I figured out that my GPU (GTX690) can easily create new ID3D11Buffer's so fast that instead up updating an old buffer with new data using ID3D11DeviceContext::UpdateSubresource, I can just use ID3D11Device::CreateBuffer with initial data. Since I only touch ID3D11Device and not ID3D11DeviceContext, the whole operation can be done on another thread.

void DXDevice::SetMatrices(std::vector<DirectX::XMFLOAT4X4A> &Matrices)
{
	auto pBuf = CreateStructuredBufferResource(Matrices.data(), Matrices.size() * sizeof(DirectX::XMFLOAT4X4A));
	if (pBuf == nullptr)
		throw std::exception("CreateStructuredBufferResource failed");
	
	m_pImmediateContext->VSSetShaderResources(0, 1, &pBuf.p); // don't thread this
}

CComPtr<ID3D11ShaderResourceView> DXDevice::CreateStructuredBufferResource(const void* pDataSrc, UINT BufferSize)
{
	CComPtr<ID3D11ShaderResourceView> pShaderResourceView{ nullptr };
	CComPtr<ID3D11Buffer> pBuffer = CreateBufferResource(pDataSrc, BufferSize, D3D11_BIND_SHADER_RESOURCE, D3D11_USAGE_DEFAULT, D3D11_RESOURCE_MISC_BUFFER_STRUCTURED);

	if (pBuffer == nullptr)
		return nullptr;

	try
	{
		D3D11_SHADER_RESOURCE_VIEW_DESC rd;
		ZeroMemory(&rd, sizeof(rd));
		rd.ViewDimension = D3D11_SRV_DIMENSION_BUFFEREX;
		rd.BufferEx.NumElements = BufferSize / sizeof(DirectX::XMFLOAT4X4A);

		HR(m_pDevice->CreateShaderResourceView(pBuffer, &rd, &pShaderResourceView));
	}
	catch (std::exception &e)
	{
		WriteFile("error.log", e.what());
		return nullptr;
	}

	return pShaderResourceView;
}

CComPtr<ID3D11Buffer> DXDevice::CreateBufferResource(const void* pDataSrc, UINT BufferSize, UINT BindFlags, D3D11_USAGE Usage, UINT MiscFlags)
{
	CComPtr<ID3D11Buffer> pBuffer = nullptr;

	try
	{
		if (BufferSize == 0)
			throw std::exception("The requested buffer resource is of size 0");

		D3D11_SUBRESOURCE_DATA sd;
		ZeroMemory(&sd, sizeof(sd));
		sd.pSysMem = pDataSrc;

		D3D11_BUFFER_DESC bd;
		ZeroMemory(&bd, sizeof(bd));
		bd.Usage = Usage;
		bd.ByteWidth = BufferSize;
		bd.BindFlags = BindFlags;
		bd.MiscFlags = MiscFlags;
		if (MiscFlags == D3D11_RESOURCE_MISC_BUFFER_STRUCTURED)
			bd.StructureByteStride = sizeof(DirectX::XMFLOAT4X4A);

		HR(m_pDevice->CreateBuffer(&bd, pDataSrc ? &sd : nullptr, &pBuffer));
	}
	catch (std::exception &e)
	{
		WriteFile("error.log", e.what());
		return nullptr;
	}

	return pBuffer;
}

StructuredBuffer<float4x4> Matrices : register(t0);

Have you left your application running for a long period of time?

I ran a 2 hour stable demo in windowed mode with stable FPS and memory usage on both CPU and GPU. But as soon as Windows shuts down the display (power saving setting) it takes just a couple of minutes to leak all memory and the application crashes (CreateStructuredBufferResource returns nullptr). I guess the memory is not getting released once the displays are turned off.

On that note, would anyone know why ID3D11Device::CreateBuffer returns E_OUTOFMEMORY after a while when the monitor shuts off? It might be that the CComPtr<ID3D11Buffer> or CComPtr<ID3D11ShaderResourceView> are not releasing when the monitor is shut off for some reason...