Data published this week added to the understanding of just how complex multiple myeloma is, not just between patients but within a single patient.

In a study of about 200 patients with multiple myeloma, published in the Jan. 13, 2014, issue of Cancer Cell, deep sequencing revealed that patients tended to have multiple mutations, and multiple subclones, or populations of cancer cells descended from different cells with different mutations.

The work followed up on an earlier, smaller study that also had shown genetic heterogeneity in multiple myeloma. The larger number of patients that were analyzed in the current study enabled researchers to confirm the mutations that had been identified in that work, as well as others that occur too rarely to be found in the roughly 40 patients sequenced earlier.

“Myeloma,” co-author Daniel Auclair told BioWorld Insight, “is like having four different diseases within the same patient.”

Treating one of those diseases – which take the form of different subclones – could do no more than allow another to take over.

The experiments showed that some treatments could actually backfire. Some multiple myeloma patients have mutations in BRAF, and there is a case report of a patient who had a response to BRAF inhibitor Zelboraf (vemurafenib, Roche AG).

But cells with wild-type BRAF but mutations in the driver genes KRAS or NRAS showed increased growth in response to BRAF inhibition.

Co-author Joan Levy told BioWorld Insight the data now published in Cancer Cell show that “one has to look at the full genetic landscape within a patient” to make good treatment decisions.

Patients with both BRAF and Ras mutations, for example, might benefit from combination treatment with BRAF and Mek inihibitors – a strategy that has been tested preclinically in myeloma, and clinically in melanoma, where BRAF mutations are frequent.

Both Auclair and Levy are part of the nonprofit Multiple Myeloma Research Consortium, which, as an institution, also had authorship on the Cancer Cell paper. The consortium, which is one initiative of the Multiple Myeloma Research Foundation, is one institution that is testing combination approaches based on individual patients’ genetic makeup, through initiatives like coMMpass (“relating clinical outcomes in multiple myeloma to personal assessment of genomic profile”).

Others, however, interpreted the data to mean that targeted therapies may not be best the way to attack complex cancers in the first place.

“I think the data are sobering, which is a phrase the authors themselves repeatedly use in their paper, and that they point us away from targeted therapies,” Brian Durie told BioWorld Insight.

“The idea of a targeted approach is very attractive to people – they are looking for a silver bullet,” he added. “It’s very appealing to look for a mutation that you can treat. But in complex cancers, it may not work.”

Durie is the co-founder and chairman of the International Myeloma Foundation (IMF), a nonprofit organization that, among other things, funds clinical trials for myeloma.

The IMF is putting money behind what it calls the Black Swan Research Initiative, which aims to find a cure for multiple myeloma. That initiative is looking at what, in a sense, is the opposite approach of targeted therapies.

Researchers are trying to take a two-step approach to getting rid of myeloma altogether. In the first step, the current best available therapies for multiple myeloma – Velcade (bortezomib, Millennium: the Takeda Oncology Co.), Revlimid (lenalidomide, Celgene Corp.) and Pomalyst (pomalidomide, Celgene Corp.) – are combined with each other, as well as with older treatments such as dexamethasone, to get rid of the bulk of the tumor cells. Those therapies all work via multiple mechanisms rather than by targeting one specific mutation.

Targeted therapies do come in during the second step, when any remaining tumor cells are analyzed in detail to understand their molecular alterations.

But Durie said the heart of the approach consists of “combining multifunctional agents that shut down multiple pathways,” rather than targeted therapies.

Durie said he believes that such an approach is more promising than combinations of targeted therapies, both from a theoretical standpoint and in terms of the necessary clinical trials, which, he said, would be “hugely time-consuming and expensive” for targeted therapy combinations.

Such an approach, he said, would in principle be applicable to other complex cancers, though “the advantage that we have in myeloma is that we have therapies that are dramatically effective . . . we are fortunate that way.”