Questions raised around myeloma treatments

In an op-ed article in Läkartidningen (October 3, 2024), Jakob Lindberg, former CSO and CEO of Oncopeptides and currently an advisor in research matters, and Per Sjöberg, consultant and former Head of the Swedish Medicines Agency’s pharmacological and toxicological unit, draw attention to two, according to them, serious problems of immunomodulatory drugs (IMiDs) and how they are prescribed to multiple myeloma (myeloma) patients.

Background

Lindberg and Sjöberg refer to data published in August 2024, showing that the effect of IMiDs on observed survival in myeloma patients decreases significantly with increased patient age, without changing biomarker data (progression-free survival, PFS) (Pawlyn et al, Blood Cancer J. 2024 – where Fredrik Schjesvold is one of the authors).

The study states that surrogate endpoints of overall survival (OS), such as PFS and response to treatment, have contributed to approval decisions by the FDA and the EMA as endpoints demonstrating clinical benefit, and the FDA has recently supported the use of minimal residual disease (MRD) as an accelerated approval endpoint in myeloma.

The review addresses situations in which the use of PFS as a surrogate endpoint warrants careful interpretation especially for specific subgroups of patients and considers ways to ensure that studies can be designed to account for possible discordance between PFS and OS. The use of subgroup analyses, including the potential for those not pre-specified, to identify target populations for new agents is also discussed in the article.

According to Lindberg and Sjöberg, the first serious problem is the public information regarding the three registration studies MM009, MM010 (lenalidomide) and MM003 (pomalidomide). They state that it gives a false positive picture of the survival effects oflenalidomide and pomalidomide without addressing the high-dose dexamethasone problem (the observed survival results are the basis for the role of IMiDs in treatment guidelines).

The second problem they point out is the large amount of consistently negative survival data that is not reported on lenalidomide and pomalidomide in elderly patients. The result is that prescribers are putting their patients at risk and that patients are running a risk they are not aware of, even though it is known to the authorities, the authors state.

This has previously been overlooked, as these registration studies do not isolate the effect of the drugs on survival.

“This has previously been overlooked, as these registration studies do not isolate the effect of the drugs on survival. In all three studies, more pre-specified high-dose dexamethasone is given to the control groups. Study E4A03 showed that high-dose dexamethasone renders significantly worse observed survival than low-dose dexamethasone together with lenalidomide,” stated Lindberg and Sjöberg in Läkartidningen.

Note: Oncopeptides, where Lindberg is the former CSO and CEO, has developed a drug for the treatment of myeloma that is approved by the EMA and can be seen as a competitor to IMiDs. Per Sjöberg has worked as a consultant for Oncopeptides and holds shares in Oncopeptides.

Q&A: Fredrik Schjesvold

Fredrik Schjesvold, MD, PhD, founder and leader of Oslo Myeloma Center, Oslo University Hospital, and Leader of the Clinical Trial task force at the Nordic Myeloma Study Group.

Describe the benefits of IMiDs for myeloma patients?

“Early on, IMiDs showed an overall survival benefit over standard-of-care therapy. The overall survival benefit of lenalidomide addition to dexamethasone in relapsed myeloma led to the approval of lenalidomide in relapse, and to lenalidomide being the backbone of new relapse regimens. In newly diagnosed elderly people, the overall survival benefit of thalidomide addition to melphalan and prednisolone led to the approval of MPT (melphalan prednisolone thalidomide) in first-line treatment for the elderly. Later, lenalidomide-dexametason (Rd) demonstrated an overall survival benefit over MPT, and after that, daratumumab addition to Rd gave an overall survival benefit and is now the standard of care.”

Overall survival has thus increased from around two years to around six to seven years for the elderly, to a large extent based on the impact of IMiDs.

“Overall survival has thus increased from around two years to around six to seven years for the elderly, to a large extent based on the impact of IMiDs. First-line treatments without lenalidomide have lower survival rates. Quality-of-life (QOL) is a more complicated issue. IMiDs have side effects, as do other drugs, but in the large majority of patients they are manageable, and in addition to the efficacy of the regimens this is good for the general QOL of patients, as far as I can understand the data.”

Describe the disadvantages of IMiDs for myeloma patients? 

“Lenalidomide is by far the most used IMiD, and thus the most important one. The most problematic disadvantage is that fatigue is not uncommon, nor is gastro-intestinal toxicity. If patients suffer from these problems, they should reduce the dose of their lenalidomide treatment, in collaboration with the treating doctor.”

In your own studies and projects, have you investigated IMiDs, and if so, what have you focused on and found? 

“I have been the national coordinator or sponsor in 32 trials containing IMiDs (or CelMods, the next generation IMiDs). In most of these, IMiDs have been part of standard-of-care, the control arm, or part of the backbone of a new regimen. Two trials have investigated the addition of IMiDs or CelMods, one is the Optimismm trial with the addition of pomalidomide to bortezomib-dex, and the other is Successor-2, which adds mezigdomide to carfilzomib-dex. The Optimismm showed PFS benefit, leading to the approval of this combination, while the Successor-2 is not mature yet.”

“I also participated in two trials where pomalidomide was challenged head-to-head, one with melflufen and one with ixazomib. Both trials showed equal survival. My opinion based on all of this is that IMiDs retain their place in standard-of-care.” 

In your opinion, based on the data that the authors of the op-ed article in Läkartidningen refer to, should treatment plans be adjusted for elderly myeloma patients or do you think other measurements should be taken? 

“I don’t agree that there has been unexpectedly low improvements in the survival of elderly patients. In Norway (Cancer Registry reports), five-year relative survival in 2018 was 35.1% for patients of 71-90 years of age; in 2023 this was 54.8%, which is more than a 50% increase on a population-based level. This broadly coincides with lenalidomide becoming standard first-line treatment for elderly patients in Norway from 2016. Daratumumab-Rd is the standard-of-care in Norway today, which I think is justified by the data and the increase in survival for these patients in Norway.” 

I don’t agree that there has been unexpectedly low improvements in the survival of elderly patients.

When it comes to future treatments of myeloma patients, what are your hopes and expectations? Is there a particular new treatment or therapy that you believe will have clinical benefit for these patients? 

“There are many new treatments coming, but the most impactful will be the immunotherapies; CAR-Ts and bispecific antibodies. They are gradually being reimbursed in the Scandinavian countries. Approvals are in late line, but studies are ongoing in the early lines of treatment.”

“We have eight studies in Norway where these therapies are being given in 1st or 2nd line, both for younger and elderly patients. My expectation is that a significant portion of patients in these trials will be cured, in the sense that they won’t relapse within their life-time.”