What’s up with Beta 2 microglobulin (B2M) and myeloma?

Why is it the sole non-cytogenetic marker used in the new IMWG high risk definition?

Why does it matter whether the creatinine is high or not?

Thread
1/ Beta 2 microglobulin goes up in myeloma with either increasing tumor burden OR decreasing renal function.

Thus a high beta 2 microglobulin in myeloma is a reflection of high tumor burden or renal failure or both.

We need to distinguish why the B2M is high!
2/

The remarkable story of Velcade.

In the year 2000, a few of us attended an angiogenesis meeting in Boston. We were there to discuss thalidomide

But a side meeting that evening led to trial that went on to get Velcade FDA approved for myeloma. @NEJM

Story in thread. Velcade (bortezomib) was first introduced to cancer research by the name PS-341.

It was a novel proteasome inhibitor developed by Julian Adams and colleagues a a potential anti cancer agent. @CR_AACR @AACR aacrjournals.org/cancerres/arti…

The fascinating story of Thalidomide: how this most notorious drug on the planet, banned in the 1960s, made an incredible comeback and revolutionized the treatment of myeloma.

I will also highlight one person whose role is not recognized: Without Dr. Leif Bergsagel there will be no thalidomide for myeloma.

Read on #MedTwitter
The thalidomide story has many takeaways and lessons.

It shows drug development from bedside to bench and back to bedside.

It shows the power and impact of astute clinicians

It shows the power of investigator courage

The role of serendipity But let’s start at the very beginning.

Thalidomide was synthesized in 1954, and then developed as a sleeping pill by the German company Chemie Grünenthal in the 1950s.

At the time the only sedatives available were barbiturates which had risks of intentional or accidental overdose.

AQUILA trial for high risk smoldering myeloma published in @NEJM today.
@thanosdimop

Personally for me, it is a huge milestone along 25 years of work that started in 1998. #ASH24 #ASH24VR

This story below may help those interested in a clinical trialist career.
1/ In 1998, as a fellow @MayoClinic I was keen to determine if early intervention delayed progression and improved survival in SMM. #ASH24

In 1999, with the help of Tom Witzig, I led a small phase II trial of thalidomide for SMM. @LeukemiaJnl
2/

Just out: Paradigm changing AQUILA randomized trial in high risk smoldering myeloma #ASH24
@thanosdimop @NEJM

Daratumumab significantly prolongs time to active myeloma and overall survival. Proud to be a lead investigator of this trial

Slides in thread nejm.org/doi/full/10.10… Main Findings

Daratumumab prolongs:
-Time to active myeloma
-Time to CRAB
-PFS2
-Overall Survival

Plus: Low toxicity, no detriment to QOL, & limited duration therapy. #ASH24 #ASH24VR

Why are prescription drug prices are far higher in the US that other developed countries.

I’ll break it down. A full 360.

1/ We don’t negotiate prices at launch of a new drug. Others do. As a result, we spend billions on common drugs that other countries spend a fraction of the price on.

Some drugs we pay 10 or 100 times more!!

FDA approval doesn’t necessarily mean standard of care.

Thread.
1/ For example FDA approved Dara VMP for frontline therapy in myeloma in 2018.

Literally no one used the regimen in the US.

Literally no one felt the regimen was standard of care in the US.

Before or after approval!
Why?

Cure is a simple word. But there is confusion when it comes to cancer. What cure is in cancer, and what we should aspire for?

When can we say that a given type of cancer is curable?
Thread
1/ There is a difference between when we can say a particular cancer is a curable type versus whether individual patients with a given cancer can be considered potentially cured.

They are not the same.
2/

The 4 big myeloma randomized trials to watch out for @ASCO #ASCO24

1. Isa-VRd vs Isa-Rd newly diagnosed
2.Isa-VRd vs VRd (IMROZ)
3.DREAMM8 Bela-Pd vs Pd
4.Ven Dex vs Pom Dex (Canova)

See thread for why they are important. 1) The Triplet vs Quad trials with will define role of quads in elderly patients with newly diagnosed myeloma. They also provide frontline phase III data with Isatuximab— and a choice between Dara and Isa. For some patients Isa will be more cost effective. @Myeloma_Doc #ASCO24

Just out: Updated mSMART recommendations for treatment of relapsed refractory myeloma. #MedTwitter @MayoMyeloma

1/ CART is now included as an option for second or higher relapse. msmart.org/mm-treatment-g… 2/ Even though CART (cilta-cel) is approved for first relapse we are NOT including it in our main algorithm. Reserved only for special circumstances in this population. We have a long track record with standard triplets, and we are concerned about CART side effects.

