An important new concept in our understanding of multiple myeloma traces its origins back to the great nineteenth century scientist, Charles Darwin.

In his writings, Darwin described how char­acter­is­tics of animal and plant species can change over time. Slight differences in inherited char­acter­is­tics within a species, combined with variations in the en­viron­ment, can lead to certain char­acter­is­tics becoming more common in en­viron­ments favorable to those char­acter­is­tics.

A good example of what Darwin described is the range of size and shapes of beaks seen on Galápagos finches. The different beaks allow the birds to eat the different types of seeds found in their environments, making them specialists for those seeds. It is clear that all of these birds are related and belong to the finch family, but they are all subtly different species.

This process of “adaptation” to the environment leads to “evolution” of the species, making them better suited to their surroundings — in this case, eating a specific seed.  The essential features of this process are genetic char­acter­is­tics that are inherited, and a “selection” process related to the environment.

Intra-Clonal Heterogeneity

It is now thought that cancer behaves according to the principles described by Darwin that we outlined above. An essential feature of this process is variability within the cancer cells, which is called intra-clonal heterogeneity (ICH).

ICH is an important new concept which recognizes that myeloma tumor cells are not all identical, and that, when a myeloma patient is diagnosed, he or she has at least three to six major subpopulations of cells, all of which have different biological char­acter­is­tics and clinical aggressiveness.

Below the level of sensitivity used for the detection of these major sub­clones, there is likely much more diversity, which is responsible for the emergence of drug resistance and relapse following exposure to the selective pressure of treatment.

The consequences of ICH also explain the progression of myeloma from a more benign to a more ag­gres­sive malignancy over time, as the most ag­gres­sive sub­clones come to dominate the others. The competitive behavior of residual myeloma cells means that they behave in a Darwinian fashion.

This competition is also present after treatment, where the rare variants which grow and survive the best come to dominate the population within the bone marrow — that is, lead to relapse.

How Is ICH Recognized In The Clinic?

There are several ways myeloma specialists see evidence of ICH as they treat and monitor the progress of their patients.

One is by using imaging technologies that don’t just look at lytic bone lesions, but which also assess the extent and aggressiveness of the myeloma both within and outside the bone marrow. PET scans and dif­fu­sion weighted MRI both can be used for these purposes.

The use of these techniques can show different sites and different disease activity within the bone marrow.  Importantly, the techniques often show different responses to treatment at different sites in the body.  This is consistent with the presence of different sub­clones at the different sites — some being sensitive, and others resistant, to treatment.

Other technologies can directly show ICH. For example, cytogenetic and gene expression profiling of bone marrow and focal lesion biopsies reveal different genetic features at different biopsy sites. Massively parallel sequencing can describe in detail the genetic differences between the myeloma cells at the different sites. It remains clear, however, that these cells are related, but with slight differences. This observation is exactly what would be expected for an evolutionary system.

Why Is ICH Important?

The evolutionary nature of multiple myeloma is important because the related subclonal cells, each derived from a myeloma stem cell that is subtly different, compete for space to grow within the bone marrow.

In this context, treatment can be considered as a “selective pressure.” It can kill most subclonal cells, but rare, resistant sub­clones can survive. And, in this setting, the resistant sub­clones will have more space to grow, leading to relapse.

Patients and doctors need to take these aspects of the ICH phenomenon into account when considering how to treat myeloma. The diversity that is present means that there are cellular subpopulations that are resistant to single treatments and can be responsible for relapse.

In this respect, using a combination of treatments that kills the maximum number of sub­clones is an im­portant strategy. Indeed, such a strategy is relevant even if there is a single dominant clone that is not ag­gres­sive. That clone, by filling all of the space in the bone marrow, is likely to be suppressing the growth of more ag­gres­sive sub­clones. Using a small number of treatments targeted at just the dominant, less ag­gres­sive clone will leave the more aggressive sub­clones untreated and with more space to grow, leading to re­lapse.

Dealing With ICH Therapeutically

One of the key strategies of induction treatment for myeloma that is intended to deal with ICH is the use of multiple different therapies in combination with one another. This approach works by achieving the max­i­mum cell kill to ensure the eradication of as many sub­clones as possible that could lead to relapse.

The use of autologous transplantation can be considered an extension of this attempt to maximize the num­ber of sub­clones eradicated, leading to complete response. Similarly, the use of maintenance treat­ment is another important step forward that seems to be improving outcomes. In this setting, the selective pressure of treatments can alter the behavior of the small number of remaining tumor cells present below the level of detection of our monitoring technology.

In general, Darwinian evolutionary concepts suggest that single drug exposure may not be the best ap­proach to treating myeloma, as it may lead to the overgrowth of resistant clones.  However, the issue of re­sistant clones could be overcome by either using combinations of dif­fer­ent drugs, or using “cyclic” ap­proaches that employ different combinations of drugs at dif­fer­ent times, in an alternating fashion.   The development of new oral and antibody myeloma ther­a­pies, with different modes of action, means that this type of strategy is now clinically possible.

ICH also implies that therapies can make an important contribution to the treatment of multiple myeloma even if they do not generate significant changes in standard disease markers, such as a patient’s M-spike.

For example, a key pathway in myeloma is the RAS/MAPK pathway, which is frequently mutated and can be treated with certain drugs. Mutations in the RAS/MAPK pathway, however, are not always present in all myeloma cells – as one would expect, given ICH.  Treating the mutations may therefore result in only a minor response, even though all the cells with the mutations are being killed, with potentially significant implications for length of remission.

───────────────── ♦ ─────────────────

This month marks the 155th anniversary of the publication of Darwin’s On the Origin of Species, the book that became the foundation for the field of evolutionary biology. In recent years, researchers have learned that evolution has a great deal to say not only about how cancer develops, but also how it should be treated.

These learnings, in turn, have led to a greater understanding of ICH and its role in multiple myeloma, im­prov­ing how we treat and monitor the disease, and offering hope for further improvements in the prog­no­sis of myeloma patients.

Gareth J. Morgan is Director, Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas.