Looking at Important Factors in Deciding Treatment for Relapsed/Refractory Multiple Myeloma

Ehsan Malek, MD

Ehsan Malek, MD, assistant professor, Department of Medicine, School of Medicine, member, Immune Oncology Program, Case Comprehensive Cancer Center, physician, Department of Hematology and Oncology, University Hospitals Cleveland Medical Center, discussed making a treatment decision for a patient with relapsed or refractory multiple myeloma.

Treatment Options for a Patient Relapsing on anti-CD38 Therapy

This patient is progressing in the face of anti-CD38 [therapy], so we can assume anti-CD38 probably is not the best option, [and they are also refractory to] lenalidomide. You’re going to still use pomalidomide [Pomalyst], as the cross-resistance rate is not high—probably 25% to 30% between pomalidomide and lenalidomide—so pomalidomide is still an option. But this patient hasn’t had any bortezomib [Velcade] yet, so there’s no mention of neuropathy, [which makes] that an option still.

Another new mechanism of action is B-cell maturation antigen [BCMA] therapy. For this patient, because they only had 1 line of therapy previously, it is not indicated based on FDA approval of the 2 BCMA-targeted agents that we have, [which are] belantamab mafodotin [Blenrep] and CAR [chimeric antigen receptor] T-cell therapy.¹ The XP01 inhibitor, selinexor [Xpovio], is FDA approved in combination with bortezomib, so that’s also a good option.² [There is also] another new mechanism of action other than anti-CD38 treatment, and that’s immunomodulatory imide drugs [IMiDs].

There are 2 totally new mechanisms of action with a proteasome inhibitor and XP01 inhibitor in elotuzumab [Empliciti], [which is] an anti-CS1. But the problem is that you must combine it with pomalidomide, as you can combine it with lenalidomide, but that is probably not the best option [for this patient]. You must combine it with pomalidomide, and it’s not a bad idea, but there is a 20% to 30% chance of cross-resistance between IMiDs.

The Value of Repeating Bone Marrow Biopsies in Multiple Myeloma

Bone marrow is not an easy procedure, because myeloma is a patchy disease. If you look at one of your myeloma patient’s PET [scans], you’re likely going to see a patchy disease. Depending on where you put your needle, you can have 10% to 15% variables, even.

However, I think people still like and recommend bone marrow biopsy to look at the fluorescence in situ hybridization [FISH] and cytogenetics results. The reason is you may pick up [that a patient has] t(11;14) multiple myeloma. [For patients with t(11;14) myeloma], venetoclax [Venclexta] turned out to be an extremely efficient drug, but [unfortunately] it’s not FDA approved. [However], because it’s FDA approved for [acute myeloid leukemia, chronic lymphocytic leukemia], and so forth, we can still get that easily.³ So, for [this patient group], venetoclax is a very important drug.

I don’t think any patient with t(11;14) multiple myeloma should be on hospice before trying venetoclax. It’s a BCL2 inhibitor.

Many people call t(11;14) myeloma the mantle cell–like myeloma. It’s somewhere between myeloma and lymphoma, and [there is usually a very low M-spike] in this disease, making it very important to repeat bone marrow biopsy at each relapse, because you may pick up [that the patient has] t(11;14) multiple myeloma.

For FISH [testing], you don’t need bone marrow biopsy, you just need aspirate. Now, the question of what the chance is of you finding another FISH cytogenetic is [also] very important. Myeloma is different than leukemia. In leukemia, if you have [a patient who has] IDH1- or FLT3- positive disease, if you are FLT3-negative at any point during the disease, it is highly likely that [the patient is] in remission.

Basically, that FLT3 mutation is [a] characteristic of that clonal disease, but in myeloma, it’s not like that. You have the multiclone at the beginning—so you have 4 clones— and if the initial presentation comes with 1 clone, let’s say del(17p), at the relapse, another clone can come up that’s del(17p)-negative [and] t(11;14)-positive. So at the beginning, that causes renal failure, but at the relapse, you may not have the renal failure.

In conclusion, myeloma does not necessarily repeat itself. It’s important to have an open mind when we look at patients [with relapsed myeloma]. I once had patients that came with cord compression when their initial presentation always was with anemia and renal failure, so it’s important to consider that we have a clonal tide instead of clonal evolution. In leukemia, when you have clonal evolution, 1 clone evolves at a time. But in myeloma, [if] you have clonal tide, then you have 4 or 5 clones that, with each relapse, 1 comes up. It’s very important to define the characteristic of the relapsed myeloma.

The Treatment Impact of Finding Del(17p)

For [a patient with del(17p)], I want to know [whether there’s an] extramedullary disease. That’s very important because, for example, in extramedullary disease, I wouldn’t use pomalidomide that much. It impacts decision-making a lot, and how you’re going to monitor their response.

