Frontline Treatment Options for Multiple Myeloma


An expert hematologist-oncologist reviews the standard of care for transplant-eligible and transplant-ineligible patients with newly diagnosed MM and explores the role of quadruplet induction regimens.

Clifton C. Mo, MD: It would be highly questionable whether this patient, who’s 79-years-young with some comorbidities, would be considered transplant eligible. Admittedly, this is a point of ongoing debate within our circle. Historically or canonically speaking, she would not be considered transplant eligible by way of her age, essentially almost 80 years old, although there are some who still do transplants for people up to age 80. There are some data suggesting that, with carefully selected patients, this is a reasonable and defendable approach. It’s another question entirely as to whether high-dose melphalan and autologous stem cell transplantation would be advisable, or in the best interest, or even necessary in a 79-year-old patient with stage I, standard-risk disease.

Hypothetically speaking, if this patient were transplant eligible, in my opinion, the standard of care in early 2021 would probably still be an IMiD [immunomodulatory drug] and proteasome inhibitor-based triplet regimen. The 2 main regimens that are given these days are RVd [lenalidomide, bortezomib, and dexamethasone] and KRd [carfilzomib, lenalidomide, and dexamethasone]. In terms of which is better, that’s a point of some debate. We now have data from the recently reported ENDURANCE study of RVd [lenalidomide, bortezomib, and dexamethasone] vs KRd [carfilzomib, lenalidomide, and dexamethasone] in newly diagnosed patients with some degree of high-risk disease included in this study, but a significant percentage of high-risk patients were excluded. Within that trial, we saw essentially no advantage of one regimen over the other, with essentially superimposed progression-free survival curves. Importantly, there were expected differences in the common toxicities, with peripheral neuropathy obviously being more common in the RVd [lenalidomide, bortezomib, and dexamethasone] arm, but cardiac, pulmonary, and renal events being more common in the Kyprolis [carfilzomib]-containing KRd [carfilzomib, lenalidomide, and dexamethasone] arm. In my opinion, both of these triplet regimens are still very much within the standard of care.

There is a hypothesis at least that Kyprolis [carfilzomib] may have some advantages in high-risk disease, although I don’t think we have proven that or know that with certainty. They’re both quite reasonable. Personally, I tend to give more RVd [lenalidomide, bortezomib, and dexamethasone], although in select patients, specifically younger patients with lower risk of cardiac complications, I seriously consider KRd [carfilzomib, lenalidomide, and dexamethasone] on a case-by-case basis. The big question in 2021 and moving forward is this: what is the role of the anti-CD38 monoclonal antibody-containing quadruplet regimens, where an antibody such as daratumumab or now even isatuximab, is added to an RVd [lenalidomide, bortezomib, and dexamethasone] or a KRd [carfilzomib, lenalidomide, and dexamethasone] triplet backbone regimen?

What we know from multiple studies now is that the addition of this type of immunotherapy results in significantly higher frequency of deeper responses, including complete responses as well as minimal residual disease-negative responses. In that sense, regimens like the daratumumab/RVd [lenalidomide, bortezomib, and dexamethasone] regimen, which recently made its way into the NCCN [National Comprehensive Cancer Network] guidelines as an option for newly diagnosed transplant-eligible patients, are more potent and have a greater chance of getting to the 99.99% eradication of the myeloma cell, which may very well ultimately translate into improved long-term outcomes. However, because these data are still relatively immature, we still can’t say with certainty that it will improve long-term outcomes.

Without talking for the next hour about the quadruplet vs triplet debate, there are potential advantages of transplant-eligible patients receiving quadruplet induction regimens on a case-by-case basis. There are knowns and unknowns, and it ultimately comes down to a very individualized decision based on multiple factors, such as the oncologist’s assessment of the risk level of the patient as well as the patient’s personal preference.

In the transplant-ineligible population, the 2 regimens that are most commonly being chosen from in our current era are the RVd [lenalidomide, bortezomib, and dexamethasone]-lite regimen, which I previously alluded to, as well as the daratumumab plus Revlimid [lenalidomide] and dexamethasone regimen, or daratumumab/Rd or DRd [daratumumab, lenalidomide, dexamethasone] as we commonly call it. Both of these are included in the NCCN guidelines, and daratumumab has actually received FDA approval in combination with Revlimid [lenalidomide] and dexamethasone for newly diagnosed patients who are transplant ineligible. This is based on a study called MAIA, which showed that all the efficacy outcomes were significantly better with this antibody-containing triplet approach as opposed to Revlimid [lenalidomide] and dexamethasone alone. In my experience, this is being increasingly used in the community, and appropriately so.

For this patient, either regimen would have been completely fine. Obviously, when somebody has baseline peripheral neuropathy, there is some degree of concern as to the patient’s ability to tolerate prolonged periods of bortezomib, which is the one myeloma drug that tends to cause more neuropathy than the others. However, when given according to an appropriately nonintensive dosing schedule, and with appropriate mitigation and supportive measures in general, I find that even patients with baseline neuropathy can tolerate an RVd [lenalidomide, bortezomib, and dexamethasone]-lite approach. However, the DRd [daratumumab, lenalidomide, dexamethasone] regimen probably affords a lower risk of running into problems with peripheral neuropathy, and this is certainly well supported by the data.

I would say that, in this patient, either of those regimens would have been completely appropriate. An important point is that triplet regimens in general are now considered preferable over doublet regimens, which would be essentially 1 FDA-approved myeloma agent plus low-dose dexamethasone,due to study after study showing improved outcomes with a 3-drug approach as opposed to 2 drugs. However, doublet regimens still have their place and are most appropriate for patients who are very elderly and/or very frail, or for patients with specific concerns about possible toxicities associated with a 3-drug approach.

Transcript edited for clarity.

Case: A 79-Year-Old Woman with Multiple Myeloma

Initial Presentation

  • A 79-year-old woman presented with intermittent nausea, decreased appetite and tingling and numbness in her feet bilaterally
  • PMH: HTN, medically controlled
  • PE: thin, tired appearing woman, otherwise unremarkable; grade I peripheral neuropathy
  • ECOG PS 0

Clinical Workup

  • Labs: Hb 9.6 g/dL, calcium 10.5 mg/dL, LDH 210 U/L, creatinine 1.1 mg/dL, albumin 3.8 g/dL, beta-2 microglobulin 3.2 mcg/mL, M-protein 2.9 g/dL, serum free kappa light chains 4.4 mg/dL, CLCr 35mL/min
  • Hepatitis B and C negative
  • Skeletal survey and MRI showed a lytic lesion in her spine L3/L4
  • Bone marrow shows 45% clonal plasma cells IgG k
  • FISH: hyperdiploid
  • Diagnosis: R-ISS stage I MM


  • Initiated lenalidomide + bortezomib + dexamethasone for 8 cycles + lenalidomide maintenance for 9 months
  • Follow-up at that time revealed disease progression
  • Initiated selinexor + bortezomib + dexamethasone
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