By Paul Richardson, MD
What can Pomalidomide/Dexamethasone do for Relapsed/Refractory Multiple Myeloma Patients? ICARIA-MM study was a randomized phase 3 international trial in which we compared Pomalidomide/Dexamethasone to the combination of Isatuximab, Pomalidomide, Dexamethasone and we showed the significant PFS (progression-free survival) benefit.
And very importantly at this meeting we presented a survival update, which showed significant survival gains. Now, one of the most important things about the drug is that Isatuximab is obviously similar to Daratumumab and when you have patients in whom Daratumumab was used after they had progressed on the control arm, which was Pomalidomide, Dexamethasone.
How did that confound the interpretation of survival? And we used a particularly sophisticated statistical method to look at that and show that there probably was an interaction. And if you discounted the Daratumumab effect, the hazard ratio for clinical benefit from Isatuximab being used early was that much more striking.
So we thought in that context, we should look at all these subsequent therapies and see how they impact. Does know Isatuximab, Pom/Dex, if you use it early, does it engender resistance or a more dangerous phenotype when the disease, recu rebounds and what we showed with this long-term follow up, looking at subsequent prior regimens.
The duration of the trial for the participants includes up to 21 days of screening (or up to 28 days for women who can become pregnant). The participants continued treatment of multiple myeloma until disease progression, an intolerable adverse reaction, the participant's desire, or another reason.
During healthcare professionals follow-up, participants who discontinued the study treatment due to disease progression were followed every 3 months (12 weeks) for survival (or until the cut-off date), whereas participants who discontinued the study treatment prior to disease progression were followed every 4 weeks until disease progression, and then every 3 months (12 weeks) for survival (or until cut-off date).
Active Comparator: Participants received pomalidomide 4 milligrams (mg) Per os (PO) on Days 1 to 21 of each 28-day treatment cycle plus dexamethasone 40 mg (participants greater than or equal to (>=) 75 years of age received 20 mg dexamethasone) PO on Days 1, 8, 15 and 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's desire to discontinue study treatment, or for any other (maximum exposure: 73.7 weeks).
Participants received isatuximab 10 mg/kg intravenous (IV) infusion on Days 1, 8, 15, and 22 of Cycle 1, and then on Days 1 and 15 of subsequent cycles, in addition to pomalidomide 4 mg orally (PO) on Days 1 to 21 of each 28-day treatment cycle and dexamethasone 40 mg (participants >= 75 years of age received 20 mg dexamethasone), PO or IV on Day 1, 8, 15, 22 of each 28-day treatment (maximum exposure: 76.7 weeks).
Even after receiving a triplet combination that contains a monoclonal antibodies, this data reveals that the majority of patients with RRMM require numerous lines of future therapy.
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Is that patients remained responsive, and even if you'd had the triplet, you still did very well in terms of overall response? And that, what we call PFS2 was still very impressive. That means you look at the second progression and how long that lasts. And so for our patients, we were clear that isatuximab, Isatuximab, Pom/Dex is a very important platform.
The Pom/Dex arm obviously didn't perform as well as the triplet, but we also showed that if you received Pomalidomide and Dexamethasone, you could be successfully treated with a CD38 platform. So really nice data on subsequent therapies and how to sequence, and certainly Isatuximab showing, you know, its value as a very potent CD38 antibody.
Dr. Paul Richardson is the R.J. Corman Professor, Medicine, Harvard Medical School, currently at the Dana-Farber Cancer Institute, he joined the Jerome Lipper Myeloma Center in 1999, became Clinical Director in 2001, and developed numerous first-generation new relapsed/refractory multiple myeloma medications, including bortezomib, lenalidomide, and pomalidomide.
Panobinostat and second-generation proteasome inhibitor like ixazomib have been studied since. Elotuzumab, daratumumab, isatuximab, antibody drug conjugates as belantamab mafotetin, and other immunotherapeutic techniques have been developed for untreated and relapsed myeloma.
He is also developing the targeted cytotoxic melflufen, the first-in-class small molecule inhibitor selinexor, which inhibits XPO-1, a critical nuclear export protein, and first-in-human investigations of cereblon E3 ligase modulators (CELMoDs) for relapsed and refractory myeloma. He has spent the past decade developing lenalidomide, bortezomib, and dexamethasone (RVD) and incorporating it into the Intergroup Francophone Myelome (IFM)/DFCI clinical trial for newly diagnosed patients candidates for a stem cell transplant who are treated with RVD.
This regimen had an unprecedented response rate, which led to its adoption in this multinational study and additional US and foreign investigations. Genetic and proteomic analyses will create a platform for individualized therapy and optimal stem cell transplant location in 2021-22. RVD also supports next-generation drugs including elotuzumab, daratumumab, isatuximab, and panobinostat.
Over 400 original publications and 330 peer-reviewed reviews, chapters, and editorials are his. He was the Chairman of the Multiple Myeloma Research Consortium (MMRC) Clinical Trials Core for five years and continues to participate on the Steering and Project Review Committees. He sat on the ASCO Hematologic Malignancies Subcommittee and Internet Cancer Information Committee for one year each in 2017.
He is Alliance Myeloma Committee chairman since 2011. The George Canellos Award for Excellence in Clinical Research and Patient Care, Tisch Outstanding Achievement Award for Clinical Research, and Royal College of Physicians (UK) Honorary Fellowship for international contributions to multiple myeloma and stem cell transplantation are among his honors. Therapeutic targeting of the ubiquitin-proteasome system earned him the 2012 Warren Alpert Foundation Prize.
He co-won the 2009 and 2017 Research Center of the Year Awards and the Accelerator Award for clinical research and patient enrollment in MMRC studies. Thomson Reuters Science Watch named him one of DFCI's 19 most cited researchers in 2016.
He received the 2015 ASH Ernest Beutler Prize for clinical science and translational research in the development of proteasome inhibition as an effective treatment for multiple myeloma, the 2016 COMY Award for MM research (Paris, France), the 2017 IMF Robert A. Kyle Lifetime Achievement Award, and the 2019 Morse Research Award.