[For example], if this patient had a del(17p) at relapse, I [would] do a PET/CT scan [to] find a liver lesion, even if I have a low light chain and everything else after salvage, I [would] repeat the PET/CT scan to see what happened with [the] extramedullary disease. [For patients with high-risk disease, and depending on the number of relapses], the chance of extramedullary is higher. Even after 4 or 5 relapses, easily 50% of your patients have extramedullary disease.

Minimal Residual Disease’s Impact on Treatment Decisions

For a trial, minimal residual disease [MRD] always is part of the trial, and so is mostly next-generation sequencing [NGS]. Now MRD is measured by 3 main methods. One is NGS and the idea [that] we define the sequence of idiotype of antibody from that plasma cell clone at the beginning. Then, with a quantitative reverse transcription polymerase chain reaction test [PCR], [which is] a very sensitive PCR test, we look for that genetic signature in subsequent bone marrow [samples]. It’s very sensitive—if you have 1 myeloma cell in 1 million bone marrow cells, you can detect [it].

Another method is next-generation flow cytometry, that is, you [must] have a very good flow cytometrist and good equipment—basically 8-color, at least. It’s very operation-dependent, but it depends on who does that, [and] it [must] be on a fresh sample.

You cannot do [this] on the slide. Flow cytometry [must] happen on a fresh sample. However, the benefit of that is [that] you have only 1 test. You don’t have to define something at the beginning [and] you know your CT signature of myeloma cells in bone marrow, so you look for that up front. You don’t have to define anything before. You [also] don’t see much danger of dilution, because you dilute with the blood. [For example], for the first 3 mL you send for your path in the institute, and another 3 mL you send for flow cytometry for MRD—that’s diluted with peripheral blood.

[Finally, the] method that is upcoming—and I think will be future of myeloma—is the mass spectrometry in peripheral blood. So, the last 2, next-generation flow cytometry, and mass spectrometry in peripheral blood, is not FDA approved. [Generally], the problem with the test in the bone marrow [is that myeloma is] a patchy disease, and it depends on where you get your sample.

I do MRD NGS as standard of care before and after transplant, as well as annually. If you ask any center, different centers have different practices, and I would say [they also have a different] school of thought, too. However, I believe more information is always useful. People that don’t do that say, “Well, sometimes we are not using that [information], so why we are making the patient anxious”?

For people like us, we believe in gathering more information [and] measuring disease more accurately is important. I can give you many examples [where] I shared this information with patients, and we changed their opinion and changed their mind on certain treatments.

more than 30 mL. However, I use selinexor with a good GFR result. I don’t recommend everybody use it, but that’s the low GFR, more than 30 mL, and you can use selinexor safely without any dose reduction.

Before selinexor, we were using cyclophosphamide, bortezomib, and dexamethasone for 6 cycles and had a very nice response and remission. But if you think that patient is [a] candidate for bortezomib, then, of course, they shouldn’t have neuropathy and so forth. But if you think the disease is sensitive, [meaning it doesn’t have much neuropathy], and the patient is a candidate for bortezomib, you can [easily] add a new mechanism of action. It’s very important to add this new mechanism of action very early in the therapy.

So with this concept, if you look at each patient with relapsed myeloma, you can find a patient that can benefit. You can add another tool to your toolbox very early in the therapy, especially in [older] patients, as we get a little nervous when patients get above 70 to 75 years old.

In that category, selinexor has a very nice efficacy among [older] patients. With bortezomib given weekly, usually neuropathy is not that big of a deal. [Of course], sometimes you get a problem, but usually the rate is not that high. So, I would say any patient that you think, still, their disease is bortezomib-sensitive and does not have neuropathy, then that’s the patient you can use selinexor in.

Backbone therapies are very important. Of course, the prior therapy is extremely important, [as well as] how patients respond to that, but there are a variety of options. The best rule of thumb is you [must] look at the prior history and what adverse event the patient is carrying on—neuropathy, heart failure, and so forth. [Clinicians need to also consider] what the toxicity profile of your regimen [is].

Of course, you want to use the newest regimen [and] the newest mechanism of action that [the] patient didn’t have more often. If the patient was on IMiDs and you have opportunity to go on to [a] CD38 and proteasome inhibitor, that probably is preferred, [rather] than daratumumab and IMiDs again.

_REFERENCES:

_{1. FDA approves first cell-based gene therapy for adult patients with multiple myeloma. News release. FDA; March 27, 2021. Accessed November 17, 2021. https://bit.ly/3HAGpjP}

_{2. FDA approves selinexor for refractory or relapsed multiple myeloma. News release. FDA; December 18, 2020. Accessed November 17, 2021. https://bit. ly/3DrqEcF}

_{3. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/ S0140-6736(20)32292-3}