ASH – Multiple myeloma therapy goes combo

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The last couple of years saw large sums of money handed over for anti-CD38 projects targeting multiple myeloma, despite the scant clinical evidence generated at the time to back this approach.

There are still only three such projects in the clinic, and two of them – Genmab’s daratumumab and Sanofi’s SAR650984 – gained prominent billing at ASH today. Judging by several doctors’ bullish comments – that these are potential blockbusters that should move to front-line therapy – companies shelling out big bucks were not wasting their money.

Daratumumab had been licensed to Johnson & Johnson in 2012 for €55m ($68m) up front, while a year later Celgene paid €71m to get its hands on MorphoSys’s MOR202. The latter project did not feature at ASH, and indeed has yet to generate data from its 82-patient phase I/II trial.

Off target?

The CD38 antigen is a logical target, being expressed in around 98% of multiple myeloma patients, but is also present on various haematopoietic cells and in solid tissue. But fears of off-target side effects were largely allayed by daratumumab’s phase I/II data presented at ASH 2012, and continuing safety was also highlighted this year (MorphoSys squares up to Genmab in multiple myeloma, June 27, 2013).

Moreover, the focus has since shifted to combination therapy. In an open-label phase Ib study daratumumab was combined with four commonly used Velcade or Pomalyst-containing chemo backbones in 24 patients at various stages of therapy.

Dr Maria-Victoria Mateos, of University Hospital of Salamanca, Spain, said all newly diagnosed patients responded rapidly, while the objective response rate (ORR) in the relapsed group was 50%. Importantly, 16mg/kg of daratumumab did not seem to cause serious adverse events above those of the backbone therapy, though there was one daratumumab-related serious event.

An even more bullish tone was struck by Dr Thomas Martin, of the University of California, San Francisco, who presented phase Ib data on Sanofi’s SAR650984 on top of Revlimid plus dexamethasone in 31 heavily pretreated patients who had received on average four lines of prior therapy.

While this was a dose-escalation study the focus fell on efficacy: the highest, 10mg/kg dose gave an ORR of 63%, while ORR across all patients was 58%. In comparison, single-agent SAR650984 in a similar population had given an ORR of just 32%, Dr Martin stated. Safety was also encouraging, with the main side effects being injection-site reactions that subsided after the second therapy cycle.

While drugs like Revlimid, Velcade and Pomalyst have made a huge difference to multiple myeloma management, there is a major need in this heavily pretreated population, where patients on average live for barely nine months.

And Dr Martin did not hold back as to the anti-CD38s’ potential. “These are the next class of blockbuster agents,” he stated. “The next five years will be fun, moving them from relapsed-refractory to first-line [use].”

The session’s moderator, Dr Brad Kahl of the University of Wisconsin, cautioned that the results were “too early to plant a flag in the ground; but this early data is very promising, and the comments about moving [anti-CD38 therapy] to first line are fully justified.”

Maintaining leadership

The multiple myeloma space is effectively controlled by Celgene with Revlimid and Pomalyst and J&J with Velcade, and clearly much of the development and deal-making here is driven by efforts to maintain companies’ positions.

Amgen’s Kyprolis is also making a strong challenge, with reported data from the phase III Aspire trial backing its use earlier in treatment – specifically when added on top of Revlimid and dexamethasone (Amgen meets aspirations with Kyprolis data, August 5, 2014).

Additional details about Aspire were profiled at ASH, and the trial’s lead investigator, the Mayo Clinic’s Dr Keith Stewart, called the progression-free survival of the Kyprolis triplet “unprecedented”. Median PFS was 26.3 months versus 17.6 months, and Dr Stewart said the triplet should become standard of care in this relapsed setting.

In comparison, the Endeavor trial of Kyprolis versus Velcade had shown a 19-month PFS in a similar patient population. Another key point is safety: in Aspire there was no relevant increase in adverse events, including peripheral neuropathy, despite the third drug being added to treatment.

As for the anti-CD38 antibodies, it seems that daratumumab is likely to be first to market, since it is already in several phase III studies, while MOR202 is the clear laggard. What is not known at this point is which will be the best, though this could come down to mechanistic subtleties.

Dr Martin made the point that each of the three MAbs binds to a slightly different part of the CD38 receptor. “Whether that makes a difference... we don’t know at this time,” he said.

To contact the writer of this story email Jacob Plieth in San Francisco at jacobp@epvantage.com or follow@JacobEPVantage on Twitter

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