Multiple myeloma (MM) – subclonal, and not?

After talking to some colleagues, it occurs to me that it’s worthwhile making a clarification about the subclonal nature of MM.

What does this mean?
A short 🧵
1/x
#mmsm It’s been 12 yrs since we published this paper with @PedalheadPHX where DNA gain/loss (aCGH) was converted to FISH probes. Each pie represents the analysis of a unique bone marrow sample, over time, in the same patient.

Multiple subclones exist

2/x

Does a "mass effect" prevent optimal results with CARTs and bispecific antibodies (BsAb) in MM?

1) I suspect so, and we need to study this in detail to improve patient outcomes.

2) Until then, I think a reasonable case can be made for using local radiation therapy in some cases with large masses not controlled by prior or bridging treatment (stay until the end).

Why?

#mmSM
1/x My thoughts started by observing cases with extramedullary disease ((EMD) enrolled in clinical trials. In some cases, some of these masses appeared indifferent to the treatment, while the rest of the tests showed good responses. Ironically, sometimes, these EMD lesions would not grow fast; they would just linger around.
2/x

Must-read paper- clinical trials can be largely predicted by the activity of individual drugs. The paper is careful, stating that "additives" are not necessarily bad. So, how did the myeloma trial studied here fare? Here is a modified Fig 3 to only show MM trial data,
#mmsm
1/x

https://twitter.com/ac_palmer/status/1725590125713777118

Those combinations in purple (POLLUX, Dara-Rd) are clearly more than additive using this model. The ones on pink state they cannot reject, which is more than the efficacy of the best drug. In white those that can reject both. I wish we could have seen MAIA.
2/x

The clinical development curse against venetoclax for t(11;14) MM -
How CANOVA was reported and why it is still critical patients with the t(11;14) have access to Ven.
#IMS23RF #mmsm
1/x
Ven is a “game changer” - a hill I am ready to die on. The first and most effective targeted therapy for MM with t(11;14). It is long overdue we have unfettered access to it for patients that need it.
2/x

Some musings on myeloma therapy after coming back from ASCO and EHA 2023 (a bit old now). Most of the interesting data used T cell therapies (CARTs and bispecific). A thread with my candid impressions, and without much curation.

A thread 🧵
#MedTwitter #mmsm
1/x *** The critical importance of IVIG replacement ***
In many trials, most patients were not replaced (~30-40% were).  We must do better, and are now working on this with our nurses.  SQ administration seems attractive?

2/x

** How to interpret MRD results reporting below LOD **

Finding a 0 (zero) result in the clonoSEQ assay is great. But sometimes a patient has a result of "Residual sequences detected at below (the) level of detection (LOD)"

What does this mean?

1/x
#mmsm How do we explain this to patients? I have found it difficult (technical), but let me share how I do it. If you think, "Who cares, the patient is negative at 10-^5." then this thread is not for you.

Is there disease in the background or not? It depends...

2/x

CIRCULATING PLASMA CELLS (cPCs) IN MYELOMA (MM)

Several studies have recently reported on the prognostic significance of cPCs in patients with MM. The study of cPCs is of high relevance, but not new. For curation purposes only, I want to cite older studies
#mmsm
1/x This will not be comprehensive or exhaustive but will provide a general framework for older studies making similar observations. The treatments were not as good, and the technology was older, but the conclusions seem to remain.
2/x

I think we cure some MM patients (I know controversial) and some thoughts on how to get there with current therapies
1/x With median OS over 13 years for standard risk (Emory ASCO 2022) minimizing ENDURING toxicity is critical. Particularly peripheral neuropathy - bortezomib-induced.
2/x

https://twitter.com/rfonsi1/status/1534665804112871425

Joan Blade presenting Ph3 Bu-MEL vs MEL
#IMS2022 #mmsm VOD IN 4 PTS.

WHAT IS THE RISK CLASSIFICATION OF THE t(11;14) in MM?
This has been a long-debated question and probably asked in the wrong way. I have always had a special interest in the t(11;14) and want to tell a story and how it relates to venetoclax.
#mmsm #ASH19
1/x In 1998 we reported the t(11;14) was a poor prognostic marker (only translocation visible in karyotypes). We were seeing the effect of abnormal karyotypes- more growth and tumor burden. @VincentRK
onlinelibrary.wiley.com/doi/full/10.10…
ncbi.nlm.nih.gov/pubmed/10459351
2/x

A quick "Tweetorial" regarding research of naturally occurring calcium isotopes to detect bone destruction. This is work we did in collaboration with brilliant scientists at @ASU including Drs @ArielAnbar @gwynnotpaltrow, Joe Skulan and others. 1/x #mmsm

ncbi.nlm.nih.gov/pubmed/24919808 I became interested as this technology as it could be used in the detection of bone disease in myeloma. Bone markers are not routinely used and imaging is like archeology; old news. Not archeology- work with geologists!

How do isotopes work? A few key principles.

So here is a thread on the use of MRD in MM. Before we start please know that I consult for Adaptive & are part of their Scientific Advisory Board. If you can get past this point thank you for coming. Prompted by @End_myeloma
#MMSM #ASCO19RF @mtmdphd @AdaptiveBiotech MRD negativity is now shown to be highly prognostic in several studies. Furthermore, the HR effect is unprecedented, and far more powerful than any genetic marker. Particularly see French (IFM) study from 2018.
bloodjournal.org/content/early/…