To my followers who wonder what MOC is, and why many doctors are tweeting about it. Thread.

1) Maintenance of Certification (MOC) is a redundant requirement thrust on US physicians by a private organization. We resent it. 2) MOC is causing frustration and burnout. Over the years, ABIM certification and MOC have become entrenched and institutions and insurers require it and will not accept any other alternative.

I am advocating on behalf of my colleagues in the US for change. To end MOC.

10 suggested action items for physician colleagues suffering under the burden of @ABIMcert MOC. #MedTwitter

1. If your institution allows it, stop participating in MOC. Personally, MOC has no value to me. 2. If your institution requires ABIM certification, advocate for @InfoNbpas as alternative option.

I see a lot of wrong analysis on accelerated approval and surrogate endpoints.

It’s always easy to criticize from the outside. The criticisms raised are well known to the FDA and investigators. They are considered. We go in eyes fully open. We try to do what’s best for patients Without accelerated approval using surrogate endpoint of overall response rate in single arm trials, for 2-3 years lives would have been lost waiting for drugs like Velcade, Revlimid, pomalidomide, Daratumumab, carfilzomib and more.

My defense of accelerated approval in MM.

https://twitter.com/vincentrk/status/1590496892676624384

My year end endorsements.

1) @costplusdrugs — where you can get >2000 prescription meds at lower price than almost any other pharmacy in America. Has revolutionized the generic prescription drug market. @mcuban costplusdrugs.com
2) @PayorDieFilm — the story of lives lost due to the high price of insulin in America. Likely contributed to why all 3 big insulin manufacturers have now cut the price of insulin by >70-80%. @scottaruderman @NSmithholt12

Watch on @paramountplus @mtvdocs

Updated treatment approach to newly diagnosed myeloma based on new #ASH23 data.

Explanation for changes in thread. #MedTwitter 1/ What’s changed?

I’m ok with quadruplet induction for standard risk based on the 2 phase IIIs at #ASH23

Better PFS and MRD-
Limited duration induction.

OS will take a long time to emerge and risk/benefit is reasonable to incorporate Quads.
2/

Two days ago I did 60 ABIM MOC questions in Heme and Onc (against my will).

Almost all were esoteric/ irrelevant questions. Rare things that doctors rarely see. #MedTwitter

What’s my opinion?

1/ I spend a lot of time in medical teaching and writing. I write for UpToDate for 20 years, and all of the major Hem Onc textbooks.

In my opinion, the MOC questions are useless for routine Hem Onc clinical practice. Useless to assess “walking/ essential knowledge”.

2/

US physicians almost unanimously oppose ABIM MOC. #MedTwitter

We have raised our voice in despair. What can we do to make change happen?

1) Urge our professional organizations to support us. More than words, we would like action. 2) Continue the pressure on social media.

Top 10 reasons why ABIM MOC should be abolished. #MedTwitter

10. It’s a bad life experience that physicians almost unanimously don’t like. 9. The questions asked in the MOC LKA or MOC exam are not what we face in practice. They are often vague zebras or designed to trip people up. (Experts get questions in their own field wrong)

Myeloma drugs — Dosing and schedule

What I do in practice #MedTwitter

1. Dex: 40 mg once a week age <70; 20 mg if age >70 or frail

Stop Dex at around one year if good response.

Days 1-4, 8, 15, 22 schedule for 1st cycle only in cast nephropathy; or VDT-PACE type regimen Velcade:

Once a week and SQ is my default.

Twice a week for 1st cycle only in acute in cast nephropathy, or with VDT-PACE type regimen

The serum free light chain FLC assay. Tutorial. #MedTwitter #MyelomaVR

Frequently ordered and frequently abnormal. This thread will reduce unnecessary headaches and referrals.

1/ Don’t order it unless you are suspecting myeloma, amyloid or related disorder 2/ The assay itself consists of 2 separate assays: a free kappa assay and a free lambda assay.

The lab also CALCULATES and reports a free kappa/lambda light chain ratio using the absolute levels.

A collection of clincally important insights in myeloma and MGUS. #MedTwitter

1/ Serum protein electrophoresis may underestimate the true size of the M protein when the level is too high. The gel saturates. So go by the quantitative IgG/IgA level to get a better estimate of M… twitter.com/i/web/status/1… 2/ Serum protein electrophoresis may give incorrect value for the true size of the M protein in IgA myeloma because IgA forms dimers and trimers. Follow the IgA level also to get a better estimate of true M spike size.