Potential of VRD + Daratumumab in Myeloma

Ajai Chari, MD:The future for this particular patient population that I think is really exciting is going to be daratumumab/VRD. And the reason that I bring this up is that if you go back in time, we know that with these melphalan-based regimens—although they are used globally because of the low cost of melphalan—the problem is that melphalan can be slow to act, it can be stem cell toxic, it’s really cleared, it doesn’t necessarily work in high-risk disease, and it can lower blood counts. So, it has a lot of features that American oncologists don’t like, and since we have the ability to use many drugs, we often don’t use melphalan. And so, when we had the first study that compared lenalidomide/dexamethasone to melphalan/prednisone/thalidomide (MPT), that showed definitively that lenalidomide/dexamethasone was superior in terms of progression-free survival and efficacy outcomes to MPT, showing that RD was probably the better regimen for elderly patients.

Then came the SWOG study that was recently published, which showed that when you take patients without an intent to transplant and do VRD plus RD, the VRD led to a better response rate, progression-free survival, and overall survival. And so, for that reason, VRD is really the preferred induction regimen. The problem with the SWOG study, though, is that it wasn’t restricted to elderly patients or transplant-ineligible patients. It was just without the intent to transplant. And so, there were relatively few patients who were above the age of 65. And also, what we really need to think about for older patients is safety, and VRD in the SWOG study was given with twice-weekly bortezomib, standard-dose lenalidomide, and standard-dose dexamethasone.

So, I think for transplant-ineligible patients, we have already published that in our series, we looked at about 120 patients at our institution who are over the age of 70, and we found that the best outcomes really occurred with VRD. But here we give bortezomib weekly; lenalidomide is dose reduced based on renal function, age, and lower doses of steroids, and we really had very impressive progression-free survival of 36 months—very high response rates. We hadn’t reached a median overall survival.

I think this is where daratumumab/VRD will be very exciting, because previous studies have shown that 4 drugs are not always better than 3 drugs. For example, the addition of cyclophosphamide to RVD did not improve outcomes and led to more neutropenia, and so not all 4 drugs are better than 3 drugs. However, what’s unique about daratumumab is its clean side effect profile. It’s a monoclonal antibody, so it has been safely combined with both proteasome inhibitors, both IMiDs, all 3 IMiDs, cyclophosphamide, and melphalan. And so, we think that this quadruplet is different from a standard quadruplet, and we already see that the daratumumab/VMP has shown superiority to VMP.

So, I think there’s a lot of interest in this daratumumab/VRD. There is a randomized frontline study comparing VRD with daratumumab/RVD in transplant-eligible patients, so we’ll see what those data look like. But at our institution, we’re very excited about the investigator-initiated study with daratumumab/VRD with dose attenuation for transplant-ineligible patients. And, of course, the other very exciting thing that will be coming forward would be the daratumumab subQ. And that, particularly for elderly patients, will be really impressive, because there’s going to be super well tolerated, with minimal volume, minimal time in the clinic. So, I think the daratumumab subQ data are really encouraging, and I think we’re all excited to see how that daratumumab/VRD with the subQ daratumumab will look in this elderly population.

Transcript edited for clarity.

• A 74-year-old woman was admitted to the ICU with pneumococcal bacteremia. She complained of recent severe fatigue, loss of appetite, nausea
• History: chronic HTN, aortic insufficiency, diabetes mellitus
• X-ray of the pelvis showed numerous lytic lesions in the ilium and a large lesion in the right proximal femur
• MRI confirmed a 9-mm lesion in the right femoral head and numerous bilateral T1 hypointense and T2 hyperintense lesions in both iliac region
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  • Ca²⁺16.35 mg/dL
  • Creatinine, 1.0 mg/dL
  • Creatinine clearance, 59 mL/min
  • M-protein, 1.6 g/dL
  • B2M, 4.9 mcg/mL
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• Bone marrow biopsy, 70% plasma cells
• Molecular testing, t(4;14)
• ECOG 2