimen in the line of treatment like waldenstrom macroglobulinaemia and kept under observation as partial response was achieved. After 3 cycles, after 6 cycles and after 9 cycles of VRD regimen serum protein electrophoresis with immuno xation was done for response evaluation. Figure 1,2,3,4 showed the respective SPEP with IF pattern of our four cases.
Response evaluation was done as per International Myeloma Working Group (IMWG) uniform response assessment criteria. As because there was no undue toxicities and good compliance to therapy; chemotherapy with same regimen was planned to continue until diseases progression. Table 2 demonstrates chemotherapy regimen, response and their outcome. Although we were not able to identify separately of different clonal subtype, overall our patients responded well with standard line of therapy.   Here we report two extremely rare biclonal pair of IgA Kappa plus IgA kappa and IgM Kappa plus IgM Lambda combinations. In such type of cases mostly arise from two independent plasma cell clones that exhibit either different light chain isotypes or the same light chain isoptype unrelated with clonality 10 . Lymphoplasmacytic lymphoma also known as waldenstrom macroglobulinaemia and other B-cell lymphoma with plasmacytic differentiation can produce similar paraproteins and has been reported to present with biclonal gammopathy 11,12 . In our fourth case presents with features like waldenstrom macroglobulinaemia with SPEP showed two peaks consisting IgM Kappa plus IgM Lambda spikes and hence the patient was responded well with BDR regimen.
Clonality studies was most important to unfold whether this exceptional combination belongs to a truly biclonal population or rather a single neoplastic clone suffered two hits was the major limitation of our case series. It was seen that anti-myeloma therapy was more effective against multiple myeloma clones rather than MGUS clones in patients with biclonal gammopathy 2 . In our patients both matched (Kappa/Kappa) and different light chain isotype (Kappa/Lambda) responded well with bortezomib and lenalidomide based therapy, indirectly indicating that there was myeloma clones rather than MGUS clone. To conclude more prospective research work needs to be done for better realization of the underlying diseases biology, pathogenesis and behavior of this rare disorder.