Treating Beyond Progression in Multiple Myeloma

Keith Stewart, MB, ChB:Progression is usually defined in multiple myeloma as the biochemical progression, which is an increase in a monoclonal protein present in the blood. On clinical trials, we require an increase of at least 0.5 g/dL in monoclonal protein or an increase in the serum free light chain of at least 10. We generally require that it’s repeated at least once to confirm the relapse is real and not just lab variation. Relapse can also occur outside of the bone marrow with extramedullary disease, which is a plasmacytoma growing outside of the bone marrow itself. And we can sometimes see that in the absence of increased biochemistry. But usually one or both of those things will be present at the time of relapse.

In an elderly patient like the one that we are discussing, a biochemical relapse alone would probably not be adequate reason to change, or at least to start, new therapy, assuming they were not currently on treatment. We could often follow a patient like this as long as they’re asymptomatic and where quality of life in important. However, if the monoclonal protein is rising rapidly or there are any signs of impending end organ damage, either by imaging symptoms or physical exam, then I think. in a patient like this. treatment would be indicated. In this patient, he has presented with an increase in pain and fatigue, clearly beginning to show signs of problems, and a switch in therapy is absolutely required.

In an elderly patient who has asymptomatic biochemical relapse, one might just give a break of therapy and watch for a while to see how long the disease will remain stable. If the physician feels therapy is recommended, one would generally look for drugs with the lowest toxicity profile to employ before going to more aggressive and more toxic therapies.

Phase III clinical trials of the use of immune modulator drugs, such as lenalidomide, have demonstrated the following: when compared to the control in a trial that was called the First Trial, probably one of the largest trials ever performed in multiple myeloma, with over 1500 patients, the control arm—which was melphalan, prednisone, and thalidomide—did about the same as those patients treated with lenalidomide/dexamethasone for 18 months who then had their treatment discontinued. The arm of the trial that was clearly superior in terms of progression-free survival was the use of lenalidomide and dexamethasone continuously. This, along with maintenance studies of lenalidomide in a posttransplant setting, confirmed that patients should really stay on these drugs somewhat indefinitely, as long as they’re tolerated and there’s no concern for secondary side effects.

In this patient, the dose of lenalidomide was escalated from 15 to 25 mg, or the full dose. I think this was appropriate to try. The patient was not suffering serious toxicities at the lower dose, was showing asymptomatic biochemical progression initially, and that’s an escalation of dose to see if that was also tolerated and whether or not that might recapture control of disease. I think it was an appropriate attempt at managing this patient given his circumstances.

Case Scenario 2:

December 2013

• The patient is a 77-year old African American male who was diagnosed 24 months ago with stage III multiple myeloma and not eligible for transplant based on his level of frailty. His cytogenetics were classified as intermediate risk.
• He received treatment with lenalidomide (15 mg daily) and low-dose dexamethasone.

December 2015

• IgA monoclonal protein spike seen on SPEP. M-protein level has risen to 0.6 g/dl.
• He continued to do well functionally.
• Lenalidomide was increased to 25 mg daily.

May 2016

• The patient now complains of increasing back pain, fatigue and weakness. He was hospitalized two months ago for pneumonia.
• Abnormal laboratory findings show:
  • Serum beta-2-microglobulin level, 6.2 mg/L
  • Albumin level of 2.1 g/dL.
  • Creatinine clearance of 32 ml/min
• Skeletal survey shows lytic lesions in the L4/L5 vertebrae.
• Bone marrow biopsy shows 30% involvement by abnormal appearing plasma cells, confirmed by CD138+ IHC stain.
• ECOG performance status is 2.
• The patient was started on pomalidomide, weekly cyclophosphamide, and low-dose dexamethasone.