Multiple Myeloma Awareness Month: Quadruplet Regimens Create New Outlook for Sequencing Therapy

Treating patients with multiple myeloma has undergone significant changes in how clinicians can sequence treatment for patients in a more personalized manner. In particular, new combination therapies have opened a promising pathway to managing the disease over time.

In 1997, thalidomide (Thalomid) was first used to treat patients with multiple myeloma and after extensive clinical trials was then approved, in combination with dexamethasone, in 2006.¹ According to the International Myeloma Foundation, this was the first effective new drug to treat patients with multiple myeloma in decades and helped to launch a new era of novel therapies in the space leading the way for the use of more immunomodulating agents, such as lenalidomide (Revlimid) and pomalidomide (Pomalyst). Moreover, the approvals of these agents have led to the use of adding them other therapies including chemotherapy, nuclear export inhibitors, antibody-drug conjugates, monoclonal antibodies, and proteasome inhibitors. A standard of care that a decade ago seemed less immediate in this space.

“For quite a number of years, triplet regimens were considered as a standard of care, and for many years, the most common regimen that was used was a triplet regimen [consisting of] lenalidomide, bortezomib [Velcade], and dexamethasone [RVd], and it had a great response rate. However, the GRIFFIN study [NCT02874742] introduced the monoclonal antibody daratumumab [Darzalex] up front [in comparison to the triplet therapy RVd] and was found to have a much more robust response,” said Santhosh K. Sadashiv, MD, in an interview with Targeted Oncology^TM.

Now, clinicians are looking at expanding traditional triplet regimens to quadruplet regimens. According to the American Cancer Society, it is preferable to use at least 2 or 3 different kinds of drugs in combination with one another as studies continue to show the efficacy of this approach.²

Clinicians can choose between all the available regimens based on patient and disease characteristics such as the stage of their disease, their age, kidney function, and response to prior therapies, allowing for a more personalized approach for each patient.

Efficacy With Quadruplet Regimens

The GRIFFIN study showed promising results for the quadruplet therapy of daratumumab plus RVd (D-RVd) for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM).³ The primary end point was to assess the stringent complete response (CR) rate at the end of post–autologous stem cell transplant (ASCT) consolidation and patients in the D-RVd arm had a higher CR rate of 42.4% compared with 32% in the triplet arm (odds ratio [OR], 1.57; 95% CI, 0.87-2.82, P = .068).

This also met the prespecified 1-sided α of 0.10, and at a median of 22.1 months follow-up, the stringent CR deepened for patients on D-RVd to 62.6% vs 45.4% in the RVd arm (P = .0177). Minimal residual disease (MRD) negativity rates were also better in the quadruplet arm than the triplet arm at 51% vs 20.4%, respectively (P < .0001).

“In terms of the patients, this means that we can get a quicker and much deeper response, which helps, and has shown to have a benefit in the overall survival,” said Sadashiv, a hematologist with Allegheny General Hospital. “[Moreover], the toxicity was not much different than going from the triplet to quadruplet regimen. So that seems to be the current, almost standard of care, unless there are some other issues that might prevent the use of [it in certain patients].”

While results from the GRIFFIN study remain impressive, many clinicians look to triplet regimens as the building blocks of treatment for patients with multiple myeloma. But with an eye to the future of quadruplet regimens, the large, international, phase 3 Perseus trial (NCT03710603) is underway looking to further evaluate the quadruplet versus triplet combinations examined in the GRIFFIN study. These results could provide further evidence for the use of D-RVd as a potential standard of care in newly diagnosed patients with multiple myeloma.

Sequencing and Treatment Management in Multiple Myeloma

Sequencing depends on several factors for each individual patient along with their diagnosis including their fitness level, age, response to prior treatment, and concerns of overlapping toxicities, explained Sadashiv. These approaches can also be modified dependent on the patients’ disease burden. For instance, patients can have a disease progression in just their protein but may not exhibit other clinical symptoms, which would allow clinicians to utilize a less aggressive approach. However, Sadashiv added if the patient’s disease is much more aggressive, then it’s important to match that with treatments such as chemotherapy that led to a quick response.

“In general, if you ask a myeloma specialist, they will say a patient should receive all of the treatments that are available, as long as there are no overlapping toxicities,” Sadashiv said. “[There's no ways that entirely avoid challenges], but you might want to keep all these factors in place.”

Keeping track of all these treatments becomes paramount, as patients can become overwhelmed with the number of agents in a regimen and the specific goal of each, which is why breaking them down drug by drug can be useful.

In an interview with Targeted Oncology^TM, Prerna Mewawalla, MD, discussed how these complicated regimens should be broken down to patients by the length of the cycle of treatment, the number of drugs in the regimen, and the relevant data they need to know about for quadruplet regimens. Moreover, she explained that it’s important to discuss each drug separately and to provide them with a calendar for the complicated regimens, so they know exactly what to expect and when.

Sequencing does change for patients depending on their disease. For instance, in patients with NDMM, an analysis of several studies has concluded that treatments should provide the best balance between efficacy and safety and cost of the treatment, but these treatments can vary depending on a patient’s biomarkers to identify their risk factors.⁴ However, patients with relapsed/refractory disease may end up on treatments further down the lines of therapy, making clinicians focus more on safety than previous lines.

