Multiple Myeloma With CNS Relapse a Challenging Puzzle for Clinicians

Innovations in therapies to treat multiple myeloma (MM) with central nervous system involvement could have an impact on risk stratification and therapeutic success, but the rarity of the disease makes it difficult to garner sufficient evidence to prove such claims, according to a new review article.

The paper, published in the journal Haematologica,¹ looks at the clinical features of the disease, considerations for physicians treating patients with it, and the latest treatment options available.

Investigators, including corresponding author H. Denis Alexander, PhD, of the Northern Ireland Centre for Stratified Medicine at Ulster University, in Northern Ireland, write that the CNS complication is so rare that over a 15-year period, their regional hematologic malignancy diagnosis center saw just 10 cases.

The authors explain that CNS involvement in MM is just one type of extramedullary disease (EMD), which afflicts up to 5% of patients with MM. EMD happens when cancer cells spread hematogenously or through the bone cortex into other tissues, including the skin, lymph nodes, or CNS, among others. However, due to the rarity of the condition, Alexander and colleagues say it has not been the subject of major clinical trials.

The median age of onset for CNS-MM is between 50 and 60 years. While that’s relatively young for MM, the authors note that most people diagnosed with CNS-MM have already been diagnosed with MM, and many have already undergone multiple lines of treatment. Once diagnosed, patients face stiff odds. The authors report that one retrospective study² of 172 patients with CNS-MM found overall survival from the onset of CNS involvement was a mere 7 months.

One problem is that diagnosing MM with CNS relapse is challenging.

“Multiple myeloma with CNS involvement is difficult to diagnose as it can produce heterogeneous symptoms related to either spinal, cranial or meningeal infiltration, which can be confounded by neurological symptoms caused by the hypercalcemia, uremia, paraproteinemia and bone damage typical in MM, as well as side-effects of drug therapy and, in some cases, amyloid protein,” they write.

Cerebral spinal fluid (CSF) cytology is the best tool for diagnosing the disease, Alexander and colleagues say. The presence of monoclonal immunoprotein and/or clonal plasma cells in CSF can confirm a diagnosis. They write that imaging techniques are effective in most cases, though there is a false-negative in about 10% of cases.

As for treatments, the authors say a newer few therapies hold promise, including proteasome inhibitors and monoclonal antibody.

“However, there remains a paucity of data to provide a clear evidence base on whether novel agents offer improved therapy for these patients, especially at relapse,” Alexander and colleagues report.

One reason for the lack of data is the difficulty of recruiting sufficient numbers of patients for meaningful clinical trials. The investigators write that worldwide group efforts to study potential therapies might be the best means by which to achieve the necessary scientific evidence.

Another question for study is the stratification of patients with the cancer. Alexander and colleagues report that the poor prognosis in CNS-MM does not appear to be merely a factor of advanced disease or level of treatment, but also of tumor biology.

“Therefore, an improved understanding of this would enable identification of MM cases at risk of CNS relapse,” they conclude. “This, in turn, would allow consideration of prophylaxis in patients thus identified as, for example, in high grade B-cell lymphoma.”

References:

1. Egan PA, Elder PT, Deighan WI, O'connor SJM, Alexander HD. Multiple myeloma with central nervous system relapse. Haematologica. 2020. doi:10.3324/haematol.2020.248518
2. Jurczyszyn A,Grzasko N,Gozzetti A, et al. Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice. Am J Hematol. 2016;91(6):575-580. doi: 10.1002/ajh.24351