PROTEASOME
Molecular Evidence (rationale) for proteasome targeted therapy in iMCD patients:
- “Bortezomib, a selective proteasome inhibitor that preferentially targets plasma cells, has lowered IL-6 levels and induced remission in 4 cases of iMCD” (Blood 2014)
Case Reports of anti-proteasome therapy for iMCD patients:
Bortezomib is “a selective proteasome inhibitor that preferentially targets plasma cells, has lowered IL-6 levels and induced remission in 4 cases of iMCD.” (Blood 2014) “Bortezomib may work in iMCD via direct inhibition of NF-kB.” (Blood 2014) Three iMCD patients that have been treated with Bortezomib have been described in published case reports. One confirmed iMCD-TAFRO patient achieved complete remission with bortezomib in combination with other drugs, while an iMCD, presumed TAFRO patient achieved partial remission with bortezomib plus steroids. Bortezomib monotherapy improved the general performance status of the third patient. Please see full patient descriptions below.
- 25-year-old male with iMCD-TAFRO received bortezomib in combination with other drugs for complete response for 15 months then relapsed and complete response for 17 months then relapsed. 1st-line corticosteroids achieved partial response for 2 months and then the patient relapsed. 2nd-line rituximab achieved partial response for 2 months and then the patient relapsed. 3rd-line siltuximab, corticosteroids, rituximab, IVIG, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin, cyclophosphamide and etoposide) and maintenance therapy of thalidomide, bortezomib, dexamethasone, rituximab (for 3 months) and ongoing siltuximab achieved a complete remission for 15 months and then the patient relapsed. 4th-line therapy of rituximab, tocilizumab, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin, cyclophosphamide and etoposide) with maintenance therapy of thalidomide (daily), bortezomib (weekly), dexamethasone (weekly), and siltuximab (every 3 weeks) for full response and then relapsed at 17 months. 5th-line therapy of rituximab, cyclosporine, IVIG, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin, cyclophosphamide and etoposide) with maintenance therapy of IVIG and sirolimus with complete response for 39 months. (Patient reported in Fajgenbaum et al with subsequent data collected.)
- 70-year-old male with iMCD with thrombocytopenia (presumed TAFRO) in the setting of multiple myeloma received 4 cycles of bortezomib plus corticosteroids (dexamethasone) with partial remission (improved labs, 75% decrease in lymph nodes and splenomegaly)after two cycles for a total of 18 months, then the patient relapsed. Disease progression treated with 6 cycles of cytotoxic chemotherapies (CHOP) plus methylprednisone, but patient died from disease progression. (Yuan et al)
- 48-year-old female with iMCD received 6 cycles of 3rd-line bortezomib with reduced IL-6 levels and improvement in general performance status. Patient was previously received 1st-line corticosteroids with partial response (hyperimmunoglobulinemia and lymphadenopathy were moderately sensitive) for 132 months then relapsed. 2nd-line corticosteroids and cyclophosphamide were not associated with improved response and were poorly tolerated. (Kreft et al)
Clinical trials targeting proteasome in iMCD:
No clinical trials targeting proteasomes in iMCD patients have been conducted.