Myeloma Round Table: Disease Progression in Relapsed/Refractory Disease - New York, November 13, 2021 Part 2

Perhaps the best evidence of the progress in myeloma treatment is much better outcomes for relapsed/refractory patients are increasing because they have more options targeting different therapeutic approaches than ever.  Until cures are verifiably achieved, the key for patients and doctors is to find the right treatment at the right time for the right patient.

In this, the second part of the Myeloma Round Table held in New York, NY on November 13, 2021, myeloma experts Suzanne Lentzsch, David Vesole, and Andrew Lesokhin discuss the range of options available.  Their talks serve as overviews of subjects that can be accessed in past Round Table programs, HealthTree University, HealthTree Podcasts (formerly Crowd Radio), and our Community Chapter programs.

Suzanne Lentzsch, Columbia University, Herbert Irving Comprehensive Cancer Center, New York, NY: Relapse - Why It’s Not Necessarily the End of the World

• There are approximately 15 approved novel agents for multiple myeloma
  • Treating myeloma is a challenge, for it changes a great deal over time (with spikes and relapses)
  • Your physician will always choose the best treatment for you with the minimum side effects
• When to start treatment? No clear paths, but here are some general indicators:
  • Some clinical symptoms (CRAB-see Part 1 of this Round Table)
  • Biochemical progression (such as M spike over 0.5) with no symptoms
  • High-risk cytogenetics
  • High-risk disease with progression
• What are the recommended regimens?
  • Lenalidomide (Revlimid) combined with other drugs
  • Two additional drugs combined with the lenalidomide, this is a triplet therapy
• Introduction to immunotherapy
  • Myeloma cells “hide from” immune system
  • They “disguise” themselves as normal cells, to not be identified as foreign
  • This creates a “tumor microenvironment” that nurtures them
• Immunotherapy medications
  • Monoclonal antibodies that target myeloma cell markers (daratumumab an isatuximab are good examples)
  • Immunomodulatories (IMiDs) — End immune suppression caused by myeloma.
  • CAR T Cells — Boost myeloma-fighting cells (which are called T cells).
• Types of antibodies.
  • Naked: used as single agent with nothing attached
  • Drug conjugates: a toxin is attached to kill myeloma cells
  • Bispecific: engineered to bind to myeloma cells with normal killer T cell and/or other therapeutic or chemotherapeutic agents
• Cancer vaccine therapy
  • An injection combining myeloma proteins with immune cell-stimulating agents
  • Considered to be therapeutic, not preventive
  • May be used during consolidation phase after stem cell transplant
• BiTES
  • Small proteins that bind to myeloma cells and kill them
• CAR T-cell
  • T cells are part of immune system that kill threatening cells
  • Each patient’s own T cells are engineered to target and kill myeloma cells directly before being infused back
  • Clinical trials show good responses in people with high-risk cytogenetics
  • Can cause CRS (cytokine release syndrome) because it ‘alerts’ immune system; it is a storm of inflammatory molecules that typically occurs 2 days after therapy

David Vesole, John Theurer Cancer Center, Hackensack, NJ: Lines of Therapy: Good News, Bad News

Current treatment for active myeloma if you are transplant eligible:

