Friday's Gem: Editors' Pick

Ghulam "Manni" Mohyuddin and Aaron "Papa Heme" Goodman takes on overtreatment in plasma cell neoplasms!

In this section, every week, we present a paper that cought our attention, it can be recent, seminal, historical, a point of view, a commentary, a clinical trial, any publication that we feel is important!

Let’s start this new column of the “Drug Develpment Letter” with this insightful comment by our friends and colleagues Ghulam Mohyuddin and Aaron Goodman. Their piece, just out in Nature Review Clinical Oncology, casts a critical eye on current treatment strategies for multiple myeloma and its precursor states, arguing that many patients are receiving more aggressive care than necessary. In this work, “Manni” and “Papa Heme” are making 3 compelling points arguing against the risk of overtreatment in the field and are urging for de-escalation trials.

From MGUS to Multiple Myeloma: a continuum

Plasma cell dyscrasias are a continuum from MGUS (Monoclonal Gammopathy of Undetermined Significance), Smoldering Myeloma (SM) and finally Multiple Myeloma (MM).

MGUS is not a “disease” but rather a condition, as most people (not patients!) are asymptomatic, and a minority will later develop MM. One issue is that not all individuals with MGUS, or even SM, will develop MM. Another issue is that even for patients with MGUS or SM who will later develop MM, it has to be proved that treating earlier those individuals really improve their long-term clinical outcomes.

The paper

The authors express concerns over a "one-size-fits-all" approach that includes intensive therapies and continuous maintenance treatment, which they argue may not only be unnecessary for patients with standard-risk disease but could also lead to detrimental outcomes. They are detailing 3 critical points :

• Maintenance therapy in Multiple Myeloma which is likely overtreating a significant number of patients, and should be reassessed in light of novel therapies

• pushing for Minimal Residual Disease (MRD) as a risk of overtreatment

• Current clinical trials landscape in Smoldering Myeloma not having placebo or surveillance as a comparator in many (or all?) trials

  

  

Overall, the authors are urging for de-escalating trials, recognizing that financial and intellectual conflict of interests are major limitations to launching those key studies. In smoldering myeloma, different observation strategies could serve as alternatives to early-treatment, as the one which is currently studied in the SPOTLIGHT trial (MRI-guided observation), a trial which was launched by Ghulam Mohyuddin himself at Huntsman Cancer Institute at the University of Utah!

Why we choose this paper?

There are times when commentaries can create a significant and long-term impact. In the field of multiple myeloma, there is a growing sense that the current system is somehow broken. The recent FDA approval of MRD as a regulatory endpoint in newly diagnosed MM (see the points made at the ODAC meeting here), concerns regarding the advancement of CAR-T cells to earlier lines of therapy, and todays concerns about overtreatment are growingly recognised issues.

During such times, a concise, crisp, and to-the-point piece can serve as a pivotal moment for one field to reflect on itself. However, there is a concern that these issues may still be relevant in the years to come.

The authors

Beyond being friends and colleagues, both are toughtful experts in trials’ critical appraisal, and great teachers, being prolific on social media and beyond. Follow Aaron Goodman’s substack, and check out Ghulam Mohyuddin’s list of tweetorials + access their full paper here! Thanks guys!