Patient Scenario: Treatment Options in MM at First Relapse

Transcript:

Joshua Richter, MD: We’re going to briefly go through a case report. Here is a 68-year-old male with IgG kappa multiple myeloma, diagnosed in 2017, Durie-Salmon stage 3a, ISS [International Staging System] stage 2. Normal karyotype and FISH [fluorescence in situ hybridization] showed a 13q–. At presentation, the patient had an M spike of over 3 g, an elevated kappa light chain, was somewhat anemic, normal renal function, a bit of a low albumin, and a borderline upper limit of normal calcium. The patient received RVD [bortezomib-lenalidomide-dexamethasone] for 4 cycles followed by stem cell harvest and autologous stem cell transplant. Received their auto mel [melphalan] 200 [mg on] day 0, April 19, 2018, and was then placed on lenalidomide maintenance starting in August of that year. The patient ultimately achieved a VGPR [very good partial response], M spike went down to 0.12, and kappa normalized. So the patient remained in a VGPR for quite some time between August 2018 and September 2021 when we started noticing a slow increase in the paraprotein. From August to September to October, the M spike rose from 0.13 to 0.42, and then up to 0.75, fulfilling criteria of concern for progression of disease. Based on this progression and these labs, we decided to transfer the patient to another type of treatment, and the patient was started on therapy with daratumumab, pomalidomide, and dexamethasone [dara-pom-dex]. Now, in terms of following some of the AEs [adverse events] the patient underwent, we started with a dose of pomalidomide at 4 mg daily, days 1 through 21 on a 28-day cycle. However, early on in the course, we noticed several episodes of neutropenia. First on cycle 1, day 15 with an ANC [absolute neutrophil count ] of 0.9, and then on cycle 2, day 8, the ANC went down to 0.4, at which point we added not only white cell growth factors, but we decided to dose reduce the pomalidomide down to 2 mg for 3 weeks on and 1 week off. Subsequently, once resumed, the patient continued on treatment and no further episodes of neutropenia were noted. The patient responded quite well to therapy, and we see over the course of several months, the patient achieved another deep remission down to an M spike of 0.08. However, of note, what we see many times when we start patients on anti-CD38 therapy, there was a compensatory hypogammaglobulinemia that went along with it. As a result, the patient had a minor URI [upper respiratory infection] in December 2021, treated with a Z-Pak. However, developed a more serious bacterial pneumonia in February 2022, requiring hospitalization and IV [intravenous] antibiotics. As such following discharge, we initiated the patient on monthly IVIG [intravenous immunoglobulin], and over the course of the next few months we saw improvement in IgG levels. No further episodes of respiratory infection, and at the time of this recording the patient remains on continued maintenance with IVIG, dara-pom-dex at the lower dose of pom, and is doing quite well. So I’d love to open it up for thoughts about options at first relapse and management choices.

Alfred L. Garfall, MD: There are a number of options to choose from these days, and dara-pom-dex is one of the favorites. It’s got excellent phase 3 data, especially for a patient who hasn’t had anti-CD38 antibodies before. I’ve been enthusiastic in this setting also about daratumumab and carfilzomib based on the CANDOR study [NCT03158688] for patients that you think can tolerate carfilzomib for long duration and don’t have cardiovascular comorbidities, [who] have some of the best PFS [progression-free survival] that’s been recorded in [the] second, third, or early relapse setting. And so I think those are both great options, and this patient also had some of the classic adverse events that happen with the neutropenia and the infections. But as you illustrate here, [they] are manageable [adverse] effects that allow the patient to tolerate the regimen ultimately and enjoy a nice myeloma response.

Joshua Richter, MD: Is everyone here [starting at] 4 mg and [going] down to 2 mg, or 2 mg and [going] up to 4 mg?

Natalie S. Callander, MD: I’d say 2 mg and hold. Particularly when we’re talking about frailty in older patients, I think 25 mg of lenalidomide…most people cannot tolerate that very long. So for pomalidomide, I usually don’t start at 4 mg. But to Al’s point, if I had a high risk relapse, I would go straight to carfilzomib. The longest PFS is the IKEMA data [NCT03275285] right now with isatuximab. And if the new delivery system, the subcutaneous formulation, comes out, you go to every other week faster. But their PFS is pretty good, it’s like 34 months.

