As the dust settles from all the activity surrounding new drug approvals and the potential for further approvals, it is time to reflect on what the future holds for myeloma patients.

The good news is that the future looks bright. The vast majority of patients will achieve excellent, deep responses with initial therapy. This can be enhanced with ASCT (autologous stem cell transplant) and sustained with maintenance. Powerful new triplet combinations are available and have a substantial impact.

The particular benefits of using carfilzomib (Kyprolis®) and daratumumab (Darzalex®) combinations early in the disease open up many new choices for key recommendations and upfront decision-making.

In the frontline setting, the Velcade® + Revlimid® + dexamethasone (VRd) regimen has emerged as a standard approach. For older or non-transplant eligible patients, VRd “lite” can be used, and, for more frail patients, either Rd or CyBorD (cyclophosphamide, bortezomib and dexamethasone) are rather well-tolerated options. ASCT is still recommended when feasible and desired by the patient.

For high-risk patients, KRd is an option across the board and, combined with ASCT, can achieve especially deep responses. With the new, very promising data from the CASTOR (daratumumab + Vd) and POLLUX (dara + Rd) trials, the much earlier use of daratumumab (Darzalex®) becomes a consideration. For example, daratumumab Rd is very active and well-tolerated, and we expect that this combination therapy will be approved in approximately a year’s time for patients who have had only one prior therapy.

The true need

What remains is the true need for a way to handle patients with persistent or recurrent minimal residual disease-(MRD)-positive myeloma. Looking ahead, the framework will be MRD-negative disease for what we hope will be a majority of patients, but for high-risk and resistant myeloma, minimal residual disease will remain a problem.  New drug development will target agents capable of eliminating MRD-positive disease, especially as new information is gathered about these clonal populations in terms of immune phenotype, mutational patterns, and drug sensitivity. I foresee two approaches going forward:

1.      Strategies to eradicate MRD-positive clones. The new immune-oncology (I-O) approaches are promising, including CAR T cells against different antigen targets, NK cells, and checkpoint inhibitor combinations. Immunoregulatory approaches are an active area of research.

2.      Strategies to achieve chronic disease control at much lower levels of disease than were ever achievable in the past may prove very effective and attractive, despite potential ongoing side effects and costs.

Both approaches, I believe, will demonstrate merits.  This big-picture approach envisions average survival typically exceeding 5-10 years, with a focus on achieving the best quality of life along the way. With the likely advent of decisively better and even curative therapies, the goal is to maintain the best health for patients such that no doors are closed to explore future options.

As patients with relapsing disease still struggle, it is important to emphasize that we anticipate great progress in avoiding these resistant states. It has been a long time coming, but the tipping point to longer survival is NOW, and we must grasp every opportunity to achieve the best results for all patients! 

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

Comments

Any bright lights you can point to for the large relapsed/refractory population who are still struggling and need effective treatment now? You referred to one four drug (including Dex) regimen above - would you recommend four or more drug regimens for those who are relapsed/refractory to just about all approved drugs?

Dear Nancy,

Thank you for this question, which is very important! There are quite a few three-drug combinations which can be considered in the later relapse setting. Examples are combinations including pomalidomide (pom), carfilzomib (car), daratumumab (dara) and elotuzumab (elo). For instance, pom/car/dex; pom/dara/dex are very active even when individual drugs have failed. A combination can be tried based upon which drugs have worked well in the past. Hope this helps!

Sincerely,
Brian Durie

The "Survival in Myeloma" chart in the above blog post does not have a description of what the lines or numbers mean. This is the most disturbing chart I have seen, especially because there is no description with it.

Dear Daryl,

I am so sorry the “survival chart” has been upsetting. If you look along the bottom, you will see the number of years of follow up. At 10 years, the red line (1996-2000) has dropped to ~20-30% (see % surviving on the left, listed as 0.2-0.3). At 10 years, the top yellow line (2011-2015) is at almost 80% (listed as 0.8 on the left). This illustrates a 50% improvement!! I am very sorry this encouraging news was not clear.

Thanks for the opportunity to explain, since this hopefully helps others as well.

Best regards,
Brian Durie

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