These are very exciting times in myeloma – so many new therapies being developed, new drug combinations being used in frontline therapy, new imaging and diagnostic techniques, and so much more!

But what is often forgotten is the surge in options in early relapsed disease. We typically think of “early” relapse as the treatment someone receives when they have had 1–3 prior lines of therapy. This is opposed to “late” relapse when patients have been treated with most available options.

I wanted to highlight this part of the journey for myeloma patients, in part because there are more treatment options than ever before. Indeed, we have no fewer than FIVE phase III clinical trials of triplet combinations recently published and now available. Another reason is to demonstrate an important shift in our approach to myeloma – we no longer “save the best for last” but use the most effective approach for the individual patient earlier in the disease course, including in frontline therapy, as we know it will have a greater impact on the patient’s long-term survival.

As myeloma relapses, it becomes harder to control, so giving patients longer remissions with effective combination therapies early on is a growing and important trend. This is a key topic of discussion as it may be challenging to choose when the menu of options is expanding. Of course, this is a good problem to have, as it was not long ago that we had so few options to control this awful disease. So what are these great choices? These are the five key clinical trials that have shaped the treatment of early relapse:

1. IKEMA clinical trial of Isa-Kd

This clinical trial of Sarclisa® (isatuximab), a CD38-directed monoclonal antibody, in combination with Kyprolis® (carfilzomib) and the steroid dexamethasone (Isa-Kd) is important as it demonstrates the longest progression-free survival (PFS) that we have seen in the early relapse setting, recently reported as 35.7 months. Achieving an average 3 years of PFS in relapsed myeloma is remarkable. It does require more visits to the clinic, though, as Sarclisa is given every other week after the first month (when it is given weekly). Sarclisa is still given intravenously, although after the first 2 infusions, it is given over only 75 minutes. In the IKEMA study, the Isa-Kd combination was shown to be superior when compared to Kd alone.

2. APOLLO clinical trial of DPd

The recently approved combination of Darzalex® (daratumumab) + Pomalyst® (pomalidomide) + dexamethasone (DPd) has been extensively studied. It is attractive because Darzalex Faspro® can be given as a short subcutaneous (under the skin) injection, as opposed to how Darzalex was previously given as a long intravenous infusion. This, coupled with the orally administered Pomalyst makes DPd considerably more convenient. DPd was shown to be superior to Pd alone.

3. BOSTON clinical trial of XVd

This unique combination incorporates the oral drug Xpovio® (selinexor), previously given in later lines of therapy but now available earlier on in the disease course. Administered weekly, as opposed to twice weekly, has made Xpovio much easier to tolerate, especially when given with two anti-nausea medications, as the drug is known to cause significant nausea. Xpovio, a nuclear transport inhibitor, has a new mechanism of action that prevents good tumor suppressors from leaving the cell nucleus. This combination also employs Velcade® (bortezomib) subcutaneously and on a weekly schedule, plus dexamethasone (XVd). The XVd combination was shown to be superior to Vd alone.

4. CANDOR clinical trial of DKd

Although the combination of Darzalex + Kyprolis + dexamethasone (DKd) has been available for a few years, it remains an important option. Although the CANDOR study used Kyprolis twice-weekly, it is now commonly used on a weekly schedule (three weeks on, one week off) and the approval for the DKd regimen allows for either twice-weekly or once-weekly dosing. DKd is commonly used when Darzalex has not been used in the frontline setting. The DKd triplet was shown to be superior to Kd alone.

5. ICARIA clinical trial of Isa-Pd

The regimen of Sarclisa + Pomalyst + dexamethasone has been available for a few years, but it remains an important option in early relapse. The long-term follow up of the ICARIA study was presented at the IMS Annual Meeting in August 2022, showing an overall survival (OS) benefit of about 7 months when compared to Pd alone.

So, how do we decide among all of these options? Of course, this requires careful discussion with your doctor. Below are a few principles to help in making the important decision:

• Do not continue the maintenance drug when relapsing.

Although we “can” just add a drug to the one someone is on, we typically discontinue the drug someone is on while relapsing, as it is likely not going to help anymore.

• Introduce a mechanism of action not yet seen.

One of the ways we overcome the “resistance” the disease develops to therapies is to introduce a drug that has a different method (or mechanism of action) of attacking the myeloma cells. This gives a better chance for a deeper and more durable response.

• Try to use a triplet when possible.

We have consistently seen in the trials above the superiority of triplets over doublets, so we tend to prefer this more intensive approach.

• Assess disease, treatment, and patient factors.

These three are fundamental to therapy selection. Disease factors include how aggressive the relapse is, the risk status and the location of disease (such as plasma cell leukemia or extra-medullary disease). Treatment factors include route of administration, expected side effects, and the efficacy of the regimen. Patient-related factors include comorbidities, prior side effects, cost, and social considerations.

• Always match the option with patient preference.

This is absolutely critical, especially now that we have more options. The patient should be a key partner in the decision-making process, something we call “shared decision-making.”

Until we reach a cure for myeloma, we will continue to treat relapsed disease. We have learned how important it is to treat early relapse effectively to provide patients both a longer quantity and better quality of life. I am thankful to see the list of options growing and look forward to even more to come!

(This article was published in the 2022 Fall Edition of the IMF's quarterly publication, Myeloma Today. Read the full publication here.)