I often discuss the good and the bad in the news. But I thought it would be great to start 2017 with just the good! The SWOG 0777 trial results, recently published in The Lancet, and serum Freelite testing, just published in Blood, will help day-to-day care of myeloma patients in a variety of ways. Both studies are considered important and have accompanying commentaries or editorials in the journals reflecting that. In a year-end review to be published shortly in Nature Reviews Clinical Oncology, the SWOG 0777 study is identified as the major “practice changing” trial for 2016.

So, what are the important points in each trial? The key point of the SWOG 0777 study is that newly diagnosed patients treated with bortezomib/lenalidomide/dexamethasone (Velcade®/Revlimid®/dexamethasone: VRd) for 6 months of frontline (induction) therapy had an average survival of more than 6 years (75 months) versus more than 5 years (64 months) with the comparison doublet Rd treatment. Remission (PFS) was also improved by about 1 year (43 months [VRd] versus 30 months [Rd]), which is also excellent! The benefits were seen for both younger transplant-eligible patients as well as the more elderly patients.

Nearly a decade to get an answer

It took a long time to arrive at this answer. Accrual of patients into this randomized phase III trial began in April 2008. So almost a decade to get an answer… an answer which at the start of the trial was uncertain, with even the need for the trial disputed. “Would six months of initial triplet therapy versus a doublet be enough to make an impact on long-term survival?” many asked. There was also concern about accrual because patients were being asked to defer upfront transplant to allow assessment of novel combination therapy alone.

The double success was that the trial accrued the required 525 patients and has gone on to reveal remission and survival benefit with reasonable toxicity. The big concern was neuropathy with Velcade, which was administered intravenously twice weekly in this protocol. Obviously, today, with Sub-Q administration of Velcade and reduced dosing schedules, particularly in the elderly, neuropathy occurs less frequently and is less often severe.

Triplet therapy better than doublet

An important advantage of the SWOG 0777 trial results is that there are broader messages. Triplet therapy is better than doublet therapy. But which triplets will be the best in 2017 and beyond? For now, VRd really becomes a new cost-effective standard of care, and has been so designated in updated guidelines and various commentaries. However, the future is upon us and we need to identify which other triplets are to be considered. Two options immediately come to mind:  KRd (Kyprolis®/Revlimid/dexamethasone), with excellent initial results, is very promising; daratumumab (Darzalex) Rd (Pollux trial) is extremely promising as a well-tolerated and effective regimen in the early relapse setting.

The other immediate broader point is the message to newly diagnosed patients in 2017. You can have an average first remission of around four years with VRd and then extend that for multiple more years with Kyprolis, dara, and other promising combinations which are already FDA-approved and available immediately. Acknowledging that this rosy picture is not yet true for all patients (for example, those with higher-risk disease), there is indeed a broad positive picture. The focus of renewed efforts of the IMF’s Black Swan Research Initiative® (BSRI) and the work of many other researchers is to achieve best results for all patients, extending survival for those with both good and poor-risk disease. (Of note, in the SWOG 0777 study, there was a strong trend for better outcomes for patients with poor-risk genetics even with just the 6 months of VRd versus Rd.)

A shorter wait for results?

The SWOG 0777 trial also brings into focus the difficulties with long-term trial assessment. Ten years is a long time to wait to have an answer! This is where the BSRI approach is positioned to help. If the achievement of an early, very deep response is what leads to better outcomes, as was the case for SWOG 0777, then that early, deep response can be used as a reliable endpoint more in the 1-3 year time frame.   A major BSRI goal is to establish this approach as a standard with the FDA and—exciting news here—meetings are already in process to accomplish this.

A number of other nuances of the SWOG 0777 trial and its results are presented in the various commentaries and reports. As the principal investigator of this trial, I know that the enormous contributions from patients and researchers to make the SWOG 0777 happen cannot be overstated. It is not easy to make this type of stepwise progress. But reliable results are the essential building blocks for the future.

Clear value of blood testing

The second “good news” story comes from France.  It is the comparison of blood versus urine testing for light-chain analysis: an IFM trial. Again, not an easy study to conduct since it required multiple tests to compare blood and urine results from the same day, starting between, in this case, November 2010 and December 2012, with subsequent serial monitoring of this trial with 700 patients.

The key point is that this IFM report focused on 113 patients (16%) with light-chain-only myeloma. Prior studies, which included patients with both heavy- and light-chain disease, have not shown the same clear value of blood testing demonstrated by the IFM team. In the IFM study, blood light chain testing (sFLC) at three months after treatment was more predictive of outcomes than was urine testing.  Improvement in sFLC levels was also correlated with subsequent achievement of MRD negativity by flow cytometry.

Several caveats

There are several caveats about immediately switching to blood testing (sFLC) only. Most importantly, these findings need to be confirmed by a second study, a standard IMWG (International Myeloma Working Group) requirement for establishing a new guideline—in this case, to switch from 24-hour urine testing to sFLC blood testing. In the commentary accompanying the Blood article, Dr. Joseph Mikhael points out that it will certainly be great to be able to move away from the 24-hour urine testing, which is both cumbersome and also sometimes inaccurate (due to under- or over-collection, for example), but is nonetheless necessary to establish a baseline for newly diagnosed myeloma; to assess for more general protein loss in the urine related to amyloidosis; and to assess discordancy between blood and urine results.

So, as Dr. Mikhael says, “Pee no more?” The answer is that we need urine testing for a little bit longer, but hopefully further data will allow us to move quickly to a new guideline and “pee no more” can (mostly) become a reality!

Thus, two new articles start off the year with positive news for myeloma patients and treating physicians. Moving through 2017, I will be looking for the positive and providing updates!  

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

In reference to the SWOG 0777 results, a reader asks: "Is the triplet VRd now always preferred over the doublet Rd?"

This is a very important point which is currently being further explored. Although overall, VRd is better than Rd, can some patients (especially older patients) do very nicely with Rd? The answer is "yes," particularly for more fragile patients, but also for good-risk patients without immediate aggressive disease. The choice can be between Rd and what is called "VRd lite," a reduced-dose version of VRd. Further details will be forthcoming to clarify this aspect and better identify the subset of patients for whom Rd is very reasonable. As always, the pros and cons of each option must be carefully discussed with the primary treating doctor.

Hope this helps!

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