Sequencing Patients’ Treatment Based on Disease Factors

Another factor that could change treatment approach is whether a patient is transplant eligible or ineligible. Eligibility is important as that determines which induction treatment will be needed for those patients that do opt for ASCT, whereas those who avoid ASCT treatment will either have to go right to alkylator-containing induction regimens or non-alkylator induction regimens instead of typical induction therapies. In both cases, the use of lenalidomide and dexamethasone has only increased as studies have shown promising response rates with continuous Rd replacing the use of melphalan, prednisone, and thalidomide.

However, choosing treatment in these cases doesn’t often come down to just 1 regimen choice as several options are available in each patient population. This makes it important to have patients referred to a transplant center early on, if possible, to discern their eligibility, explained Mewawalla, as it will allow for a clearer decision on frontline therapy. Moreover, it’s important to have a multiple myeloma specialist involved in sequencing treatment decisions if possible in addition to the community oncologist to stay abreast of and best utilize the newest treatment regimens.

“[This would help you] choose the frontline treatment and ask, ‘is it okay to just use RVd? Should we be using D-RVd, based on their risk, performance status, etc,’” said Mewawalla, who is the medical director apheresis at the Allegheny Health Network. “The referral should happen as soon as someone's diagnosed. They can, of course, go back to get their treatment locally, but just to help guide treatment, I think it's important to have a myeloma specialist involved very, very early.”

Treatment sequencing considerations also change as patients go beyond their consolidation and frontline treatments and potential relapse or become refractory to treatment. In a study published in the Journal of Clinical Oncology, researchers looked at the efficacy of treatment sequencing that included both carfilzomib and daratumumab in comparison to those without.⁵

What they found was that relapsed/refractory patients with multiple myeloma had a progression-free survival (PFS) advantage to those who did not receive these 2 treatments. A median PFS of 126 days was seen in patients given daratumumab then carfilzomib and 190 days for patients given carfilzomib first then daratumumab. In comparison, patients on just daratumumab had a median PFS of 104 days and those just on carfilzomib had a median PFS of 117 days. Moreover, the time to response was quicker in the combination groups at 39 days in the daratumumab-first group compared with 88 days in the carfilzomib-first group.

Discussing treatment sequencing should also take into consideration the adverse events (AEs) that would be associated with each regimen, even if the data is in its favor. For example, patients with a cardiac risk factor have to be careful with carfilzomib, as it has been associated with incidences of cardiotoxicity, and clinicians have to weigh the patient’s current condition with the efficacy of a regimen that could be provided. According to Mewawalla, these are serious considerations before any regimen decision needs to be made.

“Also, what I see when it comes to sequencing drugs is what have they had before? Are they refractory to what they've had before? Are they still sensitive to what they've had before like, are they [especially] lenalidomide sensitive vs refractory?” Mewawalla elaborated. “If they're sensitive, then I can still use combinations like daratumumab, lenalidomide, and dexamethasone. If they're refractory, then I can use daratumumab, bortezomib, and dexamethasone.”

The Road Ahead for Multiple Myeloma Treatment

As the past decade in the multiple myeloma field has led to major developments and novel therapies, clinicians are already looking to the next decade to see how much further developments can go. Oral therapies have helped to make sure patients can have their treatment more readily available. One topic both Mewawalla and Sadashiv echoed in their interviews is that along with stronger therapies, AEs can be more readily handled with new interventions and a better understanding of management practices.

According to Sadashiv, patients should understand that current treatments don’t have the same intensity of AEs like prior chemotherapy did, and it’s important that the usual concerns patients may have with chemotherapy-style treatments are addressed. Furthermore, those patients should be informed that current treatments can provide patients with more hope if further lines of therapy are needed. According to Mewawalla, there is still hope to consider fifth and sixth lines of treatments with novel therapies and that more are on the way.

“If you're a physician, you have a lot more to offer to the patient. So that is very comforting, as it's always very tough to tell the patient that you don't have any other option,” Sadshiv concluded. “A lot more options are coming up, which are easily tolerable, and hopefully we'll be able to cure myeloma soon.”

_References

_{1. Thalomid (thalidomide) for treatment in myeloma. International Myeloma Foundation. August 1, 2019. Accessed March 18, 2022. https://bit.ly/3txc3tv}

_{2. Treating multiple myeloma: drug therapy for multiple myeloma. American Cancer Society. December 6, 2021. Accessed March 18, 2022. https://bit.ly/3NhKVXm}

_{3. Voorhees PM, Kaufman JL, Laubach J, et al; GRIFFIN Trial Investigators. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288}

_{4. Mateos MV, San Miguel JF. Management of multiple myeloma in the newly diagnosed patient. Hematology Am Soc Hematol Educ Program. 2017;2017(1):498-507. doi:10.1182/asheducation-2017.1.498}

_{5. Tungesvik A, Sudalagunta P, Huang J, et al. Treatment sequencing patterns for relapsed refractory multiple myeloma (RRMM) in the era of new therapies in a single center institution. J Clin Oncol. 2019;37(suppl 15):e19513. doi:10.1200/JCO.2019.37.15_suppl.e19513}