Depth of Response Is a Primary Goal Through Multiple Myeloma Management

Cristina Gasparetto, MD

Patient age, frailty, and cytogenetics should be used to inform treatment decisions irrespective of whether the patient is newly diagnosed or in first or late relapse, explained Cristina Gasparetto, MD, who added that although switching treatment classes is an additional consideration in later lines of therapy, the goal of therapy remains the same: getting patients into the deepest response.

“We need to go out of the gate strong. Using a powerful induction therapy [is important]. Quadruplets are becoming the standard of care so we can achieve a deeper response and maintain the duration of response [DOR] for a prolonged period,” Gasparetto said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on multiple myeloma.

“In the relapsed setting, class switching is very important in choosing the appropriate regimen to achieve deep responses, because unfortunately, we know that we lose patients with time,” Gasparetto added.

In the interview, Gasparetto, a professor of medicine at Duke University School of Medicine and a member of Duke Cancer Institute, shared pearls from the meeting regarding treatment in frontline, early relapsed, and late relapsed multiple myeloma.

OncLive^®: You gave a presentation on early relapse in multiple myeloma. What clinical considerations and trial data inform treatment recommendations in this setting?

Gasparetto: The factors that we take into consideration when we choose the best treatment in the relapsed setting include the patient’s age, frailty, and the presence of other comorbidities, such as renal insufficiency. We also consider the rapidity of the progression and whether the patient had a clinical vs serologic relapse several years or very quickly after initial induction therapy. We also consider the genetics of the disease, in particular the higher-risk patients with deletion 17p [del(17p)], translocation and chromosome 14, and 1q amplification.

We also consider the prior therapies the patient had received and focus also on the toxicity that they experienced. For patients with profound severe peripheral neuropathy, [we may] need [to] change [the dose] and switch to another treatment class. The standard of care now [includes] initial induction with a triplet with or without a CD38-directed antibody. Most patients are progressing after induction, transplant, and maintenance on lenalidomide and then [we must] choose the next [regimen, which may include an agent of a different class].

I also highlighted the data from the phase 3 IKEMA [NCT03275285] and the ICARIA-MM [NCT02990338] studies, which led the FDA to approve the combination of isatuximab-irfc [Sarclisa] with pomalidomide [Pomalyst] and dexamethasone and then of isatuximab, carfilzomib [Kyprolis], and dexamethasone, respectively. There were a fair number of patients that were older than 65 years of age, including 75 and older, with high-risk genetics and renal [insufficiency in those trials]. We did see more myelosuppression with the immunomodulatory drug [IMiD] versus with carfilzomib, which comes with cardiotoxicity, but there was not much difference between the study arms with the addition of isatuximab vs the carfilzomib/dexamethasone control arm. With IKEMA, we’re still waiting for longer follow-up. So far, the progression-free survival [PFS] is not reached for patients on the isatuximab arm, so we’re waiting for updated analyses.

What did you find impressive about these trials?

One of the impressive results of both studies was that the addition of the CD38-directed antibody led to an increased number of deeper responses, even in the relapsed setting. For a patient in first relapse, we’re trying to change the depth of the response. Even in the relapsed setting, it was clear that particularly with the carfilzomib combination, the number of patients achieving [deep responses] was substantial, including patients with high-risk genetics. When you choose and you consider the type of disease, the rapidity [of progression], some of these combinations can have an impact on the outcome of patients with high-risk disease. I was also impressed by the tolerability [of the triplet regimens] in the older populations.

What ongoing research could help bridge unmet needs for patients with high-risk cytogenetics?

In the first relapse setting, I have been working on [research with] selinexor [Xpovio]. The combination of selinexor, bortezomib [Velcade], and dexamethasone was approved in first relapse. In the BOSTON study [NCT03110562], selinexor was also well tolerated in patients with renal [insufficiency]. There were a fair number of patients in the study with creatine clearance between 30 and 60. We saw that selinexor was well tolerated for patients with renal insufficiency, and bortezomib is also well tolerated. It’s a good indication and a good combination that showed impressive results. Also, even though the numbers are relatively small in patients with high-risk genetics, selinexor also seems to be active in this population, particularly in patients with the del(17p).

When we dissected the data of BOSTON comparing [this population with] the entire population, the PFS was very similar; in the overall population the PFS was 13.9 months and for the high-risk population the PFS was close to 13 months, as was the overall response. In first relapse in a patient with high-risk cytogenetics who is progressing after an IMiD you can re-introduce the proteasome inhibitor [PI] with a different mechanism of action like selinexor. In this setting, we have so many options, so you must choose the best option for your patient.

Peter Voorhees, MD, of Atrium Health and Levine Cancer Institute, discussed frontline therapy in multiple myeloma. How has daratumumab (Darzalex) affected traditional paradigms?

The standard of care now in transplant-eligible patients with newly diagnosed disease is the combination of a PI with an IMiD and dexamethasone, but it’s becoming clear that the addition of the anti–CD38 antibody is impactful. We have early data showing if we use the depth of response––the minimal residual disease [MRD] level––as a surrogate end point and base our decision on trying to achieve the deeper response that can translate into a better outcome and longer DOR. We now have data showing that the quadruplets are advantageous in doing that.

The quadruplets with the addition of the anti–CD38 antibodies daratumumab and isatuximab are going to replace the triplet in preparation for transplant [based on the data from] GRIFFIN [NCT02874742], the recently presented study with isatuximab and RVd [lenalidomide, bortezomib, and dexamethasone], and also the data with daratumumab and KRd [carfilzomib, lenalidomide, and dexamethasone]. In the European CASSIOPEIA study [NCT02541383] it’s clear that patients are responding more rapidly [with the quadruplet], they’re achieving a deeper response, which will, hopefully, lead to a sustained, deep response [defined by] MRD negativity. Dr Voorhees highlighted that in all these trials, over time the MRD negativity [rate] is becoming more pronounced in patients receiving the anti–CD38 antibody.