Elizabeth O’Donnell, MD: And the important thing too is, you’re coming off lenalidomide and you’re going into a proteasome inhibitor. So that’s one of the desirable things about switching to a carfilzomib-based regimen with a monoclonal antibody.

Natalie S. Callander, MD: Although your former colleague published a paper that if you…

Elizabeth O’Donnell, MD: Dara-KPd.

Natalie S. Callander, MD: No, but if you were lenalidomide-exposed, they were looking at [daratumumab- pomalidomide-dexamethasone] responses, and it didn’t make a whole lot of difference as long as you’re using the dara-pom-dex. But that’s the No. 1 choice in America right now.

Elizabeth O’Donnell, MD: There is a phase 2 study by Dr Yi Lin [MD, PhD] that is also looking at the quad. So patients who’ve not had daratumumab upfront. So…again, that’s an interesting option in terms of a high-risk patient as well. This patient had 3 years of remission, but if it was less, that’s an attractive option as well.

Susan Bal, MD: It’s hard to get people through 4 mg of pomalidomide as…was wonderfully illustrated in this case. And I start my fitter patients on 3 mg, and then the frailer on 2 mg. And most patients can’t handle the 4 mg dosing with the daratumumab.

Alfred L. Garfall, MD: Now, one thing to think about with neutropenia on IMiDs [immunomodulatory drugs], especially for a multiple myeloma patient population, that’s in reach for Black patients is Duffy-associated neutrophil count, which was previously turned [into] this benign ethnic neutropenia. It is associated, now recognized, with a certain Duffy blood group phenotype and can be tested in blood banks. And now I’ve seen clinical trials start to incorporate different neutrophil count dose adjustments based on the presence of this. And if we identify this in our patients, we probably should not be as aggressive with dose reduction, which probably should be tolerating lower neutrophil counts in these patients, maybe around 1000. Whereas otherwise we would dose-address and maybe undertreat these patients. So [it] can be tested for and should inform our management of neutropenia in Black patients.

Joshua Richter, MD: It was mentioned, this patient is CD38 naïve. CD38’s going to be part of it. Are we all saying…ALM is more common in CD38, Kyprolis [carfilzomib]only for the more aggressive? Or does anyone have any feelings about how you would choose one versus the [other]?

Natalie S. Callander, MD: I had recently a patient who has a spouse who’s also undergoing cancer treatment. And the statement that was made to me, give me the thing with the highest response rate and first relapse. And it is with K [Kyprolis]. There’s no way that you can’t say that based on the data that’s out there. But I will say another regimen that I found very useful for people who are coming in on CD38 or recently treated with CD38 is [pomalidomide-bortezomib-dexamethasone], which has also I’ve been pleasantly surprised. It’s pretty easy.

Joshua Richter, MD: I’ve been optimistic about that regimen as well.

Natalie S. Callander, MD: But I’ve had a couple of our MASTER [trial; NCT03224507] patients who’ve done very well on that. That’s also in the portfolio.

Elizabeth O’Donnell, MD: Are you doing the bortezomib once or twice weekly?

Natalie S. Callander, MD: Oh, it’s all once weekly. I’ll just ask: Does anybody use any of these drugs twice weekly?

Joshua Richter, MD: So, of course, I’d be different. When I use Kyprolis in the upfront setting, where it’s going to be for a limited duration, and just in terms of proteasome inhibition, it’s better twice than once weekly. I go more to the Jakubowiak, Chicago, 36 [mg] twice weekly. When we’re in the relapse setting and we’re at the moment until we all figure out when to stop, I do it once weekly.

Natalie S. Callander, MD: And people can get to your place? Subways or traffic and all that twice a week?

Joshua Richter, MD: If you’ve got a MetroCard, you can get there. Or a Citi Bike.

Susan Bal, MD: It’s a complex interplay of what you choose. The patient in front of you helps dictate some of that. Their comorbidities may lean you one way or the other as they do in upfront therapy. And that’s what we learned from ENDURANCE in the upfront setting. And depending on their tolerability for a PI [proteasome inhibitor], it’s a K [Kyprolis] vs PALM decision. That’s where we think [we’re at], knowing the data that we do have. To answer your question about the twice weekly, the only time that I’ve ever used twice weekly is a patient presenting in renal failure where you want to get a deep response in the light chains to help recover their renal function. That’s the only setting I’ve used.

Natalie S. Callander, MD: I was going to say the exact same thing. I do that for 2, maybe 3 cycles and then transition.

Transcript edited for clarity.