The Evolving Treatment Landscape for TCR MM


An expert in multiple myeloma shares her perspective on the significance of recent single-agent approvals for patients with triple-class refractory multiple myeloma and highlights promising combination regimens under investigation.

Adriana Rossi, MD: This patient case highlights what is a recognized unmet need—patients with triple-class refractory who have had a number of lines of therapy, have been exposed to all of our strongest agents, and are now relapsing. It’s very exciting to see as the field evolves that we do have a number of drugs that have been studied specifically in this patient population. And even if the drugs have been used as single agents, we are getting responses, which is something that was unheard of 10 years ago. Having single-agent response is going to change that landscape. In general we tend to use combination therapies for myeloma to get deeper and more durable responses. And as we combine these agents, the effect this will have on survival will be palpable. We used to say, your first remission is your best and deepest. I think it’s still a concept. You try to get that deepest first remission and try to get it to last as long as possible. But we are now seeing unprecedented responses, even MRD [minimal residual disease] negativity, in heavily pretreated patients.

As data accumulate on some exciting new agents and new modalities, I think we will see even more changes. Namely, I think in addition to ADCs [antibody-drug conjugates], there are the bispecific T-cell engagers, as well as the CAR [chimeric antigen receptor] T-cell therapies, which are cellular therapies approved in other disease states, and hopefully soon to be approved in myeloma that will provide, again, a completely novel mechanism. Based on current data, we have reason to expect very deep responses, and we are learning how to make them durable responses for these patients.

We now have data for combination therapies, not only using 3 agents, but 4, which I think in the past we would say, 4 drugs offered way too much toxicity. But the addition of a monoclonal antibody to a triplet regimen seems to be not only well tolerated, but incredibly efficacious. Especially in a patient who would be transplant ineligible, using 4 drugs to get them into that deepest MRD-negative state is a very doable thing. Using combinations of, maybe, stem cell transplants with CAR T therapies, and how to sequence such therapies in patients who are eligible, will be another interesting challenge for the field. Also combination therapies; with belantamab, we have impressive data for a single agent, but we are now working toward getting combination data. DREAMM-8 is one such study, comparing pomalidomide, dexamethasone, and belantamab to pomalidomide, dexamethasone and bortezomib. What I would say, VPd [bortezomib, pomalidomide, dexamethasone] is a very good triple. So if BPd [belantamab, pomalidomide, dexamethasone] can do even better, that would be fantastic. I think we only have reason to believe it can. There are preclinical data supporting the combination of pomalidomide and enhancing the effects of belantamab. It seems in the clinic, we’re now starting to see that come to fruition as well.

I think one of the exciting things we are missing is a system of classification for myeloma and a biomarker-driven therapeutic approach. For now we do remarkably well, and most triplets will give you a 90% or higher response rate. But we don’t know which drug works for which patient. And while multiple myeloma is considered a single diagnosis, anyone in clinic knows there are very different patients. Cytogenetics and risk stratification go some of the way. I think it informs and alters how we maintain patients or how we pick their second, or third, or fourth line. But especially high-risk patients who are going to go through everything we have available and need something else in shorter and shorter intervals, it would be great to be able to predict and say, here is a patient who really needs an alkylator, or here is a patient who doesn’t need to go through that toxicity because it is not an effective regimen. For now it’s a lot of trial and error, but there is a lot of ongoing research and efforts to try to develop either a system or a biomarker, or identifying how we can better pick the right treatment for the right patient, especially as our selection is getting so big and vast, not a problem we used to have.

Transcript edited for clarity.

Case: A 75-Year-Old Woman with Triple-Class Refractory Multiple Myeloma

Initial Presentation

  • A 75-year-old woman diagnosed with multiple myeloma 5 years ago returns to the clinic with complaints of extreme fatigue, increased muscle weakness and new bone pain in her right hip, right forearm and low back. She reports that she is currently taking antibiotics for a bacterial infection, her third in the last 12 months.
  • Treatment history:
    • Initially treated with DRd; CR lasting 20 months
    • Switched to VRd, stable disease lasting 16 months
    • Subsequently switched to KPd, achieved a PR lasting 12 months
    • Started selinexor; follow up at 9 months showed M protein increase by 0.5 g/dl; patient continued to feel well 
  • Currently, 3 months after her last visit, she returns to the clinic for follow-up
  • PE: new bony tenderness appreciated on right hip, pelvis forearm and lumbar spine; bruising and mild bleeding of the gums

Clinical Workup

  • Labs: Hb 6.2 g/dL, calcium 8.4 mg/dL, LDH 160 U/L, creatinine 2.1 mg/dL, albumin 2.7 g/dL, b2 microgloblulin 4.9 mcg/mL, serum M-protein 4.2 g/dL, lambda free light chains 4.1 mg/dL
  • HBV negative
  • Skeletal survey and MRI revealed lytic bone lesions in the left hip, pelvis and L2 vertebrae and lytic lesions as well as a hairline fracture in the distal radius of the right arm
  • Bone marrow shows 62% plasma cells IgG k
  • FISH: t(11;14) at diagnosis; new del(17p)
  • Diagnosis: R-ISS stage II MM
  • ECOG 1


  • Initiated treatment with belantamab mafodotin

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