The GEM-CESAR trial of a super aggressive approach to SMM (KRD>Transplant>KR>Len) just got published.

The results are a stunning verdict against early intervention in SMM, despite the way the results are potrayed.

Here is a peer review and critical appraisal of this
#mmsm
🧵 Link to trial:

ascopubs.org/doi/10.1200/JC…

The IMROZ trial (Isa-VRd versus VRd for transplant ineligible myeloma) just dropped.

Although the trial is successful, numerous caveats exist.

Six key take-aways regarding this trial, while we await the formal presentation at ASCO



1/

🧵meetings.asco.org/abstracts-pres… 1. The primary endpoint of PFS was met, not reached for Isa-VRd vs 54 mo for VRd

For VRd (without transplant) to get median PFS of 54 months is alot

Context= VRd in ENDURANCE:35 mo and SWOG0777 43 mo PFS

Needs more details, but speaks to fitness/biology of enrolled pts

Ten important observations about myeloma and its precursors that I often discuss with patients and teach to trainees in my clinic.

An educational thread

🧵

#mmsm

1/ 1) Most, but not all disease progressions at the time of relapse are biochemical (as in myeloma proteins increasing) and not clinical (as in new organ damage, anemia, bone lesions etc)

pubmed.ncbi.nlm.nih.gov/35413102/

The FDA just approved cilta-cel for early relapse in myeloma (1 prior line of therapy, including PI and IMiD, and refractory to lenalidomide).

My thoughts on the approval of cilta-cel for early relapse in myeloma.

An educational thread:

#mmsm

1/ Good news? Unequivocally so.

There are pts who at only one line of therapy become refractory to multiple classes of drugs.

A study showed that those progressing on or shortly after a quad had a median PFS of 2.5 months with next tx.

Cilta-cel may change disease course!

Our trial of surveillance incorporating DW-whole body MRI q6 mo for high-risk smoldering myeloma is active.

This is a multi-center effort that aims to define natural history of SMM, and show that close surveillance can prevent morbidity while keeping people off treatment

🧵

This trial involves recruiting 100 patients with high-risk SMM and surveilling closely with q6 month MRI, yearly marrows, and frequent labs.

We aim to show that "morbid" progression events such as fractures, bone lesions and renal injury that doesnt promptly reverse are rare

Inspired by a recent discussion on twitter/X about a trial- here’s a thread about the importance of intent to treat analysis, and the caveats/shortcomings of per-protocol or analysis per “compliance/adherence”.

Buckle yourself up for an educational 🧵 This was a trial of Mediterranean diet in reducing breast cancer recurrence.

We know the Mediterranean diet is good for you- in a rigorous randomized trial, it has actually reduced cardiovascular morbidity.

nejm.org/doi/full/10.10…

There is a lot of progress that happens every year in myeloma.

Learnt a lot in 2023, from both negative and positive trials, and am thankful for the progress.

In this🧵, I will highlight 🔟 important myeloma publications from 2023 that shaped my thinking and practice.

#mmsm Each study in this thread was published in 2023.

Abstracts/posters not included.

I will provide my interpretation with each study.

Some nuance may be lost, as I try to fit it within the confines of a tweet.

This is not in any particular order.

Lets start!

List of top 10 plasma cell dyscrasia #ASH23 abstracts.

List may reflect positive/negative studies, but all have influenced thinking.

I will summarize each study with teaching point.

If you are wondering if there are any practice changing myeloma studies- IMO answer is NO.

🧵 Lets start!

1. The definitions of normal versus abnormal light chain levels have changed, and many patients who would previously be called as light chain MGUS now have light chains within normal limits.

Excellent practice changing @iStopMM study

ash.confex.com/ash/2023/webpr…

Just out in @JAMANetworkOpen, we analyze use of terms that minimize toxicity in myeloma trials.

Thanks to a stellar team led by @mimi_najjar, with @rajshekharucms @Eddie_Cliff @DavidSteensma @AaronGoodman33 @HadidiSamer @MyelomaAmateur



#mmsm

🧵1/ tinyurl.com/3hfm28sw
Previous work by @oncology_bg has highlighted the use of "minimizing terms".

These are terms like "tolerable", "manageable", "safe", and "well-tolerated" that minimize the actual harms treatments inflict on patients, and are inherently subjective.

bmj.com/content/363/bm…

Just out in @eClinicalMed-

92% of clinicians recommend against treating high-risk smoldering myeloma!



Highlights how active surveillance is the prevailing standard of care- and should be the control arm in randomized trials

🧵explaining findings
1/tinyurl.com/43a2jaz9

We surveyed 146 clinicians on their management of high-risk smoldering myeloma, and myeloma defined on the basis of SLiM criteria (elevated FLC ratio above 100) alone.

This is the first and only survey of physicians on this topic. We felt this survey was necessary because..

A very common consult that hematologists get is for MGUS in the setting of neuropathy.

Are they associated? What diagnosis can explain the association? What workup needs to be ordered?

In this thread, we do a deep-dive on this important topic/outline management.

