Wallace's roots in publishing are well documented. See: http://www.scribd.com/doc/97266/A-Small-History-of-Readers-Digest for a nice summary.
It all began with a self-published pamphlet entitled "Getting the Most Out of Farming", published in 1916, that Wallace sold door to door to the tune of 100,000 copies. There are no copies presently for sale on the web. I obtained this copy, apparantly a dummy copy (see the insert on the front cover), from bookdealer Jim Cummins. It came in an expensive imprinted box, along with a "first first" issue, dated January 1920, along with a set of all the issues from 1922 in a similar box, obviously produced by someone who was pretty close to the magazine.
The first "first issue" probably only had a print run of a few hundred copies. It is expensively produced on high quality paper and was sent out to potential publishers, with little or no success. I have never seen another copy. You can get a good idea what Wallace was aiming at by the first page, essentially the prospectus.
The second "first issue" arrived in February 1922 and had a run of 5000 copies. It was reprinted in 1957 and 1972 in large quantities. Allegedly, there is a way of telling the reprints from the original. The table of contents misprinted "Is the Stage too Vulgar" as "Is the State too Vulgar" which is supposed to have been corrected in the reprint. This may be partially true.
I suspect one of the reprints (perhaps the later one) may have done this but there are just two many alleged originals around. I own four copies altogether (including the one in the box) all with the error in the table of contents. In an effort to determine a way to cull out what is really an original copy, I carefully examined all of my 1922 copies from the boxed set.
If there is any difference at all, the printing on the original copies is a bit more delicate than the later copies, and there is a distinct speckling in the hair of the female figure on the cover. The paper may also be ever so slightly more porous, but this is a very tough call.
In examining the blown up scans of the above copies after first publishing this post, I noticed a subtle but real difference. In my "copy in the box" and the other with the stippled hair (the ones I assumed to be original) the "s" in "Digest" has a small bite out of it (the March issue has it too, but not subsequent issues). Since it's on two of them in exactly the same way, it most likely isn't a one-time printing quirk. So that's how you can tell them apart. At least one can say with assurance that the ones with the nicked "s" are original.
Not exactly a cure for cancer but a lot of fun nonetheless. Gosh, I love this stuff!
All in all, I'd have to say that the multitude of copies on the web (the last sold for $100 on eBay this week) are later repros. There just can't be more than a few dozen originals extant, if that many.
Originals are worth $1000 plus. Repros are valued at the cost of reproducing them.