By Greg Brozeit | Posted - Aug 21st, 2020

 

 

 

 

MCRT Webcast: Three Newly Approved Myeloma Treatments

Three novel myeloma therapies— selinexor (XPOVIO ®), isatuximab (Sarclisa ®), and daratumumb subcutaneous (DARZALEX Faspro ®)— were discussed by three top experts in the Myeloma Crowd Round Table Interactive Webcast held on July 11, 2020:

Joshua Richter, The Tisch Cancer Institute, Mount Sinai Hospital, New York, NYSelinexor (XPOVIO) in Multiple Myeloma

  • New class of drugs: oral Selective Inhibitor or Nuclear Export (SINE)
  • Novel mechanism of action to overcome relapsed and refractory myeloma
  • Selinexor combined with Velcade and dexamethasone (SVd) has significantly better responses as compared to Velcade and dexamethasone (Vd) alone
  • Overview of STOMP study (Selinexor and Backbone Treatments Of Multiple Myeloma Patients) which compares adding selinexor with a variety of common drug treatments

 

 

 

Paul Richardson, Dana-Farber Cancer Institute, Boston, MA: Isatuximab (Sarclisa) Now Available to Treat Newly Diagnosed and Relapsed/Refractory Myeloma

  • An important monoclonal antibody that targets CD38, the same target of daratumumab, but with a different mechanism of action
  • ICARIA study compares isatuximab, pomalidomide and dexamethasone (Isa-Pd) with pomalidomide and dexamethasone (Pd) in relapsed/refractory myeloma shows meaningful improvement in progression-free survival (PFS)
  • Improves outcomes in patients who have been heavily pretreated with other drug regimens
  • Manageable side effects and no loss of quality of life
  • Additional phase 3 clinical trials expected to combine isatuximab with other drugs
  • May be important to treat patients who become refractory to daratumumab

 

 

 

Jonathan Kaufman, Winship Cancer Institute, Emory University, Atlanta, GA: Daratumumab subcutaneous (DARZALEX Faspro)

  • A monoclonal antibody that targets CD38, daratumumab is IV-based, subcutaneous administration allows drug to be absorbed through the skin by a syringe, allowing shorter, less invasive dosing
  • Shown to be non-inferior to daratumumab IV
  • COLUMBA study compared effectiveness both types of drug administration
  • Subcutaneous was found to be non-inferior to IV, essentially equivalent with fewer side effects
  • Emory Winship Cancer Institute has essentially shifted all patients from IV to subcutaneous

 

 

 

Audience Questions & Answers

 

 

 

  • 0:26 - In terms of combination therapies, for a patient who had a bone marrow transplant, what are the pros and cons of low dose Revlimid and DARZALEX as maintenance therapy?  And for a person with IgM Kappa myeloma, started with RVd (Revlimid, Velcade, dexamethasone) that didn’t work, then Dara-Pd (daratumumab, pomalidomide, dexamethasone) and continuing with Dara-Pd as maintenance, what is the thinking about maintenance especially in light of the therapies discussed today?
  • 10:00 - I am currently taking Dara-Pd (daratumumab, pomalidomide, dexamethasone).  What is the protocol to transfer to daratumumab subcutaneous?
  • 11:26 - I am 38, work full time, and want to start a treatment that has fewer side effects and toxicity.  Of the three drugs discussed today, which has the least toxicity and the most efficacy?  I have heard that selinexor has a very high toxicity level and can have a lot of side effects.  Is that true?  [To learn more about the Mayo study cited by Jenny at 14:30, click here.]
  • 22:53 - What is the impact of the 1q gain?  Are there some drugs that are better for this particular mutation or do you just not know yet?
  • 26:13 - If administration of daratumumab is weight-based in the dosing, are there any considerations you take between IV and subcutaneous?
  • 28:34 - With respect to renal issues, is there any difference between daratumumab IV and subcutaneous?
  • 31:18 - A dosing question about selinexor: is it typically given at 80 mg on days 1 and 3 or can it be given once a week?  Is there any difference in the impact?
  • 35:05 - Have any of these drugs been used in combination with Belantamab mafodotin? What are your thoughts on how this drug compares to the drugs you are discussing for high-risk patients? [Note: this newly approved drug will be featured in the Myeloma Crowd Round Table Interactive Webcast on August 22.]
  • 44:18 - If you have failed on Velcade, would you take it with Selinexor?  [Dr. Richter also answered this question online: You can take it with selinexor, however because the control arm of the BOSTON study was Velcade plus dexamethasone (Vd), patients were only eligible for that trial If that combination was an acceptable next line of therapy, i.e., they could not be refractory to Vd.  [More information on the BOSTON study can be found here and here.])
  • 48:50 - If you fail on daratumumab, can you take isatuximab?  If you fail on isatuximab, can you take daratumumab?  And do you think using isatuximab might be better than using daratumumab at first relapse in a patient who took daratumumab as part of their upfront therapy and only achieved a partial remission (PR) and then went on to have a stem cell transplant and Revlimid maintenance?

