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Vincent Rajkumar Profile picture
@VincentRK
Sep 4, 2020 • 9 tweets • 6 min read • Read on X
Behind the Scenes: A thread of randomized trials I have helped lead and publish. Each one has a story. Most have been a struggle.

This is for young physicians trying to start a career as a clinical investigator or trialist.
#MedTwitter #MedStudentTwitter #myelomaVR #mmsm

1/
1) ECOG Thalidomide Dex vs Dex for myeloma. My first RCT. I had previously led small Thal trials at Mayo. But leading this pivotal RCT required luck. I had proposed a small Ph II, so they let me be PI. But @theNCI mandated a change to Ph III RCT design. ascopubs.org/doi/10.1200/JC…
2) Celgene Thal Dex vs Dex placebo RCT. Given success of ECOG trial, which led to thalidomide approval by FDA, I was asked by Celgene to lead their company trial: a confirmatory trial for regulatory approval. Company trials are easier to run. ascopubs.org/doi/10.1200/JC…
3) ECOG high dose vs low dose dexamethasone: A patient, the late Michael Katz proposed this trial. Glad we listened. Results led to a dramatic reduction in myeloma deaths & morbidity worldwide. Also gave Rd backbone used in most regimens. @TheLancetOncol thelancet.com/journals/lanon…
4) ECOG MPT vs MPR: Slow accrual. So by the time the results of this trial came, melphalan based regimens were out of favor. Shows how long delays in opening, and slow accrual that affect many RCTs in the US. @akeithstewart the trial PI did all the work. ashpublications.org/blood/article/…
5) Mayo Clinic Thalidomide Zoledronic Acid vs Zoledronic acid for smoldering myeloma. Managed to get @NIH R01 grant to fund an RCT. Not just lab correlatives, but actual trial costs! These grants are scarce now. Precursor to Lenalidomide smoldering RCT. nature.com/articles/leu20…
6) Takeda Ixazomib vs Placebo Maintenance RCT. Great lessons from interactions with FDA and the sponsor on trial design and endpoints for maintenance. Novel design with early read out of PFS, but continue trial for OS endpoint. @TheLancet thelancet.com/journals/lance…
7) ECOG Lenalidomide versus Observation for smoldering myeloma. I’ve written a long thread about the 15 year saga. This trial together with the RCT by @mvmateos changed paradigm for high risk smoldering myeloma. Great working with trial PI @SagarLonialMD ascopubs.org/doi/10.1200/JC…
8) ECOG ENDURANCE VRd vs KRd for myeloma. 10 year effort. Was struggle to open. But accrued fast. Results show why RCTs are important. It’s also 2 RCTs in one! 2nd one: Len 2 years vs Len till progression is ongoing. Great working with trial PI @myelomaMD thelancet.com/journals/lanon…

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More from @VincentRK

Vincent Rajkumar Profile picture
Jun 27
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/
When B2M is high, it confers adverse prognosis, but why it is high determines what you can do about it.

If the B2M is high because of tumor burden our strategy will be different than if it’s high due to renal failure.

3/
Read 7 tweets
Vincent Rajkumar Profile picture
May 24
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. Image
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…Image
The ubiquitin-proteasome garbage disposal pathway in cells is a Nobel prize winning discovery.

Proteins that need to be degraded are tagged with ubiquitin tails. Tagged proteins are degraded by the proteasome complex. (This review has details )

PS-341 was a proteasome inhibitorascopubs.org/doi/10.1200/JC…Image
Read 13 tweets
Vincent Rajkumar Profile picture
May 18
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 serendipityImage
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.Image
Because thalidomide was felt to be a drug that cannot cause death due to overdose it was marketed as one of the safest sedatives.

By 1961, it was sold in over 40 countries as a sleeping. It was also tragically used to control morning sickness of early pregnancy. Image
Read 20 tweets
Vincent Rajkumar Profile picture
Dec 9, 2024
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/ Image
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/ Image
I was then so fortunate to examine the natural history of SMM, with the legendary Bob Kyle. Honored to be last author on @NEJM paper that also provided data that most progressions occur in the first 5 years of diagnosis.

The start of the concept of high risk vs low risk SMM.
3/ Image
Read 12 tweets
Vincent Rajkumar Profile picture
Dec 9, 2024
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…Image
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 Image
390 patients with high risk SMM randomized. Largest trial in SMM ever conducted.
Limited duration therapy.

Significant improvement in time to progression to active myeloma or death with Dara.

Benefit seen in almost all subgroups. #ASH24 Image
Read 13 tweets
Vincent Rajkumar Profile picture
Aug 24, 2024
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. Image
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!! Image
2) Generic and biosimilar entry, adoption, and utilization is slower in the US, and there are many barriers.

Timely and adequate free market competition is critically important for lowering price. Image
Read 21 tweets

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