• Induction
• Consolidation
• Maintenance

• If not transplant eligible:
  • Induction followed by continuous maintenance therapy
• When to consider “re-treatment”:
  • CRAB criteria are used to determine whether to treat for relapse
  • Differences between biochemical and symptomatic relapse need to be considered: a biochemical relapse shows an elevation of M-spike but no symptoms
  • Biochemical relapse (patients with an asymptomatic rise in M protein) can be observed to determine rate and nature of relapse, does not cause any harm
  • Symptomatic relapse is a strong indication for immediate treatment
• For example, a 65-year-old patient with stage 1 myeloma received Revlimid, Velcade and dexamethasone induction therapy followed by a stem cell transplant was in complete remission for 3.5 years
  • After treatment: elevated M protein 0.6g/l  with no symptoms (rising to more than 0.5 g/dl is considered to be disease progression)
  • 3 months later: more elevated M protein of 0.8 g/l
  • 6 months later: M protein 0.9 g/l
  • 9 months later, M protein 1.5 g/dl, mild anemia
• When to start treatment is difficult choice because side effects and quality of life have to be considered
  • If the protein is going up slowly with no symptoms, maybe a sit and wait approach would be good
  • However, when another symptom is presenting, treatment should be considered, so in this particular case, treatment at month 6 is correct.
• How do we stage myeloma?
  • ISS (international staging system) uses specific markers run on your blood tests called Serum beta microglobulin, albumin (a protein in your blood), and LDH (lactate dehydrogenase)
  • Stage 1: Beta micrologbulin <3.5 mg/L, serum albumin >3.5 g/dL, normal LDH and standard risk genetics.
  • Stage 2: not stage 1 or 3
  • Stage 3: Beta micro globulin >5.5 mg/L + high-risk genetics or high LDH
• Every myeloma patient is different, myeloma is independent, so one should not compare to another
• Other things to think about when starting treatment: diabetes, neuropathy, cardiac problems, elderly or frail patients, renal disease, etc.
• How do we choose therapy for myeloma?
  • Aggressiveness of disease is the strongest predictor
  • Also consider duration of remission, genetic factors, age, and co-morbidities
  • In general, if something worked before, you could try it again; however, I always give a little different cocktail to my patients.
  • We essentially mix and match; there are tons of combinations.

Alexander Lesokhin, Memorial Sloan Kettering Cancer Center, New York, NY: New in the Clinic

• Some patients are resistant to many lines of therapy and still don’t achieve remission.
• This is a medical breach that has to be filled. Some of the novel FDA-approved therapies for advanced myeloma include:
• CAR-T cell (chimeric antigen receptor T cells) therapies: immune cells (T cells) are taken out, sent to a lab, and manipulated, put back into body, ready to target the myeloma
• This is a one-time treatment, and has shown durable responses with three approved CAR T cell drugs:
  • • Ide-cel
    • Cilta-cel
    • Orva-cel
    • There are no head-to-head comparisons between ide-cel and cilta-cel, but both have had impressive responses in relapsed and refractory disease
  • Antibody-drug conjugates mimic natural antibodies but to kill myeloma cells by sticking to BCMA (a specific marker in B cells, the cells that produce plasma cells)
    • Belantamab mafoditin
  • T-cell recruiting Bi-Specifics, BiTEs
    • T cells  (immune cells) have a particular receptor, and they “chew” waste out of your body (like mutated cells, cells with abnormal chromosomes, etc.), and this is what keeps us healthy. This process does not work in myeloma because it “hides” from t-cells
    • They mimic this process to kill the myeloma
    • Shown to work well (70% of response)
    • One advantage over CAR-T is that these BiTES are easily administered
• What about multiple targets?
• The idea is that multiple immune targets could be used sequentially to enhance their natural power
  • More than one target might kill more myeloma cells
• More therapies have been and are being developed
  • Survival rates are still going up, “It’s a promising future for sure!”

Audience Questions & Answers

• 0:19 - While being in remission, what do we look for in terms of light chains?
• 5:22 - How much would a person’s history with bone damage at diagnosis play into when to treat relapse, would bone damage history make a difference in when to start?
• 7:16 - Re: drug treatment sequencing, will CAR T-cells replace a transplant in the future?
• 13:30 - Dara VTd (Velcade, thalidomide, dexamethasone) is currently approved in Germany, but I have an oncologist who can give me Dara VRd (Velcade, Revlimid, dexamethasone). Is the latter worth the considerable effort?
• 18:00 - Re: patient is currently MRD negative and in a trial that is trying to determine whether or not there’s going to be progression. So I was wondering if I am crazy or going downhill and just didn’t know it?
• 20:19 - Is there a role for allogenic transplant in relapsed myelomas or do the upcoming immunotherapies eliminate the need?
• 26:30 - I’ve been under 5 different treatments now.  I’m on Blenrep (belantamab mafoditin) but I get double and blurry vision. I no longer want this treatment, but my doctor keeps saying I don’t have any other options. Is that true?
• 31:10 - Will stem cell transplants disappear due to immunotherapies?
• 36:43 - Re: T cell exhaustion after being in treatment for a long time.  Does one’s immune system become more compromised and have a harder time fighting off infections. We have these stem cells stored away in a freezer and then use them to help boost your immune system again or even make your T-cells a little bit better?
• 41:10 - (Question re: COVID and myeloma.)

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