Last week, in Part I of my overview of abstracts released by the American Society of Hematology (ASH) in advance of the group's annual meeting in New Orleans, I focused on combinations using the approved novel agents. Hearing more details and follow-up about these novel combinations at the ASH meeting, Dec. 7-10, will be very important.
In this segment, I start by summarizing where we are with new agents in earlier trials at the Phase I-II or preclinical stages. There are eight agents which are of interest.
- anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284)
- MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983)
- ARRY 520 (abstracts #285 and #1982)
- ACY-1215 (abstracts #759 and #3190)
- selinexor (also known as KPT-330, abstract #279)
- anti-CD 138 monoclonal antibody (BT062, abstract #758)
- panobinostat (abstract #1970)
- bendamustine (abstract #1971)
As was the case last year at ASH, the most promising single-agent activity against a new target is with anti-CD 38 monoclonal antibodies. The single-agent activity of the Sanofi compound (SAR 650984; abstract #284) is illustrated in a dose escalation study involving 32 patients which produced several greater than or equal partial responses. With daratumumab in combination with Revlimid/dexamethasone (anti-CD 38 MAb; abstract #1986) all 6 patients had greater than or equal partial responses with 3 having greater than or equal VGPR. Laboratory studies using a human-mouse hybrid model (abstract #277) have shown strong synergy with lenalidomide (Revlimid).
With ARRY 520 (a kinesin spindle protein [KSP] inhibitor), a 16% partial response rate was noted in a study of 32 patients incorporating weekly dexamethasone (#285). Combined with carfilzomib, a small study showed a 58% response rate (#1982). There were again several reports about MLN 9708, the new oral proteasome inhibitor. Results in the newly diagnosed (#535), relapse (#1944), and maintenance settings (#1983) all showed promise and good tolerability.
Results with ACY- 1215 and selinexor are still early. ACY-1215 (selective HDAC 6 inhibitor) is an oral agent being evaluated in combination with Velcade (#759) and Revlimid/dexamethasone (#3190). Although the combinations are well tolerated, only a few higher-level responses have been seen thus far.
The preclinical results with the XPO 1/CRM 1-dependent inhibitor (selinexor) are reported and show good synergy with carfilzomib (abstract #279). Results with panobinostat (abstract #1970) again show some promise in combinations with Velcade and dexamethasone. Rather surprisingly, the combination of bendamustine with Velcade plus dexamethasone shows really excellent results in the relapsed/refractory setting, with PFS median results of 10.8 months and overall survival median of 23 months (abstract #1971).
And there you have it! Not a lot dramatically new to add, but it is quite encouraging that several agents are continuing to move strongly forward in clinical trials.
As we move towards 2014, the ASH abstracts that will have the biggest impact are those which provide a better understanding of underlying biology and how to test for minimal residual disease (MRD) and risk factors, and those which provide insight into trigger factors and disease subtypes such as extramedullary disease and plasma cell leukemia.
Testing for Minimal Residual Disease (MRD) and MRD-Zero
Over 25 abstracts deal with minimal residual disease testing, monitoring, and risk assessment. Abstract #402 from the Salamanca/Pamplona team with Bruno Paiva as the lead author characterizes minimal residual disease at the immune and molecular level. In abstract #531, Paiva extends these observations by identifying and characterizing subclones which emerge during the course of treatment. This understanding of subclones which persist or emerge despite current novel therapy is key to developing more successful treatment and achieving MRD-Zero--the primary goal of the Black Swan Research Initiative (BSRI).
Quite a number of abstracts touch on the comparison of various methods to most accurately assess MRD-Zero. Another key abstract from Spain on this topic (#1848) compares flow and molecular techniques. Different aspects of risk and response assessment are covered in abstracts #762, #1841, #1842, #1868, #1878, #1902, #1936, #3126, #3152, #3223, #4290, #4647. Although DNA methods may be slightly more sensitive, a new flow technique may prove to be equally, if not, more sensitive, and has the advantage of allowing identification and molecular study of any residual clones. Hearing all the details at ASH will be very important. So much more to learn!
An important report (abstract #1936) from the Bologna team shows that 29% of patients who appear to be in complete response by other methods of assessment have positive PET/CT scans. Thus, follow-up imaging is essential to confirm the residual disease status. Another abstract (#762) shows that early improvement in the serum heavy/light chain ratio (HLCR, Hevylite) predicts for a high likelihood of subsequent development of MRD-Zero.
Understanding the Biology of Myeloma
In the category of understanding the biology of myeloma better, I draw your attention to a few abstracts. A collaboration between Washington University and Mayo Clinic researchers (abstract #397) has revealed that in mice predisposed to myeloma, one particular gene (Samsn 1) is missing in all cells (called a germline mutation), which results in both B cells (precursors of myeloma cells) and microenvironmental cells such as macrophages and osteoclasts being primed for activation. Another abstract (#3116) also suggests that we take a closer look at predisposing and triggering factors for MGUS and myeloma.
The team of French researchers from Nantes shows that in 22.7% of patients with MGUS and myeloma, the monoclonal protein reacts against infection: specifically hepatitis C, Epstein-Barr Virus (EBV), and the stomach infection H. Pylori. This raises the possibility that infection can trigger initial disease and possibly relapsing disease. Clearly further studies are required. Another aspect is obesity, which is known to be linked to the onset of both MGUS and myeloma. A large epidemiologic study (abstract #1872) shows a strong association between increasing body mass index (BMI) at age 20 years and a younger age at diagnosis in African-Americans with multiple myeloma. Definitely food for thought!
Subtypes and Categories of Patients
Considering different subtypes and categories of patients with myeloma and related diseases, there are several abstracts: young patients (< 40 years: abstract #3226); older patients (abstract #687); IgD myeloma (#s 1880 and 1935); IgM myeloma (#1881); plasma cell leukemia (#761); extramedullary disease (EMP; #s 1896, 3141, and 3188); central nervous system involvement (abstract #3118); patients susceptible to very early death in â¤ 2 months (#3195) and those patients in remission for â¥ 6 years (abstract #3366). A small, but important point in abstract #3195 is that patients at risk of death within the first 2 months of the myeloma diagnosis are those with unrelated serious health issues. With the advent of novel therapies, it is only months to years later that the impact of high-risk myeloma features is seen as a challenge in controlling progressive or relapsing disease: a reassuring point.
As far as molecular risk features, there are fewer than the usual number of abstracts dealing with this topic at ASH 2013: abstract numbers 399, 529, 530, 1846, 1855, 1856, 1992, 3092, 3108, 3111, 3114, 3121, and 3147. There are two key practical points. In abstract #529, it is noted that poor risk features (such as FISH t(4;14) or -17p) will prevail even if there is hyperdiploidy (extra chromosomes: normally considered to be a good-risk feature). Thus the presence of hyperdiploidy does not counterbalance poor-risk features. A related, and somewhat frustrating point (in abstract #1992), is that the 1q21 FISH abnormality does confer poorer risk, but is not part of the standard FISH testing panel! So, back to the drawing board again to have a new recommended FISH testing panel.
And there you have it for now: many interesting abstracts, some which I predict will prove to be very important, and others where we are waiting to hear more at the time of the ASH meeting in New Orleans in December.
Please remember the IMF's various educational programs at and from ASH: live-streaming of the Satellite Symposium on Friday, December 6th, and the Conference Series on Monday, December 9th, blogs/Twitter ongoing, interviews with lead investigators immediately after ASH, and post-ASH highlights in January 2014!
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