#mmsm

🧵
1/ Firstly, we must recognize that neuropathy is actually very common (28% in those with diabetes, 11% in those without)

And MGUS is very common too

So it is almost guaranteed that you will see patients with MGUS and neuropathy.

But that doesnt mean they are related.

It is heartening to see conversations about informative censoring in the mainstream after the CANOVA study (pom/dex versus venetoclax/dex).

However, informative censoring isnt only a problem when a drug we sincerely believe in fails its randomized trial.

An educational 🧵
#mmsm The Kaplan-Meier method assumes that all patients who were censored (i.e lost to follow-up or data unavailable) had a similar risk of progression as those who stayed on trial and had data available.

This is "uninformative" censoring.

However, the reality may be different.

The most important study at #IMS23 was the CANOVA study- Pom/Dex versus Ven/Dex.

At face value- this trial failed- Ven/Dex did not beat Pom/Dex.

There is a lot to unpack here- explained in this thread.

#mmsm
#IMS23 This was a Phase 3 trial enrolling only in the 11;14 subgroup, which represents 20% of patients with myeloma.

Simply running a Phase 3 trial in a dedicated subgroup is a step forward- and I do commend the company for this.

A reason why the free light chain ratio of >100 was chosen as a myeloma defining event because limited data suggested a 80% risk of progression to myeloma with end-organ damage in 2 years.

But is that true?

A really important from Mayo Clinic showed otherwise.
🧵
#mmsm

In this study of 120 patients with myeloma based on light chain ratio- patients were categorized on whether they had baseline 24-hour urine monoclonal protein (uMCP) of ≥200 vs <200 mg/24hncbi.nlm.nih.gov/pmc/articles/P…

Oncopeptides thinks it has found a smoking gun and that IMiDs shouldnt be used in older patients with myeloma anymore.

They released a document to support their claim:



They also think melflufen is the answer

Whats the truth?

My take in this🧵

#mmsm tinyurl.com/48d5wv3a
In this doc- Oncopeptides highlight how there are few trials that isolate the effect of IMiDs, and in those trials when older patients are analyzed on subgroup analysis, a PFS benefit exists, but doesnt translate to OS benefit.

At face value. appears true. Ex 👇

Justifications for inferior control arm- the case of LIGHTHOUSE study.

This study compared dara/melflufen/dex to just dara monotherapy 💔

This was an tragically unethical control arm (3 versus 1 trial!)- and one I hope never gets repeated.

A🧵on lessons we can learn

#mmsm This trial began in December 2020.

By then- randomized data on various daratumumab triplet regimens had resulted, and daratumumab monotherapy was not an appropriate standard of care.

Nobody would recommend daratumumab monotherapy for their mother or father in this situation.

The majority of those who responded chose bortezomib as a safer option relative to carfilzomib.

Some thoughts in this brief 🧵 below.

There is a head to head trial comparing bortezomib to carfilzomib in transplant ineligible patients



Median age=72 pubmed.ncbi.nlm.nih.gov/30819926/

https://twitter.com/ManniMD1/status/1695785840180711508

The trial was powered for PFS, and did not meet its endpoint- carfilzomib was no better than bortezomib.

The dosing of both drugs was more than we what would do in practice today for such patients (twice a week)

The OPTIMUM trial just published in @JCO_ASCO is an important step forward for dedicated approaches to truly high-risk disease.

Lets talk about this trial in detail 🧵

ascopubs.org/doi/abs/10.120…

Non-paywalled link:

drive.google.com/file/d/1LkaST7…

#mmsm So lets first talk philosophically about add-on trials in myeloma.

There is no shortage of trials in myeloma adding active drugs and showing improved PFS or response rate.

Such trials are usually large trials run for regulatory approval.

Cilta-cel for early relapsed myeloma.

A deep dive-thread where we analyze this trial in incredible detail, all the nuances and subtleties.

Critical appraisal in patient/trainee friendly langauge.

Link to paper:

nejm.org/doi/full/10.10…

#mmsm
#ASCO23 Trial was a comparison of cilta-cel to investigators choice of either dara/pom/dex (86.7% of patients received this) or velcade/pom/dex (12.3% of pts).

Authors write this control arm as "highly effective" standard of care therapy. Was it?

How I view PFS and OS and discuss it to patients-

Using myeloma as an example with references.

An educational thread!

/1

#mmsm I explain what PFS is.

PFS is time from start of treatment to either disease progression or death.

I explain how we don’t have great data from trials on how relapse happens, but retrospective data indicates majority of progressions are biochemical.

onlinelibrary.wiley.com/doi/full/10.10…

The correct answer to this question was smoldering myeloma.

Time for an educational 🧵for trainees/health care folks of all specialties about how we diagnose myeloma!

What are CRAB criteria? How is anemia defined? (Key to this Q)

Whats the deal with "SLiM" criteria?

#mmsm

https://twitter.com/ManniMD1/status/1645905833749012480

What are CRAB features?

Hypercalcemia
Anemia
Lytic Bone Lesions
Renal Failure

Anemia is defined as a Hb value of 2 g/dL or 20g/L below lowest limit of normal for the lab, or less than 10g/DL (100g/L)

Is there something magical however about a Hb of 10.1 versus 9.9?