Additional Questions Submitted by Audience

  1. I'm 81 with recovery from fractures (not transplant eligible) and getting Velcade and dexamethasone since January 2020.  I have IgG Kappa.  Could Selinexor improve initial therapy for this kind of situation?

Dr. Richter answered: This would have to be discussed with your care team.

  1. Can you address the blackout side effect of selinexor?

Answer: Some side effects of selinexor include dizziness, confusion and fainting which are often related to dehydration, so it is important to drink water before and after the medication is administered.  Should you experience any of these symptoms, contact your physician immediately.

  1. Is there detail on selinexor efficacy for patients who have both t(4;14) and 1q gain?

Dr. Richter answered: There are too few patients to make any definitive statements.

  1. My husband had his first Sarclisa (isatuximab) infusion on Thursday.  Other than fatigue he had no initial reactions but is now having some left side chest pain on exertion, none at rest.  Is this a side effect of his infusion?

Answer: Dr. Tom Martin from UC San Francisco discussed this and other issues related to isatuximab in a recent Crowd Radio interview.  He addresses side effects from IV infusion starting at 40:30 in the link above.  A transcript is below the recording link.  Dr. Ravi Vij from Washington University in St. Louis discussed isatuximab in a Crowd Radio interview while it was still in clinical development.  We recommend you make your physician aware of this and follow his or her advice.

  1. Do you think isatuximab may be more efficacious than using daratumumtab again at first relapse in a patient who used dara as part of upfront treatment and only achieved a PR (partial remission prior to a stem cell transplant (ASCT) and Revlimid maintenance?  Now in a very good partial remission (VGPR).

Answer: Dr. Tom Martin from UC San Francisco discussed this and other issues related to isatuximab in a recent Crowd Radio interview.  He compares isatuximab with daratumumab starting at 9:05 in the link above.  A transcript is below the recording link.  Dr. Ravi Vij from Washington University in St. Louis discussed isatuximab in a Crowd Radio interview while it was still in clinical development.

  1. Diagnosed with lambda light chain MM, stage III last September, very aggressive. Prior to stem cell transplant (ASCT) I was on VRd for 12 weeks with great results. Had partial response to ASCT in April and now M spike is climbing. Velcade will be replaced with isatuximab with treatment expected for the next year. I would expect even a better response with this replacement?

Answer: Dr. Tom Martin from UC San Francisco talked about studies comparing isatuximab to Velcade-based regimens in a recent Crowd Radio interview, starting at 23:25 in the link above.  A transcript is below the recording link.  You may also want to ask your physician if the IKEMA trial combining isatuximab with Kyprolis and dexamethasone (Kd) is a possibility for you.  Dr. Philippe Moreau also discussed this in the June 20 Myeloma Crowd Round Table Interactive Webcast.

  1. For a patient on Dara/Pom/dex maintenance  post Transplant and myeloma is slowly returning, turned MRD-positive and labs are slowly worsening. Does it make sense to add isatuximab or replace dara with isa?

Dr. Richardson answered: It’s not likely to help because they are the same class of drugs.  It might be better to add a proteasome inhibitor.

  1. Is daratumumab combined with pomalidomide and dex FDA approved or currently only a NCCN recommendation? If the latter, can subcutaneous daratumumab be used and covered for use in combination with Pomalidomide and dex?

Answer: The National Comprehensive Cancer Network (NCCN) recommends FDA approved regimens and encourages exploring clinical trials for unapproved treatments.  Please see Myeloma Crowd stories on this subject here and here.

  1. Does dexamethasone need to be used with subcutaneous daratumumab?

Answer: The current approved administrations of subcutaneous daratumumab can be found here.

  1. (2 related questions)  Are there any patients who would you keep on daratumumab infusions rather than to try subcutaneous? / What kinds of scenarios would lead one to chose the IV vs. subcutaneous version of the medication at this point, given the similarity of efficacy between the two modes of delivery?

Dr. Kaufman answered: If a patient has bad skin side effects, then we would go back to intravenous infusions.

  1. If you start DARZALEX intravenous can you change to subcutaneous for the remainder of your treatments?

Dr. Kaufman answered:  Yes. We are doing that in almost all of our patients.

  1. (3 related questions) I just had my first DARZALEX infusion last week, wow excellant response in two days.  I did not have the Darselex sub Q because issues with my weight and lower weight less than 165 kilos could cause Neutropenia.  Will DARZALEX Faspro be in lower doses? / Why is the dose of Fas-Pro the same for everyone regardless of weight? / How come dara sc is fixed dose while the IV is weight based? It seems that it should be the same regardless of delivery.

