When Amgen (AMGN) announced its $10.4 billion offer to acquire Onyx Pharmaceuticals (ONXX), the market was buzzing not only about the upside of the union for Amgen, but also about the sheer size of the impending deal. At $10.4 billion, the buyout would be one of the biggest biopharma deals ever.

That fact raises some interesting questions, like what were the biotech industry’s biggest acquisitions? And perhaps more important, did those buyouts pay off for the suitors?

Here’s a look at the five largest deals in the history of biopharma, and how they panned out.

Amgen (Immunex)

As it turns out, the Onyx deal isn’t the biggest merger Amgen has made. The company also acquired Immunex back in December of 2001 — before mega-deals were en vogue — for a whopping $15.9 billion. The deal gave Amgen control of the rheumatoid arthritis drug Enbrel.

At the time, Enbrel was the fastest-growing ‘biologic’ … a relatively young class of drug at the time. Amgen’s then-CEO, Kevin Sharer, opined the drug could eventually produce sales of $3 billion, and maybe even more.

But every biotech company must face the same question: Will the drug come anywhere close to producing those results? In this case, the answer was a resounding yes. Between Amgen and selling partner Pfizer (PFE), Enbrel‘s sales exceeded $8 billion in 2012.

Sanofi-Aventis (Genzyme)

In 2011, French drugmaker Sanofi-Aventis (SNY) nabbed Genzyme for $20.1 billion. Sanofi mostly had its eyes on Lemtrada (also known as Alemtuzumab), which treats multiple sclerosis, though a couple of other rare-disease treatments were also placed under Sanofi’s wings.

How has the drug done? Well, it hasn’t — Lemtrada was only in trials at the time, and still is. Its development does look promising though.  It’s in Phase 3 trials, and Europe’s Committee for Medical Products for Human Use has recommended a new active substance designation for the therapy.

It’s too soon to call the acquisition a good deal or a bad deal, but forecasters don’t expect the MS treatment to produce more than $1.0 billion in annual sales. That’s not exactly a great ROI.

Merck (Schering-Plough)

Remember when Merck (MRK) bought Schering-Plough for a cool $41.1 billion in 2009? Both were behemoths with wide drug menus, so Merck didn’t score any game-changing products. Rather, the two companies mostly sought to team up so they could take on competitors like Pfizer, which had acquired Wyeth earlier in the same year.

Truth be told, it wasn’t a bad deal. But it wasn’t necessarily a good deal either. Both organizations had a strong presence in cardiovascular and respiratory drugs, and decent pipelines.

The biggest value the union brought to the table was operational synergies, which at least somewhat materialized.

Roche Holdings (Genentech)

Another major 2009 merger united Genentech and Roche Holding (RHHBY), when Roche purchased the former for $47 billion. Though Genentech had a few things on its product menu and in the pipeline, the centerpiece of the acquisition was Avastin. The drug was already Genentech’s best-selling drug, approved as a treatment for breast, colon, and lung cancer. It also held promise as a therapy for other cancers.

Worth the price? Again, this one’s hard to tell.

In 2009, Avastin’s revenue totaled $5.9 billion. In 2012, that figure barely hit $6 billion. The slow-down, however, stemmed from the fact that the drug’s FDA approval as a breast cancer treatment was retracted in 2011. Had it not been for that decision, Avastin’s revenue could have grown.

Even without the breast cancer market though, Avastin has been a cash cow, and its trials as a treatment for other cancers hold lots of promise. But it’s going to have to remain a cash cow for a long time to justify that $45 billion.

Novartis (Alcon)

The Novartis (NVS) buyout of Alcon in came with a final price tag of $52 billion — which came in bits and pieces, including a $39 billion chunk in 2010 — and gave the Swiss company control of an outstanding eye-care portfolio. While nothing under the Alcon umbrella was considered to be a budding “blockbuster” that the biopharma industry loves to aim for, it was a solid, reliable business.

The question is, however, was that “outstanding eye-care portfolio” worth the frothy price tag? As it turns out, probably not.

In 2009, Alcon’s sales reached only $6.5 billion, though the company impressively turned $2 billion of that into a profit that year. Alcon’s sales grew to a whopping $10.2 billion last year, but $52 billion is still a lot to pay for those results.

Pfizer (Wyeth)

The acquisition that set off 2009’s wave of major acquisitions — and set the bar for the industry’s mega-deals — is Pfizer’s $68 billion acquisition of Wyeth Pharmaceuticals.

Like the merger of Merck and Schering-Plough, this union wasn’t built primarily on one drug, but rather, built on a large library of drugs that would help shore up Pfizer’s deteriorating IP. The patent cliff was just around the corner at the time, and garnering Schering-Plough’s vaccines, biologic, veterinary drugs and Alzheimer’s projects added depth as well as breadth to Pfizer’s portfolio.

Yes, this acquisition has paid off. It’s been tough to see it, but the cost-savings have mostly been realized, and Pfizer’s somewhat circumvented what could have been a patent cliff disaster.

As of this writing, James Brumley did not hold a position in any of the aforementioned securities.