We briefly spoke also about the non-transplant eligible population. We’re still kind of coming out of [modifying our standard regimens for this population]. The overall survival of older patients is shorter compared with the younger population, not because the myeloma is different but because we tend to treat them less aggressively. Going back to how we choose the best treatment for patients, comorbidity, frailty, and age [are all important].

[We saw] very impressive results with the MAIA study [NCT02252172] with daratumumab, lenalidomide, and dexamethasone with a longer follow-up showing incredible PFS for this population and that the regimen is very well tolerated. It’s still unclear but it looks like we may need the PI for patients with high-risk genetics. [For others], we’re still using RVd-lite. It’s very interesting how the addition of this antibody is going to change the field of non–transplant eligible myeloma. In some patients, maybe we don’t need the transplant and instead can use a powerful quadruplet combination extrapolating from the data of the MAIA study.

Your colleague, Yubin Kang, MD, of Duke Cancer Institute, discussed the treatment landscape in triple-class refractory multiple myeloma. What distinguishes treatment considerations in this setting from those in earlier lines of therapy?

With time myeloma becomes resistant and more difficult to treat, so we have to switch treatment classes. BCMA is becoming a new target antigen [because it’s] overexpressed in myeloma cells. Blocking this protein allows patients’ [malignant cells] to go into cell cycle arrest and apoptosis. We have several ways to attack BCMA. We have the conjugated antibody from GSK that was approved by the FDA: belantamab mafodotin-blmf [Blenrep] and Dr Kang touched on that. Belantamab mafodotin is an anti–BCMA therapy approved by the FDA for use as a single agent in patients who have failed at least 4 lines of therapies and it has a unique mechanism of action. It’s an antibody that links to the BCMA and then is internalized by the myeloma cells, releasing the mafodotin, which is a microtubule toxin, bringing the cells to apoptosis. It’s interesting because the BCMA is only expressed on mature B cells and is almost totally absent on the naïve and memory cells, so it’s a good target.

The agent does come with a different type of toxicity we were not used to before with the ocular toxicity. We learned over the past couple of years the importance of partnering with eye care professionals so we can monitor patients regularly. In the DREAMM-2 study [NCT03525678], even in the updated analyses, the drug was shown to be effective with a 30% response with a duration of 11 months at a follow-up of 13 months. The keratopathy, the ocular toxicity is pretty much inevitable for most patients but is not irreversible. They were no patients in the DREAMM study that had irreversible ocular toxicity and that is a very important point. The agent is approved as a single agent in the late relapsed setting, but it’s moving earlier in a combination.

We also discussed a very interesting combination with a T-cell engager showing that the responses are improving. We’ve seen data with [the agent with] pomalidomide, with bortezomib, and we are learning how to dose belantamab mafodotin to increase the intervals [between treatment]. We know from the updated DREAMM-2 analysis that some of the responders, even the patients who had to hold the dose for 1, 2, or 3 cycles, maintain the response with some patients improving their response, which is kind of unique to this drug. In some of these combinations, we may be able to administer the drug at the lower dosage, [enabling a] longer interval with less of the ocular toxicity, hopefully, so we’re very excited about that.

We also have an FDA approval for the BCMA-directed CAR T-cell therapy, idecabtagene vicleucel [Abecma]. Dr Kang talked about the difficulty of enrolling patients on CAR T-cell therapy. In the relapsed setting, you must catch the patient at the right time. Can the patient be prepared for CAR T cells?

We’re also all very excited about the data with the bispecifics. We have the anti–CD3 [antibody] and the bispecific conjugated antibody with the anti–BCMA [approach], and we see incredible responses, preliminarily up to 80%. The toxicity is similar to the CAR T cells but is manageable. The data Dr. Kang presented from the MagnetisMM-3 study [NCT04649359] showed that there were some patients that were previously exposed to anti–BCMA therapy that still responded, so that is becoming very important. With different types of drugs targeting the same BCMA targets, we want to know whether we can sequentially use these drugs. Also, we’re trying to figure out [how to administer] some of these bispecifics, which were originally given intravenously and now are being switched to the subcutaneous, once-weekly dosing option for patient convenience. Dr. Kang also focused on the [data we have for] patients in later relapse who are triple-refractory and penta-exposed and whether we can rescue them. We saw very impressive data from the 2021 ASH Annual Meeting and Exposition [with] these agents [in this population].

What should be emphasized about the current treatment paradigm?

We put a lot of money on the initial inductions [because they’re important]. The importance of continuation [with] maintenance [is also important to highlight]. We are going to have more data on lenalidomide [maintenance] vs lenalidomide with the anti-CD38 antibody, and we’ll see in the future whether we can do even better and whether we can stretch the DOR.

[In the relapsed setting,] the number of patients that are going to sustain therapy in late relapse is smaller. Going strong from the very beginning, maintaining a good quality of life, choosing the best treatment based on the patient’s factors, the genetics, the comorbidities, the prior toxicity, and then trying to use these combinations in a proper sequence [is our goal]. That is going to be the most important piece of information. We don’t want to throw everything [at the patient] without thinking about all these factors. In the future, we’re going to see more personalized medicine such that patients might not need transplant, patients with high-risk disease that need to be treated [will receive more tailored regimens], which we are already doing with more aggressive regimens so that and the best combination is selected based on the patient’s situation, etc.