Dr. Kaufman answered: For patients under 143 pounds (65 kg) had a 10% higher chance of neutropenia than those patients who weighed more than that. I don’t change my practice based on patient’s weight. Need to keep a close eye on the neutrophils while getting treatment.  This question is also addressed at 26:13 in the video above.

  1. Can any factors, negative or positive, be attributed to the fact that DARZALEX Faspro is administered as a fixed amount versus DARZALEX IV which is tailored to the patient’s body weight? For example, might neuropathy risk be higher in a light weight patient? What ’perfect weight’ is Faspro designed for?

Dr. Kaufman answered:  There is no major difference in how well the drug works or side effects based on the patient’s weight. There are minor side effect differences but not enough to have a difference based on weight.

  1. Will patients be able to do the DARZALEX Faspro at home? Or can this only be administered in clininc/hospital setting?

Dr. Kaufman answered:  In the United States, this treatment is only available in the clinic/hospital setting.

  1. I have been taking daratumumab now for 1 year.  For the last 5 months I was taking my daratumumab infusion without dex.  Now I am taking dex again with the injection.  Can I again stop dex?  I tolerated the injection well.  My m-spike is undetectable since Jan 2020.

Dr. Kaufman answered: This has not been studied widely. We also have patients who take daratumumab without dex.  If you were able to take dara without dexamethasone, then I think it’s reasonable to try the subcutaneous dara without dex.  It will be important to talk to your doctor about the potential risks associated with this approach.

  1. How is the need to use dexamethasone with Darzalex determined regardless of the mode of administration?

Dr. Kaufman answered: Dexamethasone use is based on the overall treatment. If not needed for treatment, then a small dose can be given to prevent infusion related reactions.

  1. I recently had my first treatment of DARZALEX Faspro.  I am experiencing new side effects, dizzy spells and extreme nausea.  I did not have this with the infusion.  But I am having less post infusion bone pain with the Darzalex faspro.

Dr. Kaufman answered: This is not typical or expected. I would talk to your doctor to make sure something else isn’t going on, not related to daratumumab subcutaneous (DARZALEX Faspro).

  1. Can combining all three drugs even at a lower than recommended dosage might be of benefit?  Thinking of tolerability in the elderly.

Dr. Kaufman answered: Which drugs are you asking about? If asking about the three drugs we are talking about today, you wouldn’t want to do that as isatuximab and daratumumab are very similar.

  1. What is the general progression-free survival (PFS) for daratumumab?

Answer: You can read an article about from the 2019 American Society of Hematology meeting here, but ongoing clinical experience suggests that both PFS and overall survival (OS) rates may be longer.

  1. Does DARZALEX Faspro work for a patient who is no longer responding to DARZALEX IV?

Answer: No, the drug is still the same.  Ask your physician about alternatives.

  1. (3 related questions) Does the daratumumab subcutaneous require the same premeds (dexamethasone, benadryl) with the same waiting periods? / With subcutaous daratumabab are you still infusing all the predrugs needed before the darsalex infusion? / Do the premedications remain with SQ Dara, ie, Benadryl, Pepcid, Dex, Tylenol, Singulair and would these be able to be administered oral instead of IV?

Answer: Dr. Kaufman answers these questions in the video above at the 10:40 mark.

  1. For patients who are exquisitely sensitive to all medication dosages, is it actually easier to measure and adjust the dose with IV daratumumab to see what’s tolerated?

Answer: This is discussed in the questions at in the video above at 26:13 and 28:34 in the video above.

  1. I was diagnosed with myeloma 2 years ago. I had standard infusion of RVd. I also developed neuropathy and so have now a maintenance of Kd.  I am tolerating this well but wondered if adding a third drug will be helpful.  I have decided not to undergo stem cell therapy, hoping a better therapy will develop in the future.

Answer: You can find articles about Kd plus a third drug here, here, here and here.

  1. Is daratumumab subcutaneous meant mainly for relapsed/refractory patients or can it be used for an initial treatment?

Answer: It is approved for both.  A list of approved uses can be found here.

  1. All drugs and studies seem to almost automatically include dexamethasone.  What is the role of dexamethasone in myeloma treatment and has it been studied alone?  Have most of the newer drugs been studied without dexamethasone?

Answer: Dexamethasone is a steroid that helps the adrenal glands to increase the effectiveness of drugs used in cancer therapy.  For many years, the common wisdom was that more was better and helped other drugs to be more effective.  But in the clinical trials for lenalidomide (Revlimid), it was proven that lower doses of dex were actually much more effective to increase the benefit of the drug, which is symbolized by a lower case “d” in drug regimen (for example, RVd: Revlimid, Velcade, low dose dex).  Because of the quality of life side effects, the goal is to eventually limit or not use dex, but it is still evaluated in clinical trials.

  1. (2 related questions)  Has handling the side effects of Kyprolis improved? Especially the cardiac side effects. Are there risk factors for individual patients? / Does any panel member know the nature of the cardiac side effects of Kyprolis?

Answer: The latest information on this issue can be found here.

  1. I will begin cycle 3 using RVd.  Is it necessary to have a stem cell transplant after this?  I would prefer not to.  I have been diagnosed with high-risk disease.

Answer: We do not provide medical advice for specific patients, but a HealthTree University on this subject can be found here and you may also be interested in this article.

  1. (2 related questions) With increasing number of new combinations of drugs is a second stem cell transplant (ASCT) still a beneficial option?  If so, when in the myeloma journey? / With all of the new myeloma medications, is there a trend to skip stem cell transplant (ASCT) and stay with all of the new meds?

Answer: Information about increasing evidence that a second transplant is beneficial for patients with high-risk disease can be found here.  This article contains a link to an important study about the subject.  Dr. Jennifer Saulo from Duke University discussed how to prevent infections before and after stem cell transplant in a Crowd Radio interview.

  1. Are there any new developments in smoldering myeloma?  What are the top three numbers to watch before treatment?

Answer: Dr. Irene Ghobrial from the Dana-Farber Cancer Institute discussed smoldering myeloma progression in her Crowd Radio interview on the Promise Study starting at 17:05 in the link above.  A transcript is below the recording link.

  1. (2 related questions) Which therapy would be recommended for treatment of high-risk smoldering myeloma (SMM)? / Are there any studies or have any of the drugs discussed today been used for smoldering myeloma? What have been the outcomes? 

Answer: Treatment for high-risk SMM is only recommended in a clinical trial setting.  Our partner SparkCures lists them on their website, we encourage you to open a HealthTree profile which links your data to their information.  The Dana-Farber Cancer Institute is conducting a global study on disease progression, the Promise Study, which Dr. Irene Ghobrial discusses in a Crowd Radio interview.  You can read an article about recent studies linking genetics to disease progression here.

  1. One more question, how can we build immunization for his condition? Any other supplement that may help?

Answer: Exercise, diet, and appropriate, timely vaccines all aid the immune system.  There is no consensus expert opinion about supplements that prove increased immunity function.  Some articles on this subject can be found here, here, here and here.

  1. From recent genetic studies, are there any new treatment paradigms for BRAF positive patients or other mutations?

Answer:  A clinical trial is investigating the use of approved drugs for other cancer types with BRAF mutations in myeloma.  Information can be found here and here.

  1. My father is taking carfilzomib, pomaldomide and dexamethasone (KPd), his M spike is now 0.9, kindly share your view on it.

Answer: Results from a clinical trial on this regimen were released at the 2018 American Society of Hematology meeting.  An article with links can be found here.

  1. I am relapsed myeloma patient and my doctor started carfilzomib, pomalidomide & dexamethasone (KPd) after 3 month of it my M spike reduced from 1.90 to. 9, kindly suggest best line of treatment.

Dr. Richardson answered: I suggest you continue KPd, it may need more time.

  1. Are allogeneic transplants still used in your clinics?

Answer: Allogeneic, or allo, transplants (getting stem cells from another donor) are still relatively rare in myeloma treatment, but can be very effective for a small population of patients, mostly younger.  Dr. William Matsui from the University of Texas at Austin discussed allo transplants in a 2018 Crowd Radio program, when he was a member of the Johns Hopkins faculty, which can be found here.

  1. Are any of these drugs discussed being used for MM that has migrated to the lymph nodes?  If I recall I’m t(14;20).

Dr. Richardson answered: This is extramedullary disease (EMD) and, yes melflufen in particular helps with EMD.  (You can find a short description of EMD this HealthTree University video.)

  1. I have a blood clotting disorder and take Eliquis. Does my disorder limit the type of treatment I can receive now and in the future?

Dr. Richardson answered: No, it does not limit your treatment options, but you need to continue Eliquis, however.

  1. I'm curious about where you feel CELMoDs will fit into the treatment paradigm in the future? And a second, if I may, Are bi-specifics going to be better than the other CAR Ts?

Answer: CELMoDs will be the topic of the August 22 Myeloma Crowd Round Table Interactive Webcast.  Bispecifics and CAR T were covered in our June 20 webcastHere is a recent article on bispecifics.  Two recent articles on CELMoDs can be found here and here.

  1. Is the STOMP trial open? What are criteria for entry?  Where is trial offered?

Answer: You can find information about the STOMP clinical trial and other information on our partner SparkCures website here.  We encourage you to contact SparkCures for more guidance.

Thanks to our Myeloma Crowd Round Table sponsors

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Greg Brozeit
About the Author

Greg Brozeit - Greg is the Program Director for the Myeloma Crowd patient education programs. He is based in Northeast Ohio.

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