Second-Line Treatment Options for Multiple Myeloma


Dr Clifton Mo describes second-line treatment options for the management of multiple myeloma, and treatment approaches for IMiD- and anti-CD38–refractory MM.

Clifton C. Mo, MD: Both the number and the quality of treatment options in multiple myeloma are improving and continue to improve. Just 15 years ago, we only had 2 FDA-approved novel agents for myeloma. As of approximately a month ago, we had 13. As of approximately 3 weeks ago, we had 14. As of 4 days ago, we now have 15. This is obviously great news, and we have so many more tools in our tool shed or weapons in our holster, if you will, to choose from. This will continue to improve the long-term outlook for people with multiple myeloma. The other side of that coin is that the treatment landscape is becoming increasingly complex, and there are increasingly more options to choose from, which is a great problem to have, but of course, it can still be a dilemma.

In that context, this specific patient has multiple options for treatment in the second-line setting. She has been exposed to Revlimid [lenalidomide] and Velcade [bortezomib]. However, her myeloma is only refractory to Revlimid [lenalidomide], as her disease progressed about 9 months after discontinuation of Velcade [bortezomib] while she was on Revlimid [lenalidomide] maintenance. The other important thing to note is that she did not receive an anti-CD38 monoclonal antibody in the first-line treatment setting. I would classify this patient as being IMiD [immunomodulatory drug] and PI [proteasome inhibitor]-exposed, but refractory to Revlimid [lenalidomide] only. In a patient such as this, in most cases we would strongly consider a triplet regimen consisting of 2 FDA-approved myeloma agents plus low-dose dexamethasone. In terms of the choice of the agents, we would definitely go with something that the patient is not yet refractory to, which means that Revlimid [lenalidomide] is out.

However, drugs like Pomalyst [pomalidomide], and potentially in the near future what we call the CELMoD [cereblon E3 ligase modulator] drugs that are under study, would still have a role in patients like this. There are some thoughts that switching the class of drugs may potentially be advantageous, and there may be something to that. Conversely, it’s also true that there is a significant response rate to Pomalyst [pomalidomide] in patients who are Revlimid [lenalidomide]-refractory. Along the same lines, we know that carfilzomib has activity in patients who are Velcade [bortezomib]-refractory, so I don’t necessarily think that class switching is necessary per se. It again comes down to a thoughtful decision based on not only disease factors but patient factors, adverse effects, comorbidities, and things like that.

In a patient who is not having worsening problems with peripheral neuropathy and who may be more on the elderly side with some risk factors for cardiac complications, such as cardiac disease by itself vs hypertension that is perhaps not well controlled or other risk factors for heart attack and stroke, I would probably reach for something that doesn’t have any potential for cardiotoxicity. This means I would think about giving a Velcade [bortezomib]-based regimen again vs carfilzomib. Although, if the patient has their cardiac risk factors well controlled, I don’t feel that it’s an absolute contraindication to give carfilzomib because most patients like that do quite well.

A Velcade-based regimen would be something I would seriously consider, and then a monoclonal antibody such as daratumumab would probably be the second myeloma drug that I would include. This would be something along the lines of daratumumab plus Velcade [bortezomib] and low-dose dexamethasone [DVd], or daratumumab plus carfilzomib and dexamethasone [DKd]. Isatuximab may potentially be an option in the near future in combination with carfilzomib based on the results of the IKEMA clinical trial. That’s what would arguably be the most common type of combination that would be reached for in the second-line setting.

Importantly though, we now have another option, which would be selinexor. This was FDA approved in a heavily treated, penta-refractory multiple myeloma population. This was approximately a year-and-a-half ago in July of 2019, but much more recently in December 2020, it was approved in combination with Velcade [bortezomib] and dexamethasone in less heavily treated patients: those with at least 1 prior line of therapy. A selinexor-based triplet is a very reasonable and viable alternative in certain patients compared to an antibody-containing triplet, perhaps even in the second-line setting, but it would be a difficult decision.

Although I can’t predict the future per se, I foresee an increasing number of patients who will be what we call daratumumab-exposed, or anti-CD38 antibody-exposed, by the time they reach their second line of therapy due to the increasing adoption of antibody-based regimens in newly diagnosed disease. As I just discussed, this would include both transplant-eligible patients with daratumumab/RVd [lenalidomide, bortezomib, dexamethasone] or daratumumab/KRd [carfilzomib, lenalidomide, dexamethasone], and transplant-ineligible patients treated with daratumumab/Rd [lenalidomide, dexamethasone].

For patients who have already been exposed to an IMiD [immunomodulatory drug] and an anti-CD38 monoclonal antibody, a regimen like selinexor, Velcade [bortezomib], and dexamethasone is even more attractive as an option, as this would involve a brand new mechanism of action that the patient’s myeloma has not yet been exposed to. So it could perhaps afford a higher likelihood of a durable second remission than simply adding another antibody or the same antibody to which the patient has already been exposed. Unfortunately, we don’t have any head-to-head data of these different regimens, such as a DVd [daratumumab, bortezomib, dexamethasone] regimen vs a selinexor/Vd [bortezomib, dexamethasone] regimen. Again, this is part and parcel of these rapid advances that are being made in myeloma. But there would be good rationale for giving a regimen like selinexor/Vd [bortezomib, dexamethasone] in the second-line setting for somebody who is daratumumab- or isatuximab-exposed.

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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