ASCO 2019: ASCO Releases First-Ever Guidelines for Multiple Myeloma

Development comes on the heels of new drugs, increased overall survival, and revised diagnostic criteria

By John Otrompke

                Science recently achieved a medical milestone, with the publication of ASCO’s first set of guidelines for the treatment of multiple myeloma on May 10. Four new drugs have been approved since 2015. However, the disease remains incurable, with a median survival of slightly more than five years.

Most patients receive at least four lines of therapy, according to the article, “Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline” (Mikhael, J; Nofisat, I.; Cheung, M; et al). DOI: 10.1200/JCO.18.02096 Journal of Clinical Oncology 37, no. 14 (May 10 2019) 1228-1263.

“Survival in the last 15 years is substantially better,” said Dr. Catherine Diefenbach, MD, director of the clinical lymphoma program at the NYU Langone Perlmutter Cancer Center in New York City. “A study by Kumar et al. (Blood 2008 111:2516-2520) found a clear improvement in overall survival for multiple myeloma patients with relapsed disease after autologous stem cell transplant, with those relapsing 2000 having a median OS of 23.9,  versus 11.9 months for those who relapsed before 2000,” explained Diefenbach, who is also an ASCO committee member.

 Even with Five Year Survival, Disease Still Incurable

Therefore, the guidelines place an emphasis on newer agents; recommendation 5.2, for example, suggests that those patients ineligible for stem cell transplant should receive, at a minimum, a novel agent, and a steroid, if possible.

The guidelines are the result of an analysis of 124 relevant studies.

“The review began in 2005, because the therapies that proceeded this are not relevant to the therapies in use today,” said Diefenbach. “For example, daratumumab is an IgG1kappa monoclonal antibody directed against the antigen CD38 which is highly expressed by multiple myeloma cells,” she explained.

(Daratumumab was given breakthrough status by the FDA in 2013, which put it on an expedited approval schedule. It was also awarded orphan status by the FDA).

                Another new drug is elotuzumab, which received breakthrough status in 2014. “Dartumumab is approved for both upfront therapy of multiple myeloma and for relapsed disease in combination with other agents. Elotuzumab is approved for relapsed patients that have failed one to three lines of therapy in combination with other agents,” Diefenbach noted.

Diagnostic Criteria Updated, Especially for Smoldering Myeloma

                Along with the approval of new agents, the diagnostic criteria were updated by the International Myeloma Working Group (IMWG) in 2014. (Lancet Oncol. 2014 Nov;15(12):e538-48. doi: 10.1016/S1470-2045(14)70442-5. Epub 2014 Oct 26). “Many patients who would have previously been defined as having smoldering myeloma will now be more appropriately defined as active and in need of therapy,” according to the guidelines published in JCO.

Autologous stem cell transplant for patients in first remission remains the standard of care, and age and renal function should not be the sole criteria for determining eligibility, according to recommendation 1.2.

For those who are ineligible for transplant, or in first remission, triplet therapies should be considered. (A triplet is defined as including two novel agents, according to recommendation 7.3). According to recommendation 5.3, a combination of the four agents daratumumab, bortezomib, melphalan and prednisone can also be considered.

However, continuous therapy should be offered preferentially to fixed-duration treatment when initiating certain novel agents, such as an immunomodulatory drug or a proteasome inhibitor, according to recommendation 5.5.

“Acquired mutations are important for the progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma, but have less significance for disease progression in multiple myeloma,” said Diefenbach. (MGUS is also known as smoldering myeloma). However, “most multiple myeloma patients will relapse and become resistant to therapy over time,” she added.

                Genetic markers for high-risk disease include cytogenetic abnormalities such as t(4;14), t(14;16), t(14;20), del17p13.