Evolving Standards and Heated Debates in the Treatment of Newly Diagnosed Multiple Myeloma

Evolving standards of care in newly diagnosed multiple myeloma (MM) have given patients a wider variety of possibilities but can also be disconcerting. In a presentation during CURE®’s Educated Patient® Multiple Myeloma Summit, Dr. Clifton Mo, of Dana-Farber Cancer Institute, explores the treatment landscape and breaks down what these different options can offer patients.

Over the past decade or so, the wealth of treatment options in newly diagnosed multiple myeloma (MM) has given patients a wider variety of possibilities. Coupled with rapidly evolving new standards in care, this can sometimes lead to confusion. But according to Dr. Clifton Mo, director of autologous stem cell transplantation for multiple myeloma at Dana-Farber Cancer Institute, that only means that the treatments are improving.

“As anyone who's sought second or third opinions between different multiple myeloma centers can probably attest, you don't always walk out of the center with the same recommendation as the one before,” said Mo. “And what I tell my patients is, I understand that that can be somewhat disconcerting.”

At CURE®’s Educated Patient® Multiple Myeloma Summit, Mo spoke about how the treatment landscape of newly diagnosed MM has evolved, from single-agent chemotherapy to highly effective combinations that are continuously being examined and fine-tuned to offer patients the best outcomes.

As Mo explained, in the mid-1990s, the standard of care for this patient population was high-dose melphalan chemotherapy with autologous stem cell transplant. This plan was based on the results of two large studies that found a significant increase in overall survival between patients who were able to proceed to transplant with early high-dose melphalan compared with those who received only standard chemotherapy.

Then, after the development and approval of novel agent Velcade (bortezomib) in 2003, a new era of combined novel agent treatment began, with the most notable pair being the duo of Velcade and Revlimid (lenalidomide). “It was found that the combination of Revlimid with the proteasome inhibitor, Velcade, was very synergistic, and was much more efficacious than single-agent novel therapy alone,” Mo explained.

This combination led to further study, such as the 2012 landmark SWOG S0777 study comparing RVd (Revlimid, Velcade and dexamethasone) to single-agent Revlimid in patients without an immediate indication for stem cell transplant. In this study, patients treated with the triplet-induction regimen saw a 29% survival advantage compared with the single-agent group, leading to a new standard of care in MM and, as Mo explains, setting the stage for the current era of treatment.

But the introduction of Kyprolis (carfilzomib), a second-generation proteasome inhibitor similar to Velcade, set the stage for one of the first “great debates” in the treatment of newly diagnosed MM, said Mo.

First approved in the relapsed refractory setting, Kyprolis was found to be a potent and promising drug. But researchers were then compelled to determine which was better: RVd or KRd (Kyprolis, Revlimid and dexamethasone)?

“This is arguably one of the biggest debates within the multiple myeloma community,” Mo noted. While RVd demonstrated a 29% reduction in all-cause mortality compared with Revlimid alone in the SWOG-0777 study, researchers saw an impressive benefit of KRd compared with Revlimid alone in the relapsed and refractory setting thanks to the ASPIRE trial. Encouraging progression-free survival rates were also seen in high-risk patients treated with KRd.

However, each treatment comes with its own side effects that need to be taken into consideration. “What we've known for a long time is that these two drugs have significant differences in terms of their toxicities and risks,” said Mo. With Velcade, peripheral neuropathy is a common, though rarely dangerous. However, Kyprolis was shown to cause cardiotoxicity in less than 10% of patients, which, while uncommon, is also potentially very dangerous.

The debate between these two treatments continued mostly because there was no head-to-head data comparing the two in the newly diagnosed setting until several months ago, when results of the ENDURANCE (E1A11) phase 3 trial were presented. And while the study found that KRd was not more effective than Revlimid – which remains the standard of care in this population – some critics noted that RVd is not a better choice than KRd, especially given the toxicities associated with each, and that the trial design was flawed.

Mo, however, believes that both are still solid options. “I'm going to hedge and say that they are still both within the realm of standard of care, and both acceptable induction regimens for newly diagnosed patients who are transplant eligible. (Because) it's myeloma. So of course, it's not straightforward,” he said.

“In my opinion, the educated patient may actually know best, …so as long as the patient is aware of data, aware of the very real differences between toxicities and risks.”

Another debate in the treatment of newly diagnosed myeloma involves when to perform autologous stem cell transplant. While this debate still continues, with studies evaluating early versus delayed transplant, Mo uses a military analogy to explain: “I look at this debate as a choice between essentially using the big guns up front, versus low intensity warfare.”

Lastly, Mo examined the debates that exist between the safety and efficacy of triplet therapy versus quad-induction therapy, which combines one of the standard triplets with a CD38 antibody, usually Darzalex (daratumumab). “On the one hand, we have triplets, and we know that they are highly efficacious. They're essentially overall very well tolerated. They're lower risk than the quads in terms of risk of infection and other toxicities, they have a proven survival advantage and again, the elephant in the room, they are less expensive,” said Mo. But with a depth of response of less than 50%, quads have been found to have “unprecedented depths of response,” albeit with a potentially greater risk of toxicity.

Ultimately, Mo noted, these debates and others in the MM community continue, with more trials looking at the pros and cons of every variety of combination, all with the goal of providing patients with the safest and most effective treatments.

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