Overcoming Drug Resistance in Multiple Myeloma

Clonogenic stem cells show heightened self-renewal and differentiation capacities in multiple myeloma.

Researchers are progressing in efforts to understand the cause of drug resistance in multiple myeloma.

Multiple myeloma (MM) is a largely incurable, genetically heterogeneous plasma-cell malignancy that contains a small portion of clonogenic stem cell-like cells that show heightened self-renewal and differentiation capacities, in addition to pronounced drug resistance.

MM stem cells (MMSCs) are controversial because they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. MM is characterized by uncontrolled accumulation and growth of aberrant bone marrow plasma cells, which show hallmarks of pronounced genomic instability.

These include DNA point mutations, deletions, and amplifications across the genome, ploidy changes, and, in half of cases, chromosomal translocations that rearrange the immunoglobulin heavy chain locus.

Myelomagenesis is a multistep process that begins as asymptomatic monoclonal gammopathy of undetermined significance (MGUS), changes to smoldering MM (SMM), continues to progress to symptomatic disease and end organ damage.

This eventually leads to an aggressive, refractory neoplasia, comparable to blast crisis in CML or Richter’s syndrome in CLL. Two studies recently have provided strong evidence to support the fact that MM is preceded by MGUS in virtually all cases.

CSCs are a small population of tumor cells believed to be responsible for drug resistance and disease relapse in many cancers.

While it has been 35 years since the first seminal paper was published regarding these populations of tumor cells, many details about the exact nature and biological properties of MMSCs remain elusive.

One hypothesis is that MMSCs are part of the clonotypic plasma cell SP and exhibit increased levels of ALDH1A1 as well as the multidrug transporter, ABCG2/BCRP.

Many drugs have been tested on MM, and while initial responses are excellent to the tested regimens, relapse is always inevitable.

This experience points to MMSCs as the Achilles heel of current treatment. Therefore, MMSC-targeted therapies should be a priority in myeloma patients.

Drug-resistant CSC-like cells, such as MMSCs, are a key obstacle for curing cancer.

The increasing appreciation in the myeloma community of the MMSC concept and the realization that MMSCs are best eradicated in an adjuvant setting at a relatively early stage of the treatment plan offers much optimism for the future.

The design and testing of new drugs that may specifically target MMSCs are crucial steps to accomplish this goal.

“Overcoming this obstacle in myeloma is an important but difficult-to-achieve objective because our understanding of MMSC-autonomous and bone marrow microenvironment-dependent pathways of drug resistance is still limited,” concluded the study authors.