Relapse and retreatment of multiple myeloma

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Published: 3 Apr 2013
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Prof Heinz Ludwig, Dr Sergio Giralt

Prof Heinz Ludwig and Dr Sergio Giralt talk to ecancertv at IMW 2013.

The approach to managing relapse in multiple myeloma (MM) has changed dramatically in the last 10-15 years. The choice of therapy has expanded to include novel therapies, but will still depend on the patient group, whether they are healthy elderly, elderly frail or relapsing after a transplant, and whether they are symptomatic or asymptomatic. The present of comorbidities, renal failure and previous experience of toxicities, such as peripheral neuropathy, will also influence treatment choice.

In patients who experience long remissions after initial autologous stem cell transplant (ASCT) a second ASCT can be considered. In these patients, where an induction, consolidation and maintenance strategy has been used, the same should be offered again. This decision is based on the outcomes seen in the European trial of bortezomib, thalidomide and dexamethasone versus thalidomide and dexamethasone in relapsed patients, which demonstrated superior outcomes in the bortezomib group.

In the elderly, frail or those that do not want to go through aggressive therapy, or those that have comorbidities, renal failure or peripheral neuropathy, treatment will be tailored to the patient's requirements. In the US, a carfilzomib based regimen can be used in a patient with peripheral neuropathy, in which a proteasome inhibitor is warranted. In patients with renal failure, lenalidomide can be used according to current guidelines, or pomalidomide can be considered. In elderly patients who are symptomatic, a treatment regimen should be considered that the patient can tolerate and that will improve outcomes. In asymptomatic patients, observation only may be warranted. In Europe, the approach would be similar, except that carfilzomib and pomalidomide are not yet approved for use.
In younger patients, where relapse has occurred within 12 months, treatment can be a particular challenge. A second ASCT has not been found to be effective in this group of patients. These patients are ideal candidates for clinical trials. Allogeneic transplant may be one option. New conditioning regimens for ASCT and innovative post-transplant combinations can also be considered.

Cereblon has been shown to predict the response to immunomodulatory drugs. It could become an important predictor of response for MM in the future. Its expression has been shown to correlate to response to lenalidomide and dexamethasone therapy. However, it did not correlate with progression free survival (PFS) or overall survival (OS). However, these initial data need to be confirmed with further studies. A good antibody is needed to detect cereblon expression with immunophenotyping. ELISA could also be used to detect cereblon in serum.

In the US lenalidomide maintenance after lenalidomide induction is commonly used. In Europe, lenalidomide maintenance is not approved. It is hoped that more data will be available soon to support the use of lenalidomide as maintenance in Europe, as it has been shown to be particularly beneficial in low risk patients.

In patients who relapse on lenalidomide maintenance, the treatment choices are less clear. The choice would depend on the initial induction therapy. The preferred choice would be to switch drug class. However, if the induction regimen included a proteasome inhibitor, this is more challenging. In Europe, a conventional drug regimen is sometimes considered in patients with aggressive and early relapsed disease. The response can be significant in these patients, but is limited in duration.

Around 20% of patients experience asymptomatic or biochemical relapse. However, with the advent of maintenance therapy in the US, patients are monitored more frequently (once a month versus once every 3 months). As a result the detection rate of asymptomatic disease has risen to almost 40-50%. A full radiological examination is needed in these patients to identify new lytic lesions or signs of bone disease progression. If these are present, early intervention is warranted. In patients with no radiological progression, inclusion in clinical trials can be considered. Gene signatures may help to distinguish those patients who have indolent disease versus those with aggressive disease, and so guide appropriate treatment.

There are a three of trials ongoing to determine if novel therapy could obviate the need for transplant in the future. In the meantime, ASCT is the standard of care in younger patients.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).