21 February, 2013

Pomalidomide and Light Chain Amyloidosis

With the immunomodulatory drug pomalidomide (Pomalyst) recently approved for patients with multiple myeloma who have progressing disease within 60 days of the last of at least 2 prior therapies which had to have included lenalidomide (Revlimid) and bortezomib (Velcade), its an opportune time to review what we know (and don't know) about the drug in light chain (AL) amyloidosis. 

Pomalidomide, like lenalidomide, is a structural analogue of thalidomide. The structures of each are shown here:

source: http://www.readcube.com/articles/10.1186/2162-3619-1-27

The FDA-approved dose of POM in multiple myeloma is 4 mg/day for 21 out of every 28 days.

Investigators at the Mayo Clinic have studied POM (with dexamethasone) in 33 patients with previously treated AL amyloidosis. Patients had had a median of 2 prior therapies, with about half having had autologous stem cell transplant. A few (7) had previously been treated with other immunomodulatory drugs. 

The initial dose of POM in this study was 2 mg/day for 28 consecutive days each cycle (no break). DEX was given at 40 mg/week. POM dosing could be adjusted upward (if no response) and downward (for toxicity). The doses actually received are shown here: 

source: http://bloodjournal.hematologylibrary.org/content/119/23/5397.long

About half of the patients had hematologic responses, with the majority of these being partial. The median duration of response was 19 months. A handful of patients who had hematologic responses also had improvement in organ function, which is about what would be expected (based on prior work involving transplant, bortezomib, and other agents). Some of the responses observed occurred in patients who had had prior lenalidomide. 

A few notes regarding toxicity/adverse events: mild hematologic and gastrointestinal events were common. Peripheral sensory neuropathy (numbness, tingling) was documented in almost all patients - this was generally mild, but was more common than one might expect from, say, lenalidomide (at least in myeloma patients). The authors noted that the cardiac biomarker NT-pro-BNP (a marker of heart failure) sometimes worsened even in the setting of a hematologic response. Similar discordance between light chain measurements and cardiac markers have been noted previously in AL patients treated with immunomodulatory drugs (take a look).  In the present study, a 30% rise in the NT-pro-BNP in the first 3 months of therapy was associated with inferior survival, even though some such patients had concurrent light chain improvement.  

What we know: 
  • POM can (and undoubtedly will) be used as treatment for AL amyloidosis. 
  • Responses can be seen even in patients who have had prior autologous stem cell transplant, bortezomib, or lenalidomide.
What we don't know: 
  • Optimal dose, schedule, and duration of POM in AL amyloidosis (tsk! details!) 
  • Mechanism of NT-pro-BNP increase with POM therapy.
Study Spotlight: 

POM, like lenalidomide and thalidomide, will be studied in combination with other active drugs in patients with AL amyloidosis. The Karmanos Cancer Institute will be coordinating a national trial investigating the combination of POM, bortezomib, and dexamethasone in AL amyloidosis. This is the first trial prospectively studying an immunomodulatory drug combined with a proteasome inhibitor as front-line therapy for AL amyloidosis.  Participating centers will include Boston University, Duke University, the Colorado Blood Cancer Institute (Denver, CO) and Princess Margaret Hospital (